Cancer Therapy Advisor March/April 2018 Issue

MARCH/APRIL 2018 | VOL 4, ISSUE 4

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A20 FEATURE

The Complex Relationship Between Healthful Lifestyles and Cancer

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

A recent study is the first to demonstrate the cumulative effect of a large number of lifestyle behaviors.

1 Breast Cancer 9 Gastrointestinal Cancer 15 Genitourinary Cancer

A9 LATEST NEWS

Headlines in oncology research, including bladder cancer and side effect management

 22 Head and Neck Cancer

A19 IN THE CLINIC

 39 Skin Cancer

Optimizing the Management of Tumor Lysis Syndrome



A22 VIEWPOINT MARCH/APRIL 2018 | VOL 4, ISSUE 4

Exercise May Improve LymphomaSpecific Survival

A24 EXPERT PERSPECTIVE Periodontal Disease and Gastric Cancer Risk: An Interview With Dr Yihong Li

 29 Lung Cancer

Regimen included

A6 FEATURED PRODUCTS Drug Descriptions of Vyxeos and Yescarta

A24 EXPERT PERSPECTIVE Periodontal Disease and Gastric Cancer Risk: An Interview With Dr Yihong Li LESLIE BURGESS, MA

A8 IN THE PIPELINE The Latest on Oncology Drugs

A26 REGIMEN & MONOGRAPH INDEX

A9 LATEST NEWS Headlines in Oncology Research and Practice

1-47 CANCER THERAPY REGIMENS & ONCOLOGY DRUG MONOGRAPHS

A19 IN THE CLINIC Optimizing the Management of Tumor Lysis Syndrome

1 Breast Cancer

C. ANDREW KISTLER, MD, PharmD, RPh

A20

A22

Highlighted topics () contain both treatment regimens and drug monographs.

9 Gastrointestinal Cancer

15 Genitourinary Cancer

 22 Head and Neck Cancer

FEATURE The Relationship Between A Healthful Lifestyle and Cancer: More Than A Single Behavior

 29 Lung Cancer

CARLOS HARRISON

Small-cell Lung Cancer

 39 Skin Cancer

VIEWPOINT Exercise May Improve LymphomaSpecific Survival LEAH LAWRENCE

Head and Neck Cancer

Melanoma

48 ALPHABETICAL INDEX

Cancer Therapy Advisor (ISSN 2375-558X), March/April 2018, Volume 4, Number 4. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET).

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A4 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

Barbara Ann Burtness, MD

Lauren Burke

Yale Cancer Center  New Haven, CT

Oncology Editor

Steven J. Cohen, MD

Jonathan Goodman, MPhil

Thomas Jefferson University Hospital  Philadelphia, PA

Oncology Writer James Nam, PharmD

E. David Crawford, MD

Senior Manager, Drug Information

University of Colorado, Denver  Aurora, CO

Anissa Lee, RPh

Group Art Director, Medical Communications Jennifer Dvoretz

Isabel Cunningham, MD Columbia University College of Physicians & Surgery  New York, NY

Graphic Designer

Don S. Dizon, MD, FACP

Vivian Chang

Lifespan Cancer Institute  Providence, RI

Production Editor

Jeffrey M. Farma, MD

Kim Daigneau

Fox Chase Cancer Center  Philadelphia, PA

Production Manager Brian Wask; (646) 638-6066

Neal D. Shore, MD, FACS

Circulation Manager

Atlantic Urology Clinics  Myrtle Beach, SC

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Vice President, Sales & Business Development Scott Bugni (917) 882-0658; scott.bugni@haymarketmedia.com

Account Manager

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Contact the Editor: editor.cancertherapyadvisor@haymarketmedia.com

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A5

FEATURED PRODUCT

Vyxeos

Rx

Company: Jazz Pharmaceuticals Pharmacologic class: Anthracycline + antimetabolite Active ingredients: Daunorubicin, cytarabine 44 mg/100 mg (encapsulated in liposomes); per vial; lyophilized cake for IV infusion after reconstitution; contains copper; preservative-free.

Indication: Treatment of newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Pharmacology: Vyxeos is a liposomal formulation of daunorubicin and cytarabine at a fixed 1:5 molar ratio. The 1:5 molar ratio of daunorubicin:cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models. Daunorubicin has antimitotic and cytotoxic activity, inhibiting topoisomerase II and DNA polymerase. It affects regulation of gene expression and produces DNA-damaging free radicals.

Cytarabine is a cell cycle phase-specific antineoplastic agent and acts primarily through inhibition of DNA polymerase.

Clinical trials: Study 1 (309 patients) was a randomized, multi-center, open-label, active-controlled study that compared Vyxeos to a standard combination of cytarabine + daunorubicin (7+3) in patients with newly diagnosed t-AML or AML-MRC. Vyxeos demonstrated superiority in overall survival compared with the 7+3 control (9.6 vs 5.9 months; hazard ratio [HR], 0.69; P = .005). The complete response rate was in 38% of patients vs 26% in the 7+3 arm (P = .036).

For more information and clinical trial data, see full labeling.

Adults: Calculate the prior cumulative anthracycline exposure before initiating each cycle. Give prophylactic antiemetics.

Administer by IV infusion over 90 mins.

First induction: Vyxeos (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on days 1, 3, and 5. Second induction (may give after 2–5 weeks if remission not achieved and no unacceptable toxicity): Vyxeos (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on days 1 and 3.

Consolidation (give 5–8 weeks after last induction): Vyxeos (daunorubicin 29 mg/ m2 and cytarabine 65 mg/m2) on days 1 and 3. May give second consolidation 5–8 weeks after if no disease progression or unacceptable toxicity. Do not initiate consolidation until absolute neutrophil count recovers to at least 0.5Gi/L and platelet count to at least 50Gi/L in the absence of unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Do not interchange with other daunorubicin and/or cytarabine-containing products. Prior anthracycline therapy, pre-existing cardiac disease, or radiotherapy to mediastinum: increased risk of cardiotoxicity.

Assess complete blood count, cardiac, liver, and renal function prior to initiation.

Discontinue if impaired cardiac function unless benefit outweighs risk. If left ventricular ejection fraction is below normal or max lifetime cumulative anthracycline

A6 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

exposure limit is reached, this drug is not recommended. Monitor for hypersensitivity reactions; interrupt and reduce infusion rate if mild or moderate symptoms; permanently discontinue if severe/life-threatening reactions occur. Wilson disease: use only if benefit outweighs risk. Monitor copper levels and serial neuropsychological exam; discontinue if copper toxicity occurs. Avoid extravasation. Embryofetal toxicity. Females of reproductive potential and males (with female partners) should use effective contraception during and for at least 6 months after last dose.

Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended.

Interactions: Increased toxicity with concomitant cardiotoxic or hepatotoxic agents; monitor more frequently.

Adverse reactions: Hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, vomiting.

How supplied: Single-dose vials —2, 5 For more information call (800) 520-5568 or visit www.Vyxeos.com.

FEATURED PRODUCT

Yescarta

Rx

Company: Kite, a Gilead Company Pharmacologic class: CD19-directed genetically modified autologous T cell immunotherapy Active ingredients: Axicabtagene ciloleucel (contains max of 2×108 chimeric antigen receptor [CAR]-positive viable T cells); per dose; susp for intravenous (IV) infusion.

Indication: Treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy. Limitations of use: it is not indicated for the treatment of patients with primary central nervous system lymphoma.

Pharmacology: Yescarta binds to CD19-expressing cancer and normal B cells, thereby activating downstream signaling cascades which lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines, leading to cell death.

Clinical trials: The efficacy of Yescarta was evaluated in a single-arm, open-label, multicenter trial involving 101 adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Patients received a single IV infusion of Yescarta following lymphodepleting chemotherapy.

Efficacy was established based on the rate of complete remission (CR) and duration of response (DOR), as determined by an independent review committee.

Patients who were treated with Yescarta achieved a CR rate of 51% (95% CI, 41-62). The median time to response was 0.9 months (range, 0.8 to 6.2 months). At a median follow-up of 7.9 months, the median DOR for all responders was 9.2 months (95% CI, 5.4NE). For patients with a best response of CR, the median DOR was not reached (95% CI, 8.1-NE). Of the 52 patients who achieved CR, 14 initially had stable

disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range, 1.6 to 5.3 months).

Adults: For autologous and IV use only; confirm patient identity prior to infusion. Give lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2 IV + fludarabine 30 mg/m2 IV on the 5th, 4th, and 3rd day prior to Yescarta infusion. Premedicate with APAP and diphenhydramine approx. 60 mins prior to Yescarta; avoid prophylactic corticosteroids. Infuse contents of bag within 30 mins. Target dose: 2×10 6 CAR-positive viable T cells/kg; max 2×108 CAR-positive viable T cells.

Children: Not established.

Warnings/Precautions: Increased risk of cytokine release syndrome (CRS); do not give to patients with active infection or inflammatory disorders. Have tocilizumab readily available. Monitor at least daily for 7 days at healthcare facility following infusion for signs/symptoms of CRS and neurologic toxicities. Continue to monitor for CRS for 4 weeks after infusion; at 1st sign, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated (see full labeling). Monitor for neurologic toxicities for

4 weeks after infusion and treat promptly (see full labeling). Monitor for infection, febrile neutropenia; evaluate, manage and treat appropriately. Screen for HBV, HCV, and HIV prior to cell collection for manufacturing. Monitor blood counts, immunoglobulin levels after treatment.

Pregnancy: not recommended. Verify pregnancy status prior to starting treatment. Nursing mothers.

Interactions: Concomitant live virus vaccines: not recommended for at least 6 weeks prior to lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery.

Adverse reactions: CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, cardiac arrhythmias; hypersensitivity reactions, HBV reactivation, hypogammaglobulinemia, neurologic toxicities, prolonged cytopenias, secondary malignancies (monitor).

How supplied: Infusion bag (~68 mL)—1 For more information call (844) 454-5483 or visit www.Yescarta.com.

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A7

IN THE PIPELINE FDA Approves Abemaciclib as First-Line Therapy for Metastatic Breast Cancer

The most frequently observed grade 3 to 4 adverse events included neutropenia, leukopenia, diarrhea, infections, fatigue, abdominal pain, anemia, nausea, and vomiting.

neurofibromatosis type 1,” said Dr Roy Baynes, chief medical officer of Merck Research Labs, in a press release.

The US Food and Drug Administration (FDA) approved abemaciclib with an aromatase inhibitor (AI) for first-line endocrine-based therapy in postmenopausal patients with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer, according to a press release.

Abemaciclib — a CDK 4/6 inhibitor — was previously approved for HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant following disease progression after endocrine therapy, and as monotherapy for HR-positive, HER2-negative advanced or metastatic breast cancer among patients who had failed endocrine and chemotherapy.

The FDA based its approval on findings from the phase 3 MONARCH trial (ClinicalTrials.gov Identifier: NCT02246621), for which researchers randomly assigned 493 postmenopausal women who had not received prior systemic therapy to abemaciclib 150 mg or placebo twice on a daily continuous schedule, plus anastrozole 1 mg or letrozole 2.5 mg daily.

Abemaciclib plus AI significantly improved progression-free survival (PFS), nearly doubling PFS time compared with placebo and AI (28.2 months vs 14.8 months, respectively; hazard ratio [HR], 0.54; 95% CI, 0.418-0.698; P < .0001).

Patients in the abemaciclib arm also had an objective response rate of 55.4% compared with 40.2% among patients treated with placebo, and the median duration of response was 27.4 months vs 17.5 months among patients treated with abemaciclib vs placebo, respectively.

For more information, visit Lilly.com.

First-in-Class Pancreatic Cancer Candidate Gets Fast Track Status

Selumetinib Gets Orphan Drug Designation for Neurofibromatosis Type 1 An investigational treatment for the genetic disorder neurofibromatosis type 1 (NF1) has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA).

Selumetinib is an MEK 1/2 inhibitor being developed as part of AstraZeneca and Merck’s oncology collaboration. NF1 has no known cure and carries highly variable symptoms including cutaneous, neurological, and orthopedic manifestations.

Plexiform neurofibromas (PNs), a neurological manifestation, occur in 20% to 50% of patients with NF1. These can cause pain, motor dysfunction, and disfigurement. Mutations in the NF1 gene may result in dysregulation in RAS/RAF/ MEK/ERK signaling, which can result in PN growth. By inhibiting the MEK enzyme, selumetinib may inhibit PNs. Selumetinib is currently being examined in a National Cancer Institute– sponsored phase 1/2 SPRINT trial.

Participants include children with symptomatic NF1-related PNs. The results are expected at some point later in 2018.

The treatment was previously granted Orphan Drug Designation for stage III/ IV differentiated thyroid cancer.

“This is an important collaborative effort with our colleagues at AstraZeneca addressing an area of significant unmet medical need to potentially benef it patients with

A8 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

For more information, visit Lilly.com.

FibroGen announced that the US Food and Drug Administration (FDA) has granted Fast Track designation to pamrevlumab for the treatment of patients with locally advanced unresectable pancreatic cancer.

Pamrevlumab is a first-in-class anti-connective tissue growth factor (CTGF) antibody. CTGF is a common mediator in fibrotic and proliferative disorders. In fibrotic cancers, such as pancreatic cancer, fibrous tissue promotes abnormal spread of tumor cells and associated stromal cells.

The Fast Track designation was supported by data from a phase 2 study evaluating pamrevlumab in combination with gemcitabine and nab-paclitaxel. A phase 2 open-label study also showed pamrevlumab in combination with gemcitabine and erlotinib led to a dose-dependent improvement in 1-year survival rate.

“There are no approved treatment options for patients with locally advanced pancreatic cancer, who face a short life expectancy. We are encouraged by our phase 2 study results, where the combination of pamrevlumab with chemotherapy changed eligibility for surgical resection in a majority of treated patients who were previously not candidates for surgery,” said Peony Yu, MD, FibroGen’s chief medical officer, in a press release.

Pamrevlumab is also being investigated in the treatment of idiopathic pulmonary fibrosis and Duchenne muscular dystrophy.

For more information, visit FibroGen.com.

LATEST NEWS High Nut Intake Improves Survival Among Patients With Colon Cancer

© DIONISVERA / SHUTTERSTOCK

Patients with stage III colon cancer who have a high tree nut intake have an improved rate of disease-free and overall survival (DFS and OS, respectively), according to research published in the Journal of Clinical Oncology.

Research suggests that diet may affect the likelihood of disease recurrence or death among patients with colon cancer. Type 2 diabetes, sedentary lifestyle, Western-pattern diet, and high intake of sugary drinks and food are each associated with recurrence and death in this patient-group. Nut intake, however, is associated with a reduced risk of type 2 diabetes and insulin resistance.

For this prospective study (CALGB 89803; ClinicalTrials.gov Identifier: NCT00003835), researchers enrolled 1264 patients with stage III colon cancer to determine whether particular dietary patterns affect the risk of disease recurrence or mortality. Patients reported their dietary intake via food frequency questionnaires.

After exclusions, the final data analysis included 826 patients.

Patients with a higher nut intake were more likely to be men, had a higher alcohol intake, and were less likely to have a high glycemic load diet. While patients with a high nut intake tended to consume more calories, they did not have a higher body mass index (BMI) than others.

The median follow-up was 6.5 years. Patients who consumed at least 2 servings of nuts per week had an improved DFS over non-consumers (adjusted hazard ratio [aHR], 0.58; Ptrend = .03), as well as an improved OS (aHR, 0.43; Ptrend = .01).

This benefit did not, however, appear to apply to peanuts: a subgroup analysis showed that the DFS and OS improvements were confined to high tree nut intake only (HR for DFS, 0.54; Ptrend = .04; HR for OS, 0.47; Ptrend = .04).

The authors concluded that while “the findings of our observational study do not establish causality, the results offer further support of the role of diet and lifestyle as modifiable risk factors of outcomes in patients with colon cancer.”

Umbralisib: A Promising Therapy for Hematologic Malignancies Umbralisib, a next-generation PI3Kδ inhibitor, may be a safe and effective option for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or Hodgkin/ non-Hodgkin lymphomas, according to a study published in The Lancet Oncology.

While idelalisib, the first-in-class PI3Kδ inhibitor, showed promising activity in patients with CLL and non-Hodgkin lymphoma, the drug has a significant toxicity profile, and can induce colitis in up to 19% of patients. Umbralisib has shown improved isoform selectivity over currently used PI3Kδ inhibitors.

For this phase 1 dose-escalation study (ClinicalTrials.gov Identifier: NCT01767766), researchers evaluated the safety and efficacy of umbralisib in patients with CLL or Hodgkin/ non-Hodgkin lymphoma who had received at least 1 prior therapy. Of 90 patients enrolled and treated, 24 had CLL, 49 had B-cell non-Hodgkin lymphoma, and 6 had another hematologic malignancy.

The median treatment duration and follow-up was 133 days; the maximum tolerated dose was 1200 mg of a micronized formulation. Six patients discontinued treatment because of adverse events (AEs) that may have been drug-related, including colitis (2%), increased liver enzymes (2%), diarrhea (1%), and fatigue (1%).

Objective responses were noted in 33 (37%) patients, 30 of whom had a partial response. Fifty-six (62%) patients, however, had a CT scan–assessed reduction in disease burden. No patients who received less than 800 mg of the non-micronized formulation had an objective response.

Seventeen (85%) patients with CLL and 9 (53%) patients with follicular lymphoma had an objective response. Two patients with follicular lymphoma and 1 patient with Hodgkin lymphoma had a complete response.

The most common AEs were diarrhea (43%), nausea (42%), and fatigue (31%); the most common grade 3 to 4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

The authors concluded that “the safety, activity, and pharmacological properties of umbralisib support investigations of its use as monotherapy or in combination with other novel targeted drugs for patients with haematological malignancies.”

Mapping Chemotherapy Checking Procedures May Improve Safety Mapping checking medication procedures may reduce the likelihood of errors during drug administration for patients with cancer, according to a study published in the Journal of Oncology Practice.

Standard checking procedures within hospitals may function as safety barriers. Some hospitals, for example, require that hospital staff double check that the correct chemotherapy is being administered; this can, however, lead to a greater likelihood of error, given that double checking may lead to both staff members checking less closely. Mapping how hospitals standardize chemotherapy checking can improve standards and checking efficacy.

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A9

LATEST NEWS

Cigar and Pipe Use Significantly Increase Mortality Risk Current cigar, pipe tobacco, and cigarette use is linked with a significant cancer- and non-cancer-related mortality risk, according to research published in JAM A Internal Medicine.

While research consistently shows that cigarette smoking confers a high mortality risk, few studies have evaluated the specific risks of cigar and pipe use. While cigarette use in the United States has declined by 38.7% since 2000, non-cigarette tobacco use has increased by over 100%, including an 85.2% increase in cigar use and a 556.4% increase in pipe tobacco use.

For this study, researchers evaluated data from the National Longitudinal Mortality Study (NLMS) to update previous estimates about the mortality risks associated with cigar and pipe tobacco use. Participants provided survey-based data from 1985 through 2011. Former cigarette users reported smoking at least 100 cigarettes in their lifetime.

Most of the 357,420 participants who were current or former cigar or pipe users were men, though only 46% of current daily smokers were men. Current cigarette-only smokers had a 2-fold risk of all-cause mortality compared with the

non-smoking population (hazard ratio [HR], 1.98), and current cigar-only users had an HR for all-cause mortality of 1.2.

Death from a tobacco-related cancer occurred at a higher rate among current pipe smokers (HR, 1.58) and current cigar smokers (HR, 1.61), but especially among current cigarette smokers (HR, 4.06).

Former cigarette and cigar users had a higher risk of mortality than that of never-users, but lower than that of current cigarette, cigar, or pipe users.

The authors concluded that this study “provides further evidence that cigar, pipe, and cigarette use confers mortality risks, even among nondaily current cigarette users, with lower risks observed among former users than current users.”

mFOLFOXIRI Plus Cetuximab May Improve Resection Rate in Metastatic Colorectal Cancer Modified fluorouracil, oxaliplatin, and irinotecan (mFOLFOXIRI) with cetuximab does not improve progression-free rates (PFR), but may lead to improved surgical resection rates, among some patients with metastatic colorectal cancer (mCRC), according to a study published in JAMA Oncology.

For the prospective, non-comparative phase 2 MACBETH study (ClinicalTrials.gov Identifier: NCT02295930), researchers randomly assigned 143 patients with mCRC to receive 4 months of cetuximab plus mFOLFOXIRI induction every 2 weeks, followed by cetuximab or bevacizumab maintenance therapy.

Of the 143 enrolled patients, 116 patients had RAS and BRAF wild-type mCRC, and were included in the modified intention-to-treat (mITT) population.

After a mean follow-up of 44.0 months, neither study arm reached the primary endpoint of improving the 10-month PFR over standard therapies. The 10-month PFR among patients in the cetuximab maintenance arm was 50.8% (90% CI, 39.5%62.2%) vs 40.4% (90% CI, 29.4%-52.1%) in the bevacizumab arm.

The overall response rate was 71.6% among the 116 patients in the mITT; the disease control rate was 90.5%. Nearly 76% of patients had early tumor shrinkage.

The most frequently observed grade 3 to 4 adverse events included neutropenia, diarrhea, skin toxic effects, asthenia, stomatitis, and febrile neutropenia.

The authors concluded that “a short induction with mFOLFOXIRI plus cetuximab is feasible as first-line treatment for mCRC and allows achieving impressive activity results in RAS and BRAF wild-type patients, thus emerging as an appealing treatment option.”

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© COKA / SHUTTERSTOCK

For this study, authors aimed to “(1) compare the checks among three hospitals, with ambulatory and inpatient settings, as well as between administration routes (IV [intravenous], oral, and intrathecal); (2) investigate differences among professional groups in types and number of checks applied; and (3) get a holistic overview of when checks occur along the medication process phases.”

Two of the 3 hospitals evaluated were teaching centers; 1 was a regional hospital. The researchers analyzed internal guidelines and interviewed 15 employees overall (3 pharmacists, 6 nurses, and 6 physicians) to map standard medication checking procedures.

Checking was inconsistent between the hospitals; the lowest number of checks, however, was done during the prescription phase. No hospitals relied on single-person double checking or technology-based checking. Double checks were most common after medication production and before administration.

While checks were documented thoroughly in all 3 centers, there were no internal standards for physician checks.

The authors concluded that “application of a check uses valuable human resources, so adequate checking procedures should be defined that allow for the best possible identification of medication errors.”

BLADDER CANCER

Adjuvant Chemotherapy May Be New Standard of Care for Upper Tract Urothelial Cancer Adjuvant gemcitabine-based chemotherapy prolongs progression-free survival (PFS) among patients with upper tract urothelial cancer (UTUC), according to research presented at the 2018 Genitourinary Cancers Symposium in San Francisco, California.

For this phase 3 study of perioperative chemotherapy vs surveillance for UTUC (POUT; ClinicalTrials.gov Identifier: NCT01993979), researchers randomly assigned 345 patients with muscle-invasive or node-positive UTUC who underwent nephro-ureterectomy within the preceding 90 days to gemcitabine plus cisplatin or surveillance with subsequent chemotherapy if needed.

The median follow-up was 17.6 months at time of interim analysis. The 2-year disease-free survival (DFS) rates were 51% (95% CI, 39%-61%) and 70% (95% CI, 58%-79%) in the surveillance and chemotherapy arms, respectively. Patients treated with chemotherapy also had significantly improved PFS vs the surveillance arm (hazard ratio [HR], 0.49; 95% CI, 0.30-0.79; P = .003).

DFS events were reported in 38.2% of patients in the surveillance arm vs 23.2% in the chemotherapy arm (P = .0009). Grade 3 or worse adverse events were reported in 60% and 24% of patients in the chemotherapy and surveillance arms, respectively.

The authors concluded that “whilst follow up for [overall survival] continues, this should be considered a new standard of care in these patients.”

© BRIAN A JACKSON / SHUTTERSTOCK

Ramucirumab Plus Docetaxel May Improve QoL in Urothelial Carcinoma Ramucirumab plus docetaxel does not negatively affect quality of life (QoL) among patients with urothelial carcinoma (UC) compared with placebo and docetaxel, according to research presented at the 2018 Genitourinary Cancers Symposium in San Francisco, California.

For the phase 3 RANGE study (ClinicalTrials.gov Identifier: NCT02426125), investigators randomly assigned 530 patients with advanced or metastatic UC who had progressed on platinum-based therapy to receive ramucirumab 10 mg/kg plus docetaxel 75 mg/m2 (experimental) or placebo plus docetaxel (control) for up to 10 cycles. Ramucirumab plus docetaxel

| LATEST NEWS

improved progression-free survival and the overall response rate, but the impact of treatment on QoL was not previously reported.

Patients were asked to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) at baseline, prior to each cycle, and at the 30-day follow-up. Mean baseline scores were comparable between the study arms.

QoL remained consistent for both study arms over the course of treatment; the only improvement observed from baseline was for pain. Patients in the experimental arm had significantly improved QoL pain scores at cycles 4 and 7 (P < .05), and patients in both study arms experienced improvements for pain (ramucirumab, 14%-25%; placebo, 8%-24%) relative to other QoL scales during cycles 1 to 4.

A post hoc analysis suggested that patients who were responsive to treatment may experience greater relief from pain when treated with ramucirumab and docetaxel compared with placebo plus docetaxel: patients in the experimental arm reported an improvement of 31% to 32% in pain score compared with 14% to 26% among controls.

The authors concluded that “trends in improved [time to sustained deterioration] and improved rates of pain associated with tumor response favored [ramucirumab plus docetaxel].”

First-Line Pembrolizumab May Be Effective in Cisplatin-Ineligible Urothelial Cancer Pembrolizumab has potential as a first-line treatment option for patients with locally advanced, unresectable, or metastatic urothelial cancer who are ineligible for cisplatin, according to a study published in Lancet Oncology.

Approximately 50% of patients with advanced urothelial carcinoma are unable to receive the standard first-line cisplatin-based chemotherapy because of various comorbidities, renal dysfunction, or poor performance status, indicating a need for additional treatment options.

For the single-arm, phase 2 KEY NOTE-052 study (ClinicalTrials.gov Identifier: NCT02335424), researchers treated 370 chemotherapy-naive patients with at least 1 dose of intravenous pembrolizumab 200 mg every 3 weeks. Tumor samples were analyzed to determine PD-L1 expression.

At a median follow-up of 5 months, 89 (24%; 95% CI, 20%-29%) patients achieved a centrally assessed objective response. Median time to response was 2 months.

Patients with PD-L1-expression greater than 10% demonstrated a higher frequency of response to therapy. Forty-two

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A15

LATEST NEWS | BLADDER CANCER (38%) patients with a combined positive score of 10% or greater had an objective response.

The most common grade 3 to 4 adverse events (AE) reported were fatigue, alkaline phosphatase increase, colitis, and muscle weakness. Ten percent of study patients experienced a serious treatment-related AE. One death was caused by a treatment-related AE, and 17 patients died from non-treatment related AEs. The authors concluded that “in view of the antitumour activity and favourable safety profile, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible and for those who might not be suitable candidates for chemotherapy.”

— and discovered that there was an anti-proliferative effect.

Finally, they assessed the effect of SB203580 plus lapatinib on these cell lines; the anti-proliferative effect was significantly greater in combination compared with either agent alone (P < .0001). A similar effect was observed with erlotinib.

The authors concluded that “p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease.”

p38 MAPK May Be A Therapeutic Target in Bladder Cancer

Ramucirumab plus docetaxel may improve progression-free survival (PFS) compared with chemotherapy alone among patients with platinum-refractory advanced urothelial carcinoma, according to a study published in The Lancet.

A phase 2 study previously demonstrated that ramucirumab, an IgG1 monoclonal antibody that inhibits VEGFR-2, significantly improved median PFS with docetaxel compared with docetaxel alone.

For the phase 3 RANGE trial (ClinicalTrials.gov Identifier: NCT02426125), researchers randomly enrolled 530 patients with advanced or metastatic urothelial carcinoma who had progressed after 14 months or less after receiving platinum-based chemotherapy to receive ramucirumab plus docetaxel or placebo plus docetaxel. Tumor response was assessed every 6 weeks for 1 year then every 12 weeks.

Median PFS was 4.07 months (95% CI, 2.96-4.47) among patients receiving ramucirumab plus docetaxel compared with 2.76 months (95% CI, 2.60-2.96) among patients receiving placebo plus docetaxel (hazard ratio [HR], 0.757; 95% CI, 0.607-0.943; P = .0118).

Patients in the ramucirumab arm had an objective response rate of 24.5% (95% CI, 18.8-30.3) vs 14.0% (95% CI, 9.4-18.6) among patients in the placebo arm.

The most frequently reported grade 1 to 2 adverse events (AE) in either treatment group were fatigue, alopecia, diarrhea, decreased appetite, and nausea. Serious treatment-related AEs occurred in 24% and 20% of patients receiving ramucirumab and placebo, respectively, and grade 3 AEs occurred at similar rates in both arms.

The authors noted that ramucirumab plus docetaxel is the first regimen to demonstrate superiority in PFS over chemotherapy in a phase 3 study, and concluded that the data “validate inhibition of VEGFR-2 signaling as a potential new therapeutic treatment option for patients with urothelial carcinoma.”

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The evaluation of downstream signaling resulting from EGFR and/or HER2 inhibition among patients with bladder cancer suggests that p38 MAPK may be a therapeutic target in this population, according to a study published in Urology.

For this study, researchers exposed various cell lines of bladder cancer to erlotinib (an EGFR inhibitor) and lapatinib (a dual EGFR/ HER2 inhibitor), and utilized phosphokinase assays and immunoblotting to analyze the impact these medications had on downstream signaling pathways.

In the first phosphokinase array, RT112 cancer cell lines were exposed to erlotinib. Analysis revealed an altered expression of 10 protein targets: overexpression of p38 MAPK, GSK-3α/β, MEK1/2, Akt, TOR, Src, p27, p27 (Thr198), p27 (Thr157), and PLCɣ-1, and a reduced expression of STAT4.

A second phosphokinase array was performed to confirm the fi ndings of the first assay, but this time cell lines were exposed to lapatinib. Compared with the first array, only 3 of the 10 phospho-proteins previously identified had altered expression: p38 MAPK, GSK-3α/β, and STAT4.

To validate these fi ndings, researchers utilized Western blot analyses to assess the phosphorylation status of the affected proteins in response to erlotinib plus lapatinib. No differences were observed for GSK-3α/β and STAT4, but p38 MAPK continued to be overexpressed.

The authors hypothesized that cancer cells use increased p38 MAPK phosphorylation as a resistance mechanism in response to EGFR/HER2 inhibition. They exposed multiple cell lines to compound SB203580 — a p38 MAPK inhibitor

Ramucirumab Prolongs ProgressionFree Survival in Platinum-Refractory Urothelial Cancer

SIDE EFFECT MANAGEMENT

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Glioblastoma: Temozolomide, Bevacizumab May Improve Outcomes Among Elderly Patients Temozolomide plus bevacizumab may benefit elderly patients with glioblastoma with a low Karnofsky performance score (KPS), according to research published in The Oncologist.

About 45% of patients with glioblastoma are older than 65 years, and there is no standard treatment for patients older than 70 years with a KPS lower than 70.

Preclinical evidence suggested that temozolomide with bevacizumab might improve clinical outcomes and quality of life in this patient population.

For this non-randomized phase 2 trial (ClinicalTrials.gov Identifier: NCT02898012), researchers enrolled 66 patients with glioblastoma to evaluate the safety and efficacy of upfront temozolomide with bevacizumab.

The median patient age was 76 years; the median KPS was 60. Patients received temozolomide (130-150 mg/m2 daily) for 5 days every 4 weeks and bevacizumab (10 mg/kg) every 2 weeks.

About one-third of patients had an objective response. The median progression-free survival was 15.3 weeks and the median overall survival (OS) was 23.9 weeks, which was nearly twice the authors’ unpublished data showing an expectancy of 12 weeks with supportive care alone.

Quality of life and cognition, furthermore, improved during treatment: 33% of patients became transiently capable of self-care with KPS scores over 70.

The most common grade 3 or worse adverse events were hematologic (20%), high blood pressure (24%), venous thromboembolism (4.5%), cerebral hemorrhage (3%), and intestinal perforation (3%).

The authors concluded that “the estimated OS median of 24 weeks that we found appears higher than the 12 weeks of OS that we found in a similar patient population treated with supportive care alone (personal data, unpublished).”

Survey May Help To Identify Patients With Cancer at Risk of HBV Reactivation A selective screening model may help to identify patients receiving anticancer treatment who are at risk of reactivating a hepatitis B virus (HBV) infection, according to research published in the Journal of Clinical Oncology.

| LATEST NEWS

Patients with HBV receiving anticancer therapy can have virus reactivation resulting from immunosuppression. HBV reactivation is, furthermore, linked with liver failure and mortality. The best method for identifying patients with inactive HBV infection is, however, unclear.

For this prospective study, researchers enrolled 2206 patients initiating anticancer treatment at MD Anderson Cancer Center to determine whether a 19-question demographics survey would help to identify patients with HBV prior to treatment.

Of enrolled patients, 2124 completed the survey and HBV testing. The mean patient age was 58 years, 54% were female, and 77% were non-Hispanic white. Twenty percent had a hematologic malignancy and 80% had a solid tumor. One percent of patients had a hepatocellular carcinoma.

Among all included patients, 0.3% had a chronic HBV infection and 6% had prior HBV infection. Chronic or prior infection was most common in Asian patients (31%), followed by nearly 16% in African Americans and 4.6% in white patients.

Patients born outside the United States were the most likely (about 18%) to have HBV infection; about 15% of patients with a parent born outside the US had HBV infection. Less than 5% of patients born in the US with a parent born in the US had HBV infection.

Over 42% of men who had sex with other men and nearly 28% of past injected drug–users had an HBV infection.

The authors noted that “all patients with chronic or past HBV infection would have been identified if we had serologically tested all patients with at least one affirmative answer to any of the survey’s 19 questions.”

They concluded, however, that more than 90% of patients using the survey would require verification through direct HBV testing. More study is needed.

Comparing Aromatase Inhibitors in Patients With HR-Positive Breast Cancer Adjuvant aromatase inhibitor (AI) therapy for 5 years did not improve disease-free survival (DFS) compared with 3 years of AI therapy after 2 years of tamoxifen among patients with hormone receptor (HR)-positive early breast cancer, according to a study published in The Lancet Oncology.

Previous studies showed that while AIs can improve outcomes in this patient-group, the superiority of treatment schedule and type of AI requires further exploration.

For the phase 3 First Adjuvant Trial on All Aromatase Inhibitors study (FATA-GIM; ClinicalTrials.gov Identifier: NCT00541086), researchers randomly assigned 3697 patients

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LATEST NEWS | SIDE EFFECT MANAGEMENT

PPI, H2RA Use With Pazopanib Does Not Affect PFS, OS in Renal Cell Carcinoma Administering proton-pump inhibitors (PPI) or histamine type-2 receptor antagonists (H2RAs) with pazopanib does not negatively affect outcomes among patients with metastatic renal cell carcinoma (mRCC), according to a study published in The Oncologist.

Patients with mRCC frequently experience dyspepsia or gastroesophageal reflux disease (GERD).

Previous studies found, however, that an elevated pH environment leads to nearly a 40% reduction in pazopanib exposure.

For this retrospective study, researchers evaluated the outcomes of 90 patients with mRCC who took pazopanib alone or concurrently with a PPI/H2RA. The majority of study patients were men, had a median age of 60 to 65 years, an ECOG performance status of 1, and had received 0 to 2 prior systemic therapies.

Patients who took a PPI/H2RA had a median progression-free survival (PFS) of 9.0 months (95% CI, 8.0-13.0) compared with 11.0 months (95% CI, 6.0-16.0) among patients who took pazopanib alone (hazard ratio [HR], 1.25; 95% CI, 0.76-2.07; P = .85).

The median overall survival (OS) was 28.0 months (95% CI, 19.0-41.0) vs 30.1 months (95% CI, 17.0-47.0) among patients who took concomitant PPIs/H2RAs vs pazopanib alone, respectively (HR, 0.99; 95% CI, 0.51-1.93; P = .92).

The only adverse event that occurred at a significantly different rate was dyspepsia/GERD: 33% of patients in the pazopanib alone arm reported dyspepsia/GERD compared with 4% among patients who received a PPI/H2RA (P = .005).

There were no significant differences in PFS or OS associated with PPI vs H2RA use.

Receptor Agonists With Palonosetron May Reduce Needed Dexamethasone Duration Administering a neurokinin-1 receptor antagonist (NK1-RA) with palonosetron plus dexamethasone reduces the number of dexamethasone doses necessary for successful antiemetic treatment among patients with cancer receiving highly emetogenic chemotherapy (HEC), according to a study published in the Journal of Clinical Oncology.

Dexamethasone is a mainstay treatment for chemotherapy-induced nausea and vomiting, but prolonged administration leads to adverse events (AEs) that may significantly reduce patient quality of life (QoL). Recent studies showed that combination therapy with novel antiemetic drugs can spare dexamethasone on days 2 and 3 during moderately emetogenic chemotherapy.

For this double-blinded phase 3 study, researchers randomly assigned 401 patients with malignant tumors receiving HEC to receive dexamethasone on day 1 and placebo on days 2 and 3 with an NK 1-RA and palonosetron (Arm D1), or dexamethasone on days 1 to 3 (Arm D3).

Patients completed a QoL questionnaire at baseline and after study completion, and also maintained a diary throughout 5 days to record the effectiveness of antiemetic therapy, the use of rescue medications, and any treatment-related AEs. Of the 401 patients initially enrolled in the study, 396 were eligible for analysis.

Patients in Arm D1 had a complete response (CR) rate of 44.0% compared with 46.9% for patients in Arm D3 (95% CI, -12.6% to 6.8%; P = .007) overall.

The CR rates on day 1 (acute phase) were 63.3% vs 64.5% for patients in Arms D3 and D1, respectively (95% CI, -12.6% to 6.8%; P = .007). During days 2 to 5 (delayed phase), the CR rate was 56.6% vs 51.5% among patients in arms D3 and D1 (95% CI, −14.8% to 4.6%; P = .023), respectively.

The most frequently observed dexamethasone-related AEs were hot flushes and tremors on days 4 and 5 among patients in Arm D3. For patients in Arm D1, higher rates of anorexia, depression, and fatigue were reported on days 2 and 3. There were no significant differences in QoL between study arms.

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to 1 of 6 treatment groups: upfront AI therapy (anastrozole, exemestane, or letrozole) for 5 years, or tamoxifen for 2 years followed by a switch to 1 of the 3 AIs for 3 years.

After median follow-up of 60 months, 11% (211) of patients in the switch group and 10% (190) of the patients in the upfront group reported having a DFS event. The 5-year DFS rate was 88.5% (95% CI, 87.9%-91.7%) vs 89.8% (95% CI, 88.2%-91.2%) among patients in the switch arm vs upfront arm, respectively (hazard ratio [HR], 0.89; 95% CI, 0.73-1.08; P = .23).

The 5-year DFS rates were 90.0% for patients receiving anastrozole, 88.0% for exemestane, and 89.4% for letrozole (P = .24).

The most frequently reported grade 3 to 4 adverse events (AEs) included musculoskeletal AEs, occurring in 7% of patients in both study arms.

The authors concluded that upfront administration of AIs for 5 years was not superior to switching to AIs from tamoxifen after 2 years, and noted that “patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting.”

C. ANDREW KISTLER, MD, PharmD

Optimizing the Management of Tumor Lysis Syndrome TLS, which is linked with serious issues including acute kidney injury, is considered an emergency, so it’s crucial to initiate therapy as soon as possible.

© HERO IMAGES / GETTY IMAGES

T

umor lysis syndrome (TLS) is a group of clinical and metabolic findings seen in patients with highly proliferative tumors who undergo chemotherapy. Cytotoxic chemotherapy can cause massive lysis of tumor cells, which leads to the release of multiple intracellular components into the bloodstream, including phosphate, potassium, and uric acid.1 This release can cause direct kidney damage and acute kidney injury. Patients can present with flank and abdominal pain, decreased urine output, hematuria, nausea, vomiting, diarrhea, seizures, and overall malaise.

Although TLS can be seen in any metabolically active malignancy, it is most frequently seen in patients with acute lymphoblastic leukemia (ALL) and lymphomas such as Burkitt.2 Criteria frequently used to diagnose TLS using laboratory data are found in the Cairo-Bishop classification system. These criteria are applicable at the time of presentation and up to within 7 days of treatment. Adult patients must meet at least 2 of the following criteria: potassium of at least 6 mEq/L, phosphorus of at least 4.5 mg/dL, uric acid of at least 8 mg/dL, or calcium levels of 7 or lower mg/dL.3 There is also a grading system, which ranges from 0 (least severe) to 5 (death). This grading system uses serum creatinine levels and the presence of seizures and/or cardiac arrhythmias.

Prior to therapy initiation, the TLS diagnosis should be confirmed and graded. Patients with highly proliferative malignancies can spontaneously progress to TLS before chemotherapy is initiated; the syndrome is, furthermore, considered an emergency, so it’s crucial to initiate therapy as soon as possible.

Management for patients with TLS includes prompt initiation of intravenous

Prior to therapy initiation, the TLS diagnosis should be confirmed and graded.

| IN THE CLINIC fluids and close monitoring of their electrolytes (eg, potassium, phosphorous, calcium) and uric acid levels. A baseline electrocardiogram (ECG) should be obtained and repeated if the patient develops significant electrolyte abnormalities or becomes symptomatic.

Patients should avoid foods high in potassium, phosphorous, and uric acid; health care practitioners should avoid the administration of medications in fluids high in those components. Renal consultation should also be done early in the patient’s care to assist in the electrolyte management.

Hyperphosphatemia, which is associated with TLS, can be treated using binders such as lanthanum, sevelamer, calcium carbonate, and aluminum hydroxide. Moderate hyperkalemia (potassium between 5 and 7 mEq/L) can be treated with a binder such as sodium polystyrene sulfonate, though only if there are no significant ECG changes.

Hyperkalemic patients who are symptomatic, who have significant ECG changes, or who have a level greater than 7 mEq/L require more aggressive therapy, including intravenous calcium gluconate and an agent aimed at shifting the potassium intracellularly. This intracellular shift is only temporary, so these patients require close cardiac monitoring, frequent labs, and fluid hydration. Hyperkalemia has the most potential for causing deleterious effects because of its potential to induce life-threatening arrhythmias.

Patients with hypocalcemia should have their hyperphosphatemia corrected before calcium is administered to avoid binding and precipitation leading to further kidney injury. If, however, the patient is acutely hypocalcemic and symptomatic, she/he should receive intravenous calcium gluconate to avoid the development of cardiac or neurologic sequelae.

Continued on page A25

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FEATURE

CARLOS HARRISON

O

verwhelming evidence suggests that simple lifestyle changes can dramatically reduce the risk of cancer.

The recently published results of a prospective study that followed 343,150 people for 5 years found a significant reduction in cancer incidence among those who maintained “healthy behaviours: low alcohol intake, non-smoking, healthy BMI [body mass index], physical activity and a healthy diet.”1 “Compared with subjects who followed none or a single healthy behaviour,” the study’s authors reported, “a healthy lifestyle based on all five behaviours was associated with a reduction of about one-third in incident cancer.”

The study’s lead author, Peter C. Elwood, MD, DSc, an epidemiologist at Cardiff University in Wales and a fellow of the Royal College of Physicians, told Cancer Therapy Advisor that the study is further proof that “a healthy lifestyle is better than any pill, with no cost and no side effects.”

The study is hardly the first to find potent links between lifestyle choices and cancer. But it’s the first to involve a cohort of such sweeping magnitude and to demonstrate a cumulative effect of so many lifestyle behaviors.

“Each additional healthy behaviour was independently associated with an

A recent study is the first to demonstrate the cumulative effect of a large number of lifestyle behaviors.

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average of 8% reduction in risk for all cancers,” the authors wrote.

Plus, Dr Elwood said, “the effect of a lifestyle is quantitative. That is, the more the better. The more exercise the better. The lower the body mass index the better. Not going to the extreme of course. But they can all be improved and there will be additional benefits.”

Dr Elwood is also the co-author of one of the most cited studies on the effect of lifestyle on health. The Caerphilly Prospective Study followed a cohort of 2235 men aged 45 to 59 years for more than 3 decades.2 It, too, found about a 35% reduction of cancer incidences, “but the numbers were too small,” Dr Elwood said. “The two studies were remarkably similar. But one is highly significant. Totally persuasive.

The other was just too small to give definite conclusions.”

The link between smoking and cancer is, of course, well known. Numerous studies and major medical organizations have also addressed the hazards of ignoring the healthful behaviors.

“In 2012, 5.5% of all new cancer occurrences and 5.8% of all cancer deaths worldwide were estimated to be attributable to alcohol,” the Cancer Prevention Committee of the American Society of Clinical Oncology (ASCO) said in a policy statement earlier this year.3 “In the United States, it has been estimated that 3.5% of all cancer deaths

© WESTEND61 / GETTY IMAGES

The Relationship Between A Healthful Lifestyle and Cancer: More Than A Single Behavior

FEATURE are attributable to drinking alcohol.

Alcohol is causally associated with oropharyngeal and larynx cancer, esophageal cancer, hepatocellular carcinoma, breast cancer, and colon cancer.”

Similarly, the National Cancer Institute (NCI) notes “consistent evidence that higher amounts of body fat are associated with increased risks of a number of cancers.”4 Among the risks the NCI lists are: a 2 to 4 times’ increase for endometrial cancer; twice as much for esophageal adenocarcinoma; up to twice as high for liver, kidney, pancreatic, and colorectal cancers; a 20% to 40% increased chance of developing breast cancer among postmenopausal women.

The connection between a healthful diet and cancer, too, has been long established. A 1992 review of approximately 200 studies looking at the impact of fruit and vegetable consumption found strong correlations between intake and cancers of the “lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary.”5 “For most cancer sites,” the review stated, “persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those

with high intake, even after control for potentially confounding factors.”

A 2016 meta-analysis of data from 12 prospective study cohorts in the United States and Europe involving 1.44 million participants found a significant association between physical activity and 13 different kinds of cancer, “with risk reductions of 20% or more for 7 of the cancers.”6 Naturally, Dr Elwood said, a healthful lifestyle alone will not prevent cancer in all people.

“There is no magic bullet. There are numerous factors. After all, there are genetic factors. There are various mutations which lead to cancer. And looking for a magic bullet which will explain the whole pattern of disease is just naive,” he said. “Some individuals perhaps will show no benefit. Some will show quite large benefit.”

Also, he added, looking at healthy habits solely in connection with cancer is too limiting.

“It’s a mistake to say, ‘Well, there’s one take-home message about cancer.’

There are a lot of take-home benefits from a healthy lifestyle and a disciplined healthy lifestyle,” he said. “Adding life to years is our objective, rather than just adding years to life.” ■

References 1. Elwood PC, Whitmarsh A, Gallacher J, et al.

Healthy living and cancer: evidence from UK Biobank. ecancer. 2018 Jan 4. doi: 10.3332/ecancer.2018.792 [Epub ahead of print] 2. Elwood P, Galante J, Pickering J, et al.

Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study. PLoS One. 2013;8(12):e81877. doi: 10.1371/journal. pone.0081877 3. LoConte NK, Brewster AM, Kaur JS, Merrill JK, and Alberg AJ. Alcohol and cancer: a statement of the American Society of Clinical Oncology. J Clin

Oncol. 2018;36(1):83-93. doi: 10.1200/ JCO.2017.76.1155 4. Obesity and cancer. National Cancer Institute website. https://www.cancer.gov/ about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet. Updated January 17, 2017. Accessed January 2018.

5. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer.

1992;18(1):1-29.

6. Moore SC, Lee IM, Weiderpass E, et al.

Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176(6):81625. doi: 10.1001/jamainternmed.2016.1548

Looking for information to share with your patients?

These easy-to-read fact sheets may be printed and distributed to patients to enhance their education. Our goal is to provide you with resources to foster communication with your patients.

▶ Recent fact sheet topics include:

• Alcohol and Cancer • Meat Intake and Cancer • Vitamin Intake and Cancer

• Microbiota and Cancer • Proinflammatory Diet and Cancer

Visit www.CancerTherapyAdvisor.com/FactSheets

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A21

VIEWPOINT | BY LEAH LAWRENCE

Exercise May Improve Lymphoma-Specific Survival Patients who indicated a decreased level of physical activity post-diagnosis had a worse overall and lymphoma-specific survival compared with others.

P

hysical activity may improve survival among patients with lymphoma, according to the results of a study presented at the 59th A merican Societ y of Hematolog y (ASH) Annual Meeting in Atlanta, Georgia.1 The observational study showed that increasing physical activity not only decreased patients’ risk for death from all causes, but decreased the risk of lymphoma-specific mortality.

“We found that, in addition to improving quality of life and decreasing mortality from cardiac issues, there is some potential for exercise to decrease the risk from death from lymphoma itself,” Priyanka Pophali, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota, told Cancer Therapy Advisor. “That means exercise is something people should strive to do overall, before they are diagnosed with something like lymphoma, and even if they are diagnosed at later time.”

According to Dr Pophali, physical activity is recommended for all cancer survivors based on evidence from studies of various solid tumors showing that

“Exercise is something people should strive to do overall, before they are diagnosed.”

activity has an effect on quality of life and overall survival.

“Studies show that physical activity in lymphoma patients improves quality of life, but we were curious if there was evidence to recommend physical activity as a way to improve survival,” Dr Pophali said.

The study included 4087 patients enrolled within 9 months of a lymphoma diagnosis at the Mayo Clinic between 2002 and 2012. The researchers evaluated physical activity in 3 ways: first, patients reported their usual level of mild, moderate, and strenuous physical activity during most of their adult life at baseline and again at 3 years. The authors used this information to calculate a Godin Leisure Score Index, a validated tool for measuring physical activity in patients with cancer. At 3 years’ follow-up, patients self-reported change in physical activity since diagnosis as an increase, decrease, or no change.

Patients with a higher level of activity prior to diagnosis had significantly better overall and lymphoma-specific survival compared with those who were less physically active. Patients who increased their level of physical activity after their diagnosis had, furthermore, significantly better overall and lymphoma-specific survival rates compared with those who were less physically active.

In contrast, patients who indicated a decreased level of physical activity at 3

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years after diagnosis had a worse overall and lymphoma-specific survival compared with those who did not report a change.

Dr Pophali noted that the term “lymphoma” can include a broad range of disease. At one extreme are patients diagnosed with indolent disease who are observed and under no active treatment.

“Most of the time these patients do not have a lot of symptoms and will be able to be active,” Dr Pophali explained.

At the other extreme are patients with very aggressive lymphoma. In this situation the disease can limit a patient’s ability to be physically active. Some treatments for lymphoma can also limit physical activity. Patients may suffer from neuropathies or have significant fatigue.

In this study, most included patients had an ECOG performance status of less than 2 and were capable of being physically active.

“That is also why we looked at activity at the 3-year time point, by which time most patients completed treatment and were able to pursue physical activity if desired,” Dr Pophali said.

At this time, little is understood about why physical activity might affect lymphoma-specific survival.

“Our study provides more reason to look at those mechanisms in subsequent research studies,” Dr Pophali said.

There have been some reports in other cancer types suggesting that physical activity decreases overall inflammation in the body and inflammation can be a trigger for cancer. Physical activity can also stimulate your immune system, which can prevent or delay cancer occurrence or progression. ■ Reference 1. Pophali P, Larson MC, Rosenthal AC, et al.

The level of physical activity before and after lymphoma diagnosis impacts overall and lymphoma-specific survival. Blood.

2017;130:914(suppl).

Lymphoma Advisor A section of Cancer Therapy Advisor that features exclusive news and clinical content for oncologists who specialize in the treatment of patients with lymphoma.

Visit CancerTherapyAdvisor.com/lymphoma to gain access to the following and more: • Articles on the latest news in lymphoma written by experts • • Lymphoma Treatment Regimens adapted from NCCN Guidelines® • • An extensive range of current and concise drug information • • Videos of oncology experts speaking about key topics in the field of lymphoma management •

EXPERT PERSPECTIVE | LESLIE BURGESS, MA

Periodontal Disease and Gastric Cancer Risk: An Interview With Dr Yihong Li Cancer Therapy Advisor interviewed Dr Li about her research into the relationship between periodontal disease and gastric cancer.

More than 26,000 Americans will be diagnosed with gastric cancer in 2018, and 10,800 will die of the disease.1 Gastric cancer is the second most common malignancy worldwide, with 5-year survival rates in the United States of 31%, lagging far behind those for breast cancer, colorectal cancer, melanoma, and prostate cancer. Prevention is a key strategy for reducing mortality associated with this disease.

Recommended strategies for precancerous gastric lesions include regular endoscopic surveillance for early cancer detection and eradication of Helicobacter pylori. Patients at high risk for developing precancerous lesions should be monitored and assessed regularly.2 Risk factors for precancerous lesions and gastric cancer are being identified, one of which may be periodontal disease.

Yihong Li, DDS, MPH, DrPH, is a professor of basic science and craniofacial biology at the New York University (NYU) College of Dentistry in New York, New York, and co-author of a recent article in the Journal of Periodontology that examined the role of periodontal disease in the development of precancerous gastric lesions.3 The authors found that bacterial infection in the oral cavity, chronic periodontal inflammation, and not flossing teeth regularly might increase an individual’s risk of gastric cancer. Cancer

Therapy Advisor (CTA) interviewed Dr Li about this research and its implications for oncologists.

Cancer Therapy Advisor (CTA): What inspired you and your colleagues to evaluate the association between periodontal issues and gastric lesions?

DR LI: The original project was led by Dr Yu Chen, an associate professor and epidemiologist in the department of population health at NYU’s School of Medicine.

Dr Chen was the principle investigator of a National Institutes of Health (NIH)-funded project to study the association between the periodontal disease with gastritis and intestinal metaplasia in the stomach. Although gastric cancer is the second most common malignancy worldwide, the lack of early diagnosis biomarkers has always been challenging.

Periodontal disease is one of the main causes of tooth loss for people over 40 years of age, and several population-based prospective cohort studies have suggested a positive association between the risk of gastric cancer and tooth loss.

The etiological connections are, however, not fully understood. As an epidemiologist, Dr Chen led a team of clinical investigators in conducting this hospital-based case-control study to determine if periodontal disease is associated with an increased risk of

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chronic atrophic gastritis and intestinal metaplasia, which are common precancerous lesions of gastric cancer.

Using an advanced molecular microbiology approach, our team at the NYU College of Dentistry designed and performed a series of experiments to measure key periodontal pathogens in the oral cavity. The identification of links between oral bacteria involved with inflammatory periodontitis and also with a gastric lesion that leads to cancer would provide new scientific evidence for more biological-mechanistic studies of the oral disease and systemic disease connections.

CTA: Please describe the results of your study. Which is the most important finding? Which individual patient characteristics affected the risk of periodontal disease and gastric lesions?

DR LI: There were 3 main findings. First, individuals with precancerous lesions of gastric cancer had more bleeding in their gums, a sign of inflammation, and had higher levels of Treponema denticola and Aggregatibacter actinomycetemcomitans in their dental plaque and saliva compared with the controls.

Second, individuals who were of Asian descent, married with families, or did not floss regularly experienced significantly worse periodontal conditions, had higher bacterial levels than the other groups, and therefore were more likely to have an increased risk of developing precancerous lesions of gastric cancer.

Third, the presence and level of the 4 periodontal pathogens — Porphyromonas gingivalis, Tannerella forsythia, T. denticola, and A. actinomycetemcomitans — were highly correlated in the saliva and periodontal pockets. The correlations were even greater among individuals with precancerous lesions of gastric cancer.

The study finding provides new evidence supporting the polymicrobial

EXPERT PERSPECTIVE infection and synergy in chronic periodontal disease and the plausible role of polymicrobiota in gastric cancer etiology.

CTA: Three specific pathogens were associated with increased risk for precancerous gastric lesions. How common are these pathogens in the general population?

DR LI: The prevalence of the 3 periodontal pathogens is very low, ranging from 5% to 15% in the general population without periodontal disease. The prevalence can be significantly increased in patients with chronic periodontal disease; for example, the prevalence of T. forsythia is 75% to 85%, of A. actinomycetemcomitans is 30% to 40%, and of T. denticola is 60% to 75%.

CTA: Are there other types of cancer that may be associated with periodontal disease?

DR LI: In addition to gastrointestinal cancer, there is increasing evidence for an association between chronic periodontal disease and different types of cancer, in particular oral, esophageal, head and neck, pancreatic, lung, breast, and pancreatic cancers.

Although the exact mechanism is not clear, more studies are focusing on the

In the Clinic Continued from page A19

Rasburicase is an intravenous medication that promotes the conversion of uric acid to allantoin, an inactive soluble metabolite that assists in lowering uric acid levels.4 It can be used in patients with high-risk malignancies to prevent TLS and for TLS treatment.

Although rasburicase has data to support preventive and treatment indications in TLS, its cost and unclear impact on direct clinical outcomes make routine

“Individuals with precancerous lesions of gastric cancer had more bleeding in their gums.” links between chronic periodontal infection, bacteremia, and the host immune response with the inflammatory microenvironment of cancer.

health. A high level of periodontal pathogens in saliva can be a biomarker for more deleterious gastrointestinal flora, leading to the increased cancer risk.

Communit y oncologists should include those symptoms and biomarkers in gastric cancer screening and prevention programs. Dentists and periodontists can play a crucial role: treating oral bacterial infections and periodontal inflammation may reduce their patients’ risk of developing gastric cancer. ■ References 1. Cancer facts & figures, 2018. American Cancer

CTA: How can your findings translate into clinical practice?

DR LI: Although major risk factors for gastric cancer, including H. pylori infection, tobacco smoking, and intake of salty foods have been identified, it has been hypothesized that chronic inflammation is responsible for the early stages of disease progression.

Our study provides new evidence of the high levels of periodontal pathogens leading to increased risk for gastric cancer. Gum bleeding, dental plaque accumulation, poor oral hygiene, and tooth loss are indicators of poor periodontal

use challenging.5 Rasburicase has, furthermore, several black box warnings, including methemoglobinemia, hypersensitivity reactions, and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. These warnings may preclude some patients from initiating therapy. ■

Society website. http://bit.ly/2CXzEaX. Accessed January 15, 2018.

2. Dinis-Ribeiro M, Areia M, de Vries AC, et al.

Management of precancerous conditions and lesions in the stomach (MAPS): guideline form the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy.

2012;44:74-94. doi: 10.1055/s-0031-1291491 3. Sun J, Zhou M, Salazar CR, et al. Chronic periodontal disease, periodontal pathogen colonization, and increased risk of precancerous gastric lesions. J Periodontol. 2017;88:1124-34.

strategies and classification. Br J Haematol.

2004;127(1):3-11.

3. Coiffier B, Altman A, Pui CH, Younes A,Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol.2008;26(16): 2767-78. doi: 10.1200/JCO.2007.15.0177 4. Elitek prescribing information. Sanofi

References 1. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):184454. doi: 10.1056/NEJMra0904569 2. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic

website. http://products.sanofi.us/elitek/ elitek.html. Accessed January 2018.

5. Lopez-Olivo MA, Pratt G, Palla SL, Salahudeen A. Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis.

Am J Kidney Dis. 2013;62(3):481-92.

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR A25

REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS 1

Breast Cancer

9 Gastrointestinal Cancer 15 Genitourinary Cancer 22 Head and Neck Cancer

 Head and Neck Cancer

29 Lung Cancer

 Small-cell Lung Cancer

39 Skin Cancer

 Melanoma

To view the complete collection of cancer treatment regimens for all cancer types visit CancerTherapyAdvisor.com/TreatmentRegimens.

To view the complete collection of drug monographs visit CancerTherapyAdvisor.com/DrugMonographs.

A26 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

IMPORTANT INFORMATION FOR ALL READERS CANCER THERAPY ADVISOR is an up-to-date guide to commonly prescribed pharmaceuticals, as well as certain OTC products. It has been produced to provide an easily accessible reminder of basic information useful to review when prescribing medications, such as specific indications for use, dosage, and a checklist of precautions, interactions, and adverse drug reactions. Reference should always be made to each drug being coadmin­ is­tered. The information it contains is intended solely for use by the medical profession. IT IS NOT INTENDED FOR LAY READERS. This reference has been assembled and edited by an experienced staff of pharmacists uti­ liz­ing information available from FDA-approved labeling.

Distinctions have not necessarily been made between those reactions that are well-documented and/or clinically significant, and those that carry only a theoretical risk. A renowned board of consulting medical specialists has also independently reviewed the product references.

However, although every effort is made to assure accuracy, the information in MPR is not necessarily reviewed by the supplier of a particular drug. If any questions arise about information in MPR, the physician should verify it against labeling or by contacting the company marketing the drug. The publisher and editors do not warrant or guarantee any of the products described or the information describing them. THE PUBLISHER AND EDITORS DO NOT ASSUME, AND HEREBY EXPRESSLY DISCLAIM ANY LIABILITY WHATSOEVER FOR ANY ERRORS OR OMISSIONS IN SUCH INFORMATION OR FOR ANY USE OF ANY OF THE PRODUCTS LISTED. No prescription drug should be used except on the advice of, and as directed by, a physician. The training and experience of a physician are essential to forming any opinion on the appropriateness of a specific drug for a specific patient. The information in this publication is not by itself sufficient for a lay person—or even a physician—to evaluate the risks and benefits of taking any particular drug.

In reaching professional judgments on whether to prescribe a pharmaceutical, which to prescribe, and under what regimen, the physician should thoroughly understand the options available for any clinical application, the potential effectiveness of each product, and the associated risks and side effects. This knowledge should be considered in light of the special circumstances of the patient, for each patient is unique. No single reference can substitute for medical training and experience. The physician must be familiar with the full product labeling, provided by the manufacturer or distributor of the drug, of every product he or she prescribes, as well as the relevant medical literature.

Certain additional qualifications are important in using this book. First, MPR has been deliberately kept concise, with a standardized format, so that it could be a convenient reference tool. This means that lengthy and detailed explanations about certain aspects of drugs commonly found in labeling are omitted or condensed.

Second, by revising and reprinting quarterly, MPR should be one of the most up-to-date guides to prescription drugs now available in print. Only the current issue should be used.

The prescribing decision is ultimately the responsibility of the physician. MPR is offered to assist physicians in this area. © 2018 Haymarket Media, Inc.

DRUG MONOGRAPHS

BREAST CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically contraindicated).

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3.

260mg/m2 by IV infusion over 30 mins every 3 weeks. If severe neutropenia (neutrophil <500 cells/mm3 for ≥1week) or severe sensory neuropathy occurs: reduce subsequent doses to 220mg/m2; reduce to 180mg/m2 if severe neutropenia or sensory neuropathy recurs. If grade 3 sensory neuropathy occurs, suspend use until resolution to grade 1 or 2; reduce subsequent doses. Hepatic impairment: see full labeling.

Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5XULN or AST >10XULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis. Renal dysfunction.

Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

AFINITOR Novartis mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: Postmenopausal women with advanced hormone receptor-positive, HER2negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

℞

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily; continue until disease progression or unacceptable toxicity. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risks.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor.

Concomitant strong CYP3A4/PgP inducers: avoid; if required, consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines.

Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation.

Elderly. Embryo-fetal toxicity. Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); see Adult.

Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal

pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

How supplied: Tabs—28 (4 blister cards × 7 tabs)

ARIMIDEX AstraZeneca

℞

Aromatase inhibitor. Anastrozole 1mg; tabs.

Indications: In postmenopausal women: adjuvant treatment of hormone receptor-positive early breast cancer; first-line treatment of hormone receptor-positive or unknown locally advanced or metastatic breast cancer; advanced breast cancer with disease progression after tamoxifen therapy.

Adults: 1mg once daily. Advanced disease: continue until tumor progression.

Children: Not applicable.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X).

Warnings/Precautions: Pre-existing ischemic heart disease. Severe hepatic impairment.

Monitor bone mineral density, cholesterol.

Nursing mothers: not recommended.

Interactions: Antagonized by tamoxifen, estrogens; do not give concomitantly.

Adverse reactions: Hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, lymphedema, dyspnea, dizziness, paresthesia, vaginal bleeding, cough, hypercholesterolemia.

How supplied: Tabs—30

AROMASIN Pfizer

℞

Aromatase inhibitor. Exemestane 25mg; tabs.

Indications: In postmenopausal women: adjuvant treatment of estrogen-receptor positive early breast cancer after 2–3yrs of tamoxifen therapy to complete a total of 5yrs of hormonal therapy; advanced breast cancer with disease progression after tamoxifen therapy.

Adults: Give after a meal. 25mg once daily.

Concomitant strong CYP3A4 inducers (see Interactions): 50mg once daily.

Children: Not established.

Warnings/Precautions: Not for treatment in premenopausal women. Osteoporosis; assess bone mineral density (BMD) at start of treatment. Monitor all patients for BMD loss and treat as appropriate. Perform routine assessment of Vit. D levels prior to initiation; supplement if deficient. Hepatic or renal impairment. Embryo-fetal toxicity. Pregnancy.

Females of reproductive potential: should undergo pregnancy testing within 7 days prior to initiation; use effective contraception during and for 1 month after final dose. Nursing mothers: not recommended (during and for 1 month after final dose).

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DRUG MONOGRAPHS

BREAST CANCER Interactions: Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort).

Adverse reactions: Hot flashes, fatigue, arthralgia, headache, insomnia, increased sweating, nausea, increased appetite; reductions in BMD. How supplied: Tabs—30

FASLODEX AstraZeneca

℞

Estrogen receptor antagonist. Fulvestrant 50mg/mL; soln for IM inj.

Indications: As monotherapy: for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. In combination therapy with palbociclib or abemaciclib: for HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy.

Adults: Give by IM inj slowly (1–2 mins/injection).

500mg (as two 5mL injections, one in each buttock) on Days 1, 15, 29, then once monthly thereafter. For combination therapy: give with palbociclib 125mg daily with food for 21 days, followed by 7 days off, or with abemaciclib 150mg twice daily; in pre/perimenopausal women: also treat with LHRH agonists. Moderate hepatic impairment: 250mg (as one 5mL injection) on Days 1, 15, 29, then once monthly thereafter. Other dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use.

Moderate-to-severe hepatic impairment. When administering at the dorsogluteal inj site due to proximity of the sciatic nerve. Embryo-fetal toxicity. Pregnancy: do testing within 7 days prior to initiating; use effective contraception during therapy and for 1 year after last dose. Nursing mothers: not recommended (during therapy and for 1 year after last dose).

Interactions: May interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.

Adverse reactions: Inj site pain (including sciatica, neuralgia, neuropathic pain, peripheral neuropathy), nausea, vomiting, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation; increased hepatic enzymes, hypersensitivity reactions.

How supplied: Prefilled syringe kit (2 × 5mL)—1

FEMARA Novartis Aromatase inhibitor. Letrozole 2.5mg; tabs.

Indications: In postmenopausal women: Adjuvant treatment of hormone receptor positive early breast cancer; Extended adjuvant

℞

treatment of early breast cancer after 5 years of adjuvant tamoxifen therapy; First-line treatment of hormone receptor positive or unknown, locally advanced or metastatic breast cancer; Treatment of advanced breast cancer with disease progression following antiestrogen therapy.

Adults: 2.5mg once daily. Adjuvant or extended adjuvant therapy: discontinue at tumor relapse; see full labeling. Advanced breast cancer: continue until tumor progression is evident.

Severe hepatic impairment or cirrhosis: 2.5mg every other day.

Children: Not established.

Contraindications: Pregnancy.

Warnings/Precautions: Monitor bone mineral density, serum cholesterol. Severe renal or hepatic impairment. Embryo-fetal toxicity; exclude pregnancy prior to initiation. Use effective contraception during and for ≥3wks after last dose. Nursing mothers: not recommended (during and for ≥3wks after last dose).

Adverse reactions: Pain (bone, musculoskeletal, and others), hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, GI upset, fatigue, somnolence, dyspnea, cough, insomnia, hypertension, anorexia, weight changes; thromboembolic or cardio- or cerebrovascular events (rare).

How supplied: Tabs—30

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the breast.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs.

Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor.

Eribulin mesylate 0.5mg/mL, soln for IV inj.

Indications: Treatment of metastatic breast cancer in patients who have previously received at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Adults: Give by IV inj over 2–5mins. 1.4mg/m² on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate-to-severe renal impairment (CrCl 15–49mL/min): 1.1mg/m² on Days 1 and 8 of a 21-day cycle. Moderate hepatic impairment (Child-Pugh B): 0.7mg/m² on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm³, platelets <75000/mm³, or grade 3 or 4 non-hematological toxicities.

Delay or reduce dose according to toxicities; see full labeling. Do not re-escalate dose after it is reduced.

Children: <18yrs: not established.

Warnings/Precautions: Monitor CBCs prior to each dose; increase frequency of monitoring if grade 3 or 4 cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4 neutropenia lasting >7 days develops.

Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less. Congenital long QT syndrome: avoid. CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval. Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (ChildPugh C): insufficient data. Embryo-fetal toxicity.

Pregnancy (avoid). Use effective contraception during treatment and for ≥2 weeks (females) or 3.5 months (male partners) after final dose.

Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor.

Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, abdominal pain, pyrexia, hypokalemia, hypocalcemia; febrile neutropenia, possible QT prolongation, elevated liver enzymes.

Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids.

How supplied: Single-use vial (2mL)—1

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DRUG MONOGRAPHS

BREAST CANCER HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic breast cancer as a single agent in patients who have received one or more chemotherapy regimens; or in combination with paclitaxel in patients who have not received chemotherapy. Adjuvant treatment in HER2-overexpressing, node-positive or nodenegative breast cancer (as a single agent following multi-modality anthracycline based therapy; in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or in combination with docetaxel and carboplatin).

Adults: Do not substitute for or with adotrastuzumab emtansine. Give as IV infusion.

Initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins weekly; administer until tumor progression. Adjuvant treatment (administer trastuzumab weekly for 52 weeks; therapy >52 weeks: not recommended); In combination therapy: with doxorubicin and cyclophosphamide, followed by either paclitaxel or docetaxel; or with docetaxel/carboplatin: initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins once weekly for the 1st 12 weeks (concurrently w. paclitaxel or docetaxel) or 1st 18 weeks (concurrently w. docetaxel/carboplatin). One week after the last trastuzumab weekly dose, give trastuzumab 6mg/kg over 30–90 mins every 3 weeks. Following multi-modality anthracycline based therapy: initially 8mg/kg over 90 mins, then 6mg/kg over 30–90 mins every 3 weeks. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops.

Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma).

Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation. Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF,

insomnia, fatigue, dyspnea, rash, neutropenia, anemia, thrombocytopenia, stomatitis, mucosal inflammation, weight loss, nasopharyngitis, dysgeusia, myalgia, thrombosis/embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapy-induced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction).

Note: Enroll pregnant women with breast cancer who are using trastuzumab in the MotHER-the Herceptin Pregnancy Registry (800) 690-6720.

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent) ℞

nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, enzalutamide, St. John’s wort). May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs.

Adverse reactions: Neutropenia, leukopenia, infections, fatigue, anemia, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, rash, asthenia, pyrexia; febrile neutropenia.

How supplied: Caps—21

Kinase inhibitor. Palbociclib 75mg, 100mg, 125mg; caps.

Indications: Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or fulvestrant in women with disease progression following endocrine therapy.

Adults: Swallow whole. Take with food. 125mg once daily for 21 consecutive days followed by 7 days off to complete a 28-day cycle, in combination with an aromatase inhibitor or with fulvestrant 500mg on Days 1, 15, 29, and once monthly thereafter (see each drug’s full labeling for dosing/duration). In the combination with fulvestrant therapy: pre/perimenopausal women should be treated with LHRH agonists according to clinical practice standards. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg/day.

Children: Not established.

Warnings/Precautions: Monitor CBCs prior to initiation and at start of each cycle, as well as on Day 15 of first 2 cycles, and as clinically indicated.

Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. If maximum of Grade 1–2 neutropenia develops in first 6 cycles, monitor CBCs for subsequent cycles every 3 months, at start of each cycle, and as clinically indicated. Monitor for fever. Moderate or severe hepatic impairment. Severe renal impairment. Embryo-fetal toxicity. Use effective contraception during therapy and for at least 3 weeks (females) or 3 months (males) after last dose. Pregnancy; exclude status prior to initiation.

Nursing mothers: not recommended (during and for 3 weeks after last dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone,

Epothilone microtubule inhibitor. Ixabepilone 15mg/vial, 45mg/vial; pwd for IV infusion after constitution and dilution; diluent contains alcohol, polyoxyethylated castor oil.

Indications: Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and as monotherapy after failure of an anthracycline, a taxane, and capecitabine.

Adults: Pretreat with both H1 and H2 blockers 1hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2

by IV infusion over 3hrs, once every 3wks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature).

Neuropathy, myelosuppression, concomitant strong CYP3A4 inhibitors: reduce dose.

Concomitant strong CYP3A4 inducers: consider gradual dose increases. See literature.

Children: Not recommended.

Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3.

AST or ALT >2.5XULN or bilirubin >1XULN (in combination with capecitabine).

Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10XULN or bilirubin >3XULN: not recommended; ALT or AST >5XULN: limited data, use caution). Diabetes. Neuropathy.

Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/symptoms of neuropathy, neutropenia.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice); avoid. Caution with mild or moderate CYP3A4 inhibitors; consider alternative agents. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, phenobarbital); avoid.

Avoid St. John’s wort.

IBRANCE Pfizer

IXEMPRA Bristol-Myers Squibb

℞

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DRUG MONOGRAPHS

BREAST CANCER Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others.

How supplied: Kit—1 vial (w. diluent)

KADCYLA Genentech

℞

HER2-targeted antibody-drug conjugate. Adotrastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution.

Indications: Treatment in patients with HER2positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.

Adults: Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely for possible SC infiltration during infusion. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Permanently discontinue if serum transaminases >3XULN and with total bilirubin >2XULN. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate.

Embryo-fetal toxicity: verify pregnancy status prior to initiation. Permanently discontinue if interstitial lung disease or pneumonitis occurs.

Monitor for signs/symptoms of extravasation, infusion-related or hypersensitivity reactions; if significant, slow or interrupt infusion; discontinue if life-threatening. Monitor platelets at baseline and prior to each dose; if platelets <50,000/mm3, delay dose until recovery to ≥75,000/mm3; if platelets <25,000/mm3, delay until recovery to ≥75,000/mm3 and reduce dose.

If thrombocytopenia occurs <100,000/mm3 and concomitant anticoagulants, monitor closely.

Monitor for neurotoxicity; withhold temporarily if Grade 3 or 4 peripheral neuropathy occurs.

Test for HER2 protein overexpression or gene amplification using FDA-approved tests by labs with demonstrated proficiency. Pregnancy: avoid.

Use effective contraception during therapy and for 7 months (females) or 4 months (males) after last dose. Nursing mothers: not recommended (during and for 7 months after last dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, indinavir, ritonavir, nefazodone, nelfinavir, saquinavir, telithromycin); if unavoidable, consider delaying therapy. Caution with concomitant anticoagulation or antiplatelet therapy; monitor closely.

Adverse reactions: Fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache; increased transaminases, constipation, epistaxis, oligohydramnios (do fetal testing if occurs), infertility.

Note: Enroll pregnant women who were exposed to Kadcyla in the MotHER Pregnancy Registry (800) 690-6720.

How supplied: Single-use vial—1

KISQALI Novartis

℞

Kinase inhibitor. Ribociclib 200mg; tabs.

Indications: In combination with an aromatase inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced or metastatic breast cancer.

Adults: Swallow whole. 600mg once daily for 21 consecutive days followed by 7 days off treatment for a complete 28-day cycle. Take preferably in the AM with letrozole 2.5mg once daily throughout the 28-day cycle (see full labeling of letrozole or for dosing/administration with other aromatase inhibitors). Dose modifications for toxicity: see full labeling.

Moderate and severe hepatic impairment: initially 400mg once daily.

Children: Not established.

Warnings/Precautions: Avoid in patients with long QT syndrome, uncontrolled or significant cardiac disease including recent MI, CHF, unstable angina and bradyarrhythmias, electrolyte abnormalities. Assess ECG prior to initiation; start therapy only if QTcF values <450 msec. Repeat ECG at Day 14 of Cycle 1, beginning of Cycle 2, and as clinically indicated; monitor more frequently if any QTcF prolongation occurs. Monitor serum electrolytes prior to initiation, at the beginning of the first 6 cycles, and as clinically indicated; correct any abnormality before starting.

Permanently discontinue if QTcF >500msec or >60msec change from baseline and associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or serious arrhythmia. Perform LFTs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; monitor more frequently if Grade ≥2 abnormalities noted. Discontinue if AST/ALT >20XULN, Grade 3 (AST/ALT >5 to 20XULN) recurs, or AST/ALT >3XULN with total bilirubin >2XULN. Perform CBCs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Hepatic

impairment. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception during and for ≥3 weeks after last dose. Nursing mothers: not recommended (during and for ≥3 weeks after last dose).

Interactions: Avoid concomitant with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, voriconazole); consider alternatives; if unavoidable, reduce to Kisqali 400mg once daily. Avoid grapefruit, grapefruit juice, pomegranates, pomegranate juice. Avoid concomitant with strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort); consider alternatives. Caution with concomitant CYP3A substrates with a narrow therapeutic index (eg, alfentanil, cyclosporine, ergots, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus); may need to reduce these doses. Avoid concomitant with drugs known to prolong QT interval (eg, amiodarone, bepridil, chloroquine, clarithromycin, disopyramide, halofantrine, haloperidol, methadone, moxifloxacin, IV ondansetron, pimozide, procainamide, quinidine, sotalol).

Adverse reactions: Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain; QT prolongation, hepatobiliary toxicity, possible infertility.

How supplied: Blister pack—14, 21

KISQALI FEMARA CO-PACK ℞

Novartis

Kinase inhibitor + aromatase inhibitor. Ribociclib 200mg; with letrozole 2.5mg; tabs.

Indications: Initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced or metastatic breast cancer.

Adults: Take together preferably in the AM. Swallow whole. Kisqali: initially 600mg once daily for 21 consecutive days, followed by 7 days off treatment for a complete 28-day cycle. Femara: 2.5mg once daily throughout the 28-day cycle.

Concomitant strong CYP3A4 inhibitors: avoid; if coadmin necessary, reduce Kisqali to 400mg once daily. Hepatic impairment: initially Kisqali 400mg once daily (moderate and severe); Femara 2.5mg every other day (cirrhosis and severe dysfunction). Dose modifications for toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Avoid in patients with long QT syndrome, uncontrolled or significant cardiac disease including recent MI, CHF, unstable angina and bradyarrhythmias, electrolyte abnormalities. Assess ECG prior to initiation; start therapy only if QTcF values <450 msec. Repeat ECG at Day 14 of Cycle 1, beginning of Cycle 2, and as clinically indicated; monitor more frequently

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DRUG MONOGRAPHS

BREAST CANCER if any QTcF prolongation occurs. Monitor serum electrolytes prior to initiation, at the beginning of the first 6 cycles, and as clinically indicated; correct any abnormality before starting.

Permanently discontinue if QTcF >500msec or >60msec change from baseline and associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or serious arrhythmia. Perform LFTs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; monitor more frequently if Grade ≥2 abnormalities noted. Discontinue if AST/ALT >20XULN, Grade 3 (AST/ALT >5 to 20XULN) recurs, or AST/ALT >3XULN with total bilirubin >2XULN. Perform CBCs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Hepatic impairment. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception during and for ≥3 weeks after last dose. Nursing mothers: not recommended (during and for ≥3 weeks after last dose).

Interactions: Avoid concomitant with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, voriconazole); consider alternatives or see Adult. Avoid grapefruit, grapefruit juice, pomegranates, pomegranate juice. Avoid concomitant with strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort); consider alternatives. Caution with concomitant CYP3A substrates with a narrow therapeutic index (eg, alfentanil, cyclosporine, ergots, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus); may need to reduce these doses. Avoid concomitant with drugs known to prolong QT interval (eg, amiodarone, bepridil, chloroquine, clarithromycin, disopyramide, halofantrine, haloperidol, methadone, moxifloxacin, IV ondansetron, pimozide, procainamide, quinidine, sotalol).

Adverse reactions: Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain; QT prolongation, hepatobiliary toxicity.

How supplied: Cartons—28 days of therapy (63 tabs × 200mg + 28 tabs); (42 tabs × 200mg + 28 tabs); (21 tabs × 200mg + 28 tabs)

LYNPARZA TABLETS

℞

AstraZeneca

Poly (ADP-ribose) polymerase (PARP) inhibitor.

Olaparib 100mg, 150mg.

Indications: Treatment of deleterious or suspected deleterious germline BRCA-mutated, HER2-negative (as detected by an FDA-approved test) metastatic breast cancer in patients who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting

(patients with HR-positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy).

Adults: Swallow whole. 300mg twice daily; max 600mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 250mg twice daily; may further reduce to 200mg twice daily. Concomitant strong or moderate CYP3A inhibitors: avoid; if co-admin unavoidable, reduce olaparib dose to 100mg twice daily (with strong inhibitors) or 150mg twice daily (with moderate inhibitors). Moderate renal impairment (CrCl 31–50mL/min): reduce to 200mg twice daily; max 400mg daily.

Children: Not established.

Warnings/Precautions: Caps and tabs are not interchangeable on a mg-to-mg basis. Monitor CBC for cytopenia at baseline and monthly thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Interrupt therapy and evaluate if new or worsening respiratory symptoms occur; discontinue and treat if pneumonitis is confirmed. Mild renal impairment: monitor closely. Moderate or severe hepatic impairment, severe renal impairment or ESRD (CrCl ≤30mL/min): not studied. Embryofetal toxicity. Pregnancy; exclude status prior to initiating therapy. Females of reproductive potential should use effective contraception during therapy and for 6 months after last dose.

Males (w. female partners) should use effective contraception and do not donate sperm during and for 3 months after last dose. Nursing mothers: not recommended (during and for 1 month after last dose).

Interactions: Increased myelosuppressive toxicity with concomitant other myelosuppressive anticancer agents, including DNA damaging agents. Avoid concomitant strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil); if unavoidable, reduce dose (see Adults). Avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice.

Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); if unavoidable, be aware of potential for decreased efficacy.

Adverse reactions: Anemia, nausea, fatigue, asthenia, vomiting, neutropenia, leukopenia, nasopharyngitis/URI/influenza, diarrhea,

arthralgia, myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, stomatitis, lab abnormalities (see full labeling); MDS/AML, pneumonitis.

How supplied: Caps—112; Tabs—60, 120

NERLYNX Puma Biotechnology

℞

Kinase inhibitor. Neratinib 40mg; tabs.

Indications: Extended adjuvant treatment of early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumabbased therapy.

Adults: Initiate antidiarrheal prophylaxis (loperamide) with the first dose and continue during the first 2 treatment cycles (56 days); see full labeling. Swallow whole. Take with food. 240mg once daily for 1 year. Severe hepatic impairment (Child-Pugh C): reduce initial dose to 80mg. Dose modifications for adverse reactions: First dose reduction: 200mg/day; Second dose reduction: 160mg/day; Third dose reduction: 120mg/day; discontinue if unable to tolerate 120mg/day. Dose modifications for diarrhea, hepatotoxicity, or other general toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor and treat diarrhea as needed; interrupt and reduce subsequent doses if severe diarrhea with dehydration occurs. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3/4 or any grade of diarrhea with complications. Measure total bilirubin, AST/ALT, alkaline phosphatase prior to initiation, monthly for the first 3 months, then every 3 months during treatment and as clinically indicated. Severe hepatic impairment: reduce dose. Embryo-fetal toxicity. Use effective contraception during therapy and for at least 1 month (females) or 3 months (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for at least 1 month after last dose).

Interactions: Avoid concomitant PPIs, H2receptor antagonists, strong or moderate CYP3A4 inhibitors (eg, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir and [ombitasvir and/or dasabuvir], posaconazole, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, voriconazole, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil), and strong or moderate CYP3A4 inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, modafinil).

Separate dosing by 3hrs after antacids.

Increased cardiotoxicity risk with digoxin.

May inhibit transport of P-gp substrates (eg, dabigatran, fexofenadine).

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BREAST CANCER Adverse reactions: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST/ALT increase, nail disorder, dry skin, abdominal distention, weight decreased, urinary tract infection; hepatotoxicity.

How supplied: Tabs—126, 180

PERJETA Genentech

℞

Human epidermal growth factor receptor (HER2) dimerization inhibitor. Pertuzumab 420mg/14mL (30mg/mL); soln for IV infusion; preservative-free.

Indications: In combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. In combination with trastuzumab and chemotherapy: for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer (EBC); or for the adjuvant treatment of patients with HER2-positive EBC at high risk of recurrence.

Adults: Test and confirm for HER2 protein overexpression or HER2 gene amplification using FDA-approved tests. Initially 840mg IV over 60mins, followed every 3 weeks thereafter by a dose of 420mg IV over 30–60mins. Give in combination with trastuzumab 8mg/kg IV over 90mins, followed every 3 weeks by a dose of 6mg/kg IV over 30–90mins. MBC: also give with docetaxel 75mg/m2 IV infusion; may escalate to 100mg/m2 every 3 weeks if tolerated.

Neoadjuvant: give every 3 weeks for 3 to 6 cycles as part of one of the treatment regimens for EBC: see full labeling. Adjuvant: give every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unacceptable toxicity, whichever occurs first, as part of a complete regimen for EBC: see full labeling. Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued. Dose modifications (missed dose, LVEF, or infusion reactions): see full labeling.

Children: Not established.

Warnings/Precautions: Risk of left ventricular dysfunction. Assess LVEF prior to initiation and at regular intervals during treatment (eg, every 12wks for MBC or EBC [once for neoadjuvant therapy]); withhold pertuzumab and trastuzumab for LVEF decreases (see full labeling); discontinue if LVEF has not improved or clinically significant decrease in left ventricular function is confirmed.

Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occur; permanently

discontinue if severe. Embryo-fetal toxicity.

Pregnancy; exclude status prior to initiation.

Females of reproductive potential should use effective contraception during and for 7 months after last dose. Nursing mothers.

Adverse reactions: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy, vomiting, thrombocytopenia, anemia, constipation, headache, asthenia, mucosal inflammation, myalgia; hypersensitivity reactions (monitor), left ventricular dysfunction; pregnant women: possible oligohydramnios (monitor).

Note: Encourage women who are exposed to Perjeta during pregnancy to enroll in the MotHER Pregnancy Registry: (800) 690-6720.

How supplied: Single-use vial—1

SOLTAMOX ORAL

SOLUTION DARA BioSciences

levels reduced by CYP3A4 inducers (eg, rifampin, aminoglutethimide). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, oligomenorrhea, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, liver abnormalities, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Soln—150mL

Tamoxifen (various) ℞

Antiestrogen. Tamoxifen (as citrate) 10mg/5mL; licorice and aniseed flavors; sugar-free; contains alcohol.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation.

Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: Not recommended.

Contraindications: For reduction in incidence in high-risk women and women with DCIS: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma), stroke and pulmonary embolism. Women with advanced disease: discontinue if severe hypercalcemia occurs.

Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Pregnancy (Cat.D); avoid. Premenopausal: use effective non-hormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (–) B-hCG pregnancy test first. Nursing mothers: not recommended.

Interactions: See Contraindications. May potentiate oral anticoagulants; if co-administered, monitor PT. Concomitant anastrozole: not recommended. Antagonizes letrozole. Plasma

℞

Antiestrogen. Tamoxifen (as citrate) 10mg, 20mg; tabs.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation.

Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: McCune-Albright Syndrome, precocious puberty: see literature.

Contraindications: For risk reduction: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism, planned pregnancy. Pregnancy (Cat.D). Nursing mothers.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma) and thrombotic events. Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Premenopausal: use effective non-hormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (–) B-hCG pregnancy test first.

Interactions: May potentiate oral anticoagulants (see Contraindications). Antagonizes anastrozole (avoid concomitant use); letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin).

Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, rash, headache,

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DRUG MONOGRAPHS

BREAST CANCER nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, jaundice, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Contact supplier.

TREXALL Teva

myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

TYKERB GlaxoSmithKline ℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Breast cancer.

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat. X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment.

Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency.

Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics.

May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection,

℞

Tyrosine kinase inhibitor. Lapatinib 250mg; tabs.

Indications: In combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Limitation of use: patients should have disease progression on trastuzumab before initiating Tykerb in combination with capecitabine. In combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated.

Adults: Take 1hr before or 1hr after a meal (capecitabine should be taken with food or within 30mins after food). HER2 metastatic breast cancer: 1250mg (5 tabs) once daily on Days 1–21 continuously in combination with capecitabine 2000mg/m2/day (administered orally in 2 doses approx. 12hrs apart) on Days 1–14 in a repeating 21 day cycle; continue until disease progression or unacceptable toxicity occurs. After recovery from left ventricular ejection fraction (LVEF) decrease: 1000mg/day.

Severe hepatic dysfunction (Child-Pugh Class C): 750mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 4500mg/day (no clinical data for this dose adjustment). Hormone receptor positive, HER2 positive metastatic breast cancer: 1500mg (6 tabs) once daily continuously in combination with letrozole 2.5mg once daily.

After recovery from LVEF decrease: 1250mg/day.

Severe hepatic dysfunction: 1000mg/day (no clinical data for this dose adjustment).

Concomitant potent CYP3A4 inducers: may titrate up to 5500mg/day (no clinical data for this dose adjustment). For both: Concomitant potent CYP3A4 inhibitors: 500mg/day (no clinical data for this dose adjustment). Interrupt if diarrhea is NCI CTC grade 3, or grade 1 or 2 with complicating features develop; may restart at lower dose (reduced from 1250mg/day to 1000mg/day or from 1500mg/day to 1250mg/day) when resolves ≤ grade 1; permanently discontinue if diarrhea is grade 4. Other toxicities: discontinue if ≥grade 2 NCI CTC toxicity occurs; may restart at 1250mg/day if toxicity improves to grade 1; if recurs, may restart at 1000mg/day (with capecitabine); 1250mg/day (w. letrozole).

Children: Not established.

Warnings/Precautions: Risk of severe and fatal hepatotoxicity; discontinue if occurs;

do not retreat. Monitor liver function tests before, every 4–6 weeks during therapy and as indicated. Confirm normal LVEF before starting.

Discontinue if ≥grade 2 decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Monitor for interstitial lung disease or pneumonitis; discontinue if pulmonary symptoms ≥grade 3 (NCI CTCAE). Discontinue if severe skin reaction (eg, Stevens-Johnson syndrome, toxic epidural necrolysis) is suspected. Severe hepatic impairment: consider dose reduction. Diarrhea: promptly treat with anti-diarrheal agents; if severe, may require fluids, electrolytes, antibiotics and therapy interruption/discontinuation.

Monitor ECG. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole), grapefruit; reduce dose if unavoidable. Avoid potent CYP3A4 inducers (eg, carbamazepine); slowly titrate dose up if unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8, CYP3A4.

Adverse reactions: Diarrhea (may be severe), hand/foot syndrome, nausea, rash (may be severe), vomiting, fatigue; hepatotoxicity, decreased LVEF, QT prolongation, interstitial lung disease, pneumonitis.

Testing considerations: HER2 protein overexpression How supplied: Tabs—150

VERZENIO Lilly

℞

Kinase inhibitor. Abemaciclib 50mg, 100mg, 150mg, 200mg; tabs.

Indications: In combination with fulvestrant for the treatment of women with HR-positive, HER2negative advanced or metastatic breast cancer with disease progression following endocrine therapy. As monotherapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Adults: Swallow whole. Take at the same time every day. Combination with fulvestrant (see full labeling): initially 150mg twice daily; in pre/perimenopausal women: also treat with a gonadotropin-releasing hormone agonist according to current practice standards.

Monotherapy: initially 200mg twice daily. Both: continue until disease progression or unacceptable toxicity. Dose modifications for adverse reactions, concomitant strong CYP3A4 inhibitors: see full labeling. Severe hepatic impairment: reduce frequency to once daily.

Children: Not established.

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DRUG MONOGRAPHS

BREAST CANCER Warnings/Precautions: Advise patients to initiate antidiarrheal (eg, loperamide) and increase fluids at first sign of loose stools; discontinue if Grade 3/4 diarrhea occurs or hospitalization required, until resolves to ≤Grade 1, then resume at next lower dose. Monitor CBCs and LFTs prior to initiation and every 2 weeks for the first 2 months, then monthly for the next 2 months, and as clinically indicated. Dose interruption/reduction/discontinuation or delay in starting treatment cycles if Grade 3/4 neutropenia, recurrent Grade 2 or Grade 3/4 transaminase elevation occurs. Monitor for signs/symptoms of venous thromboembolic events; treat appropriately.

Severe hepatic impairment (Child-Pugh C). Embryofetal toxicity. Females of reproductive potential should use effective contraception during therapy and for at least 3 weeks after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for at least 3 weeks after the last dose).

Interactions: Avoid concomitant ketoconazole, grapefruit products. Concomitant other strong CYP3A inhibitors: reduce abemaciclib dose.

Avoid concomitant strong CYP3A inducers (eg, rifampin): consider alternative agents.

Adverse reactions: Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, thrombocytopenia; venous thromboembolic events, hepatotoxicity.

How supplied: Blister pack—14

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: Metastatic breast cancer resistant to both paclitaxel and an anthracyclinecontaining chemotherapy regimen or resistant to paclitaxel when further anthracycline therapy is not indicated (eg, prior cumulative doses of 400mg/m2 of doxorubicin or its equivalents).

With docetaxel for metastatic breast cancer after failure of prior anthracycline-containing regimen.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Combination therapy: give with docetaxel 75mg/m2 IV infused over 1 hour every 3 weeks. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards.

Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (eg, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal impairment. Monitor and correct dehydration

at initiation. Coronary artery disease.

Interrupt therapy if Grade 2/3 hand-and-foot syndrome, Grade 2/3 or 4 diarrhea occurs (give antidiarrheals) until resolves or reduces to Grade 1. Permanently discontinue if severe mucocutaneous reactions (eg, SJS, TEN) occur.

Dihydropyrimidine dehydrogenase deficiency.

Elderly. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception (during therapy and for 6 months) and males with female partners (during and for 3 months) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose.

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, handand-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

FDA PREGNANCY CATEGORIES When pregnancy appears as a contraindication or precaution to the use of a drug, it is usually qualified by a category as assigned by the FDA.

A: Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: Animal studies have failed to show a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; or animal studies have shown an adverse effect but adequate and wellcontrolled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy and there is no evidence of a risk in later trimesters.

C: Animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the potential benefits may outweigh the risks; or there are no animal studies and no adequate and well-controlled studies in humans.

D: Positive evidence of human fetal risk but the benefits may outweigh the risks.

X: Animal or human studies have shown fetal abnormalities or toxicity, or both, and the risks clearly outweigh any possible benefits.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic colorectal carcinoma, in combination with 5-FU-based chemotherapy for first- or second-line treatment; or in combination with fluoropyrimidine-irinotecanor fluoropyrimidine-oxaliplatin-based therapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. Limitation of use: not for adjuvant treatment of colon cancer.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 5mg/kg (when used with bolus-IFL) or 10mg/kg (when used with FOLFOX-4) once every 2 weeks until disease progression detected; 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks (when used with fluoropyrimidineirinotecan- or fluoropyrimidine-oxaliplatin-based therapy).

Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event.

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome (PRES), or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection.

Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage,

lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, PRES, infusion reactions, ovarian failure, neutropenia, infection.

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. Gastric cancer: 8mg/kg every 2 weeks.

When given in combination: administer prior to paclitaxel. mCRC: 8mg/kg every 2 weeks prior to FOLFIRI. Continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery; resume based on adequate healing; discontinue if complications develops during therapy until wound is fully healed. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months

after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions.

How supplied: Single-dose vial (10mL, 50mL)—1

ELOXATIN Sanofi Aventis

℞

Alkylating agent (organoplatinum complex).

Oxaliplatin 5mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Adjuvant treatment for Stage III colon cancer in patients who have undergone complete resection of the primary tumor (in combination with infusional 5-FU/LV). Treatment of advanced colorectal cancer (in combination with infusional 5-FU/LV).

Adults: See full labeling. Premedicate with antiemetics. Give by IV infusion every two weeks for a total of 6 months (12 cycles) for adjuvant use or until disease progression or unacceptable toxicity for advanced disease.

Day 1: 85mg/m2 + leucovorin, followed by 5-FU. Day 2: Leucovorin followed by 5-FU. Severe renal impairment: initially 65mg/m2. Neuropathy, other toxicities: see full labeling for dose adjustments.

Children: Not established.

Contraindications: Known allergy to other platinum compounds.

Warnings/Precautions: Monitor for allergic reactions; discontinue if occurs; do not rechallenge. Have epinephrine, corticosteroids, antihistamines available during infusion. Monitor for neuropathy; reduce dose or discontinue if needed. Severe neutropenia: delay therapy until neutrophils ≥1.5 × 109/L; withhold for sepsis or septic shock; reduce dose after recovery. Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each cycle. Discontinue if interstitial lung disease or pulmonary fibrosis is suspected. Patients with CHF, bradyarrhythmias, concomitant drugs known to prolong the QT interval, and electrolyte abnormalities: monitor ECG. Correct hypokalemia or hypomagnesemia prior to initiation; monitor periodically during therapy. Congenital long QT syndrome; avoid.

Renal impairment. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with concomitant nephrotoxic agents. Monitor oral anticoagulants.

Adverse reactions: Peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, GI upset, increased liver enzymes, fatigue, stomatitis; allergic reactions, pulmonary fibrosis (may be fatal), hepatotoxicity, QT prolongation, ventricular arrhythmias,

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER rhabdomyolysis (may be fatal; discontinue if occurs).

Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg)—1

ERBITUX Lilly

(eg, hypomagnesemia), sepsis, renal failure, pulmonary embolus.

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis, B-RAF mutation analysis.

How supplied: Single-use vials—1 ℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: K-Ras (wild-type), EGFRexpressing metastatic colorectal cancer: for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, or in combination with irinotecan (if refractory to irinotecan-based chemotherapy), or as a single agent (after failure of both irinotecanand oxaliplatin-based regimens or if irinotecanintolerant). Limitation of use: not indicated for Ras mutant colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) or when Ras mutation test results are unknown.

Adults: Confirm EGFR expression status (using FDA-approved tests) and absence of Ras mutation prior to initiation. Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity. Complete administration 1hr prior to FOLFIRI. Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr postinfusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for serious infusion reactions; immediately interrupt and permanently discontinue if occur. Risk of cardiopulmonary arrest and/or sudden death; carefully consider use (w. irradiation or platinumbased therapy with 5-FU) in coronary artery disease, CHF, or arrhythmias. Monitor electrolytes (eg, magnesium, potassium, calcium) during and for ≥8wks after cetuximab therapy. Interrupt for acute onset or worsening pulmonary symptoms; permanently discontinue if interstitial lung disease confirmed. Monitor for dermatologic toxicities (eg, acneiform rash) and infection; avoid sun exposure. Additive cutaneous reactions with irradiation. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin.

Adverse reactions: Cutaneous reactions (eg, rash, pruritus, nail changes), headache, diarrhea, infection; infusion reactions (may be severe), cardiopulmonary arrest, interstitial lung disease, dermatologic toxicities, electrolyte abnormalities

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the colon, rectum, and stomach.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs.

Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

FUSILEV Spectrum

℞

Folate analogue. Levoleucovorin (as calcium pentahydrate) 50mg/vial; pwd for IV inj after reconstitution; contains mannitol 50mg/vial; 175mg/17.5mL; soln for IV inj; preservative-free.

Indications: Palliative treatment of advanced metastatic colorectal cancer in combination with 5-fluorouracil (5-FU).

Adults: Administer levoleucovorin and 5-FU separately to avoid precipitate formation.

Regimen 1: give levoleucovorin at 100mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-FU at 370mg/m2 by IV inj. Regimen

2: give levoleucovorin at 10mg/m2 by IV inj, followed by 5-FU at 425mg/m2 by IV inj. Both: Treat daily for 5 days. Five-day treatment course may be repeated at 4 week (28 days) intervals for 2 courses, and then repeated at 4–5 week (28–35 days) intervals provided that patient recovered completely from toxic effects from prior treatment course. Dose adjustments for subsequent treatment course: see literature.

Children: Not recommended.

Warnings/Precautions: Not for treating pernicious anemia and megaloblastic anemia.

Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates 5-fluorouracil toxicity. Antagonizes TMP/SMZ. Antagonizes anticonvulsants (eg, phenobarbital, primidone, phenytoin). May be affected by drugs that affect MTX elimination.

Adverse reactions: Stomatitis, nausea, diarrhea.

How supplied: Single-use vial (pwd, soln)—1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Kit (CD117) (+) unresectable and/or metastatic malignant GI stromal tumors (GIST).

Adjuvant treatment of adults following complete gross resection of Kit (CD117) (+) GIST. Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: GIST: 400mg once daily; up to 800mg daily (given as 400mg twice daily) may be considered if clinically indicated.

Adjuvant GIST treatment: 400mg once daily; 36 months of treatment recommended (see full labeling). If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Not recommended.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; renal function at baseline and during therapy; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Diabetes. Hypertension. CHF. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use.

Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy.

Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Embryo-fetal toxicity. Pregnancy (avoid); exclude status prior to initiation. Females of reproductive potential should use highly effective contraception during treatment and for 14 days after cessation. Nursing mothers: not recommended (during and for 1 month after final dose).

Interactions: Avoid grapefruit juice.

Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus) or CYP2C9 (use heparin instead of warfarin). Caution with concomitant CYP2D6 substrates that have a narrow therapeutic window.

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, StevensJohnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment.

Adults: Do not substitute for or with adotrastuzumab emtasine. Give as IV infusion.

Initially 8mg/kg over 90 mins, followed by 6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if

adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDAapproved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma).

Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation.

Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor).

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent)

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservativefree.

Indications: Unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient: colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression on or after ≥2 prior therapies including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/ neu-targeted therapy. Limitations of use: the safety and efficacy of Keytruda in pediatrics with MSI-H CNS cancers have not been established.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression,

unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Gastric cancer: not established.

Give as IV infusion over 30mins. MSI-H cancer: 2mg/kg (max 200mg) every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 develops.

Monitor for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free.

Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min.

200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course).

Children: See literature.

Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency.

Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose.

May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprimsulfamethoxazole.

Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope.

How supplied: Single-use vials—1

LONSURF Taiho Oncology

℞

Antineoplastic thymidine-based nucleoside analog + thymidine phosphorylase inhibitor.

Trifluridine, tipiracil; 15mg/6.14mg, 20mg/8.19mg; tabs.

Indications: Treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Adults: Take within 1 hour after completion of AM & PM meals. Initially 35mg/m2 twice daily on Days 1–5 and 8–12 of each 28-day cycle until disease progression or unacceptable toxicity; max 80mg per dose (based on trifluridine component). Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Obtain CBC prior to and on Day 15 of each cycle, and as clinically indicated. Do not initiate cycle until ANC ≥1,500/mm3 or febrile neutropenia is resolved, platelets ≥75,000/mm3 or Grade 3/4 nonhematological adverse reactions resolved to Grade 0/1. Withhold dose if ANC <500/mm3 or febrile neutropenia, platelets <50,000/mm3, or Grade 3/4 non-hematological adverse reactions occur; upon recovery, resume at a reduced dose (see full labeling). Moderate or severe hepatic impairment: do not initiate. Moderate renal impairment: may require dose modification; severe (CrCl <30mL/min) or ESRD: not studied.

Elderly. Pregnancy. Females of reproductive potential must use effective contraception during treatment; males must use condoms during and for ≥3 months after final dose. Nursing mothers: not recommended (during treatment and for 1 day after final dose).

Adverse reactions: Anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, pyrexia.

How supplied: Tabs—20, 40, 60

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Unresectable hepatocellular carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) in patients ≥12yrs who has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.

Adults: Give as IV infusion over 60mins. 240mg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5xULN (non-HCC) or AST/ALT >10xULN (HCC) or total bilirubin >3xULN, SCr >6xULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, Grade 3 myocarditis, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5xULN or total bilirubin >1.5–3xULN, SCr >1.5–6xULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI, pyrexia, headache, abdominal pain; also with ipilimumab: vomiting; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL, 24mL)—1

STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tabs.

Indications: Metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy.

Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) in patients who have been previously treated with imatinib mesylate or sunitinib malate. Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.

Adults: Swallow whole with water after a lowfat meal (contains <600 calories and <30% fat). 160mg once daily for the first 21 days of each 28-day cycle; until disease progression or unacceptable toxicity. Dose modifications: reduce by 40mg increments (see full labeling).

Children: <18yrs: not established.

Warnings/Precautions: Risk of severe liver injury (may be fatal). Obtain LFTs before starting and at least every 2 weeks during first 2 months of treatment; interrupt and reduce or discontinue if persistent hepatotoxicity or hepatocellular necrosis occurs. Severe hepatic impairment: not recommended. Increased risk of infections; withhold if Grade 3/4 occurs or infection of any grade worsens; resume when resolved. Permanently discontinue if severe or life-threatening hemorrhage occurs. Interrupt and reduce or permanently discontinue if dermatological toxicity occurs (eg, hand-foot skin reaction [a.k.a. palmarplantar erythrodysesthesia], rash). Ensure BP is controlled before starting; monitor weekly for the first 6 weeks then every cycle or as clinically indicated; withhold if severe or uncontrolled.

Increased risk of myocardial ischemia/infarction: withhold if new or acute onset develops; resume when resolved. Discontinue if reversible posterior leukoencephalopathy syndrome (RPLS) or GI perforation/fistula develops. Wound healing complications: stop treatment at least 2 weeks

before surgery; discontinue if wound dehiscence occurs. Asian patients (monitor). Dialysis.

Embryo-fetal toxicity. Females and males of reproductive potential should use effective contraception during treatment and up to 2 months after completion. Pregnancy. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole); avoid. Antagonized by strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort); avoid. Potentiates BCRP substrates (eg, methotrexate, fluvastatin, atorvastatin); monitor closely. Monitor INR levels with concomitant warfarin.

Adverse reactions: Asthenia/fatigue, decreased appetite and food intake, handfoot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, dysphonia, hyperbilirubinemia, GI and abdominal pain, rash, fever, nausea; hepatotoxicity, hemorrhage, GI perforation, cardiac ischemia/infarction, RPLS. How supplied: Tabs—84 (3 × 28)

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; hard gel caps.

Indications: Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Risk of hepatotoxicity (may be severe or fatal). Monitor LFTs before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart.

Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs.

History of QT prolongation or pre-existing cardiac disease, bradycardia, electrolyte disturbances; perform periodic ECG, monitor electrolytes.

Monitor BP; suspend if severe hypertension develops until controlled. Not for use in lung cancer patients. Perform serial CBCs and physical exams. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to

treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation. Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists. Temporary interrupt if undergoing major surgery. Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Embryo-fetal toxicity. Use effective contraception during and for ≥4 weeks (females) or 7 weeks (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥4 weeks after last dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider alternatives or reduce dose if needed (see Adult).

May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider alternatives or increase dose if needed (see Adult). Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysguesia/altered taste, dyspepsia, thrombocytopenia; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs).

How supplied: Caps—28

VECTIBIX Amgen

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Panitumumab 20mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: First-line treatment of wild-type RAS (both KRAS and NRAS as determined by an FDA-approved test) metastatic colorectal carcinoma (mCRC) in combination with FOLFOX, or as monotherapy following disease progression after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. Limitation of use: not for treating RAS-mutant mCRC or for whom RAS mutation status is unknown.

Adults: Confirm absence of a RAS mutation using an FDA-approved test prior to initiation.

6mg/kg by IV infusion over 60mins once

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER every 14 days. If 1st infusion is tolerated, give subsequent infusions over 30–60mins.

Doses >1000mg: infuse over 90mins. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for dermatologic or soft tissue toxicities; withhold or discontinue if severe or life-threatening inflammatory or infectious complications occur.

Discontinue if severe infusion reactions develop.

Interrupt therapy if acute onset or worsening of pulmonary symptoms; discontinue if interstitial lung disease (ILD) is confirmed. Limit sun exposure. Monitor electrolytes (eg, magnesium, calcium) prior to initiation, during, and for 8wks after completing therapy. Monitor for ocular toxicities (eg, keratitis); interrupt or discontinue if develop or worsen. Embryo-fetal toxicity; use effective contraception during and for 2mos after last dose. Pregnancy. Nursing mothers: not recommended during and for 2mos after last dose.

Interactions: Concomitant bevacizumab and chemotherapy: increased mortality and toxicity may occur. Risk of acute renal failure with concomitant chemotherapy.

Adverse reactions: Rash, paronychia, fatigue, nausea, diarrhea; dermatologic or soft tissue toxicities (may be fatal), hypomagnesemia, hypocalcemia, hypokalemia, infusion reactions, ILD, pulmonary fibrosis, photosensitivity, keratitis. With FOLFOX: also stomatitis, mucosal inflammation, asthenia, anorexia.

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis.

How supplied: Single-use vial (5mL, 20mL)—1

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: First-line treatment of metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Continue for a total of 8 cycles. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards.

Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (eg, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal impairment. Monitor and correct dehydration

at initiation. Coronary artery disease.

Interrupt therapy if Grade 2/3 hand-and-foot syndrome, Grade 2/3 or 4 diarrhea occurs (give antidiarrheals) until resolves or reduces to Grade 1. Permanently discontinue if severe mucocutaneous reactions (eg, SJS, TEN) occur.

Dihydropyrimidine dehydrogenase deficiency.

Elderly. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception (during therapy and for 6 months) and males with female partners (during and for 3 months) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose.

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, hand-andfoot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

ZALTRAP Sanofi US and Regeneron

℞

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every 2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed.

Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient

ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5x109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs.

Pregnancy (Cat. C). Use effective contraception during and up to 3 months after the last dose.

Nursing mothers: not recommended.

Adverse reactions: Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache.

How supplied: Single-use vials (100mg/4mL)—1, 3; (200mg/8mL)—1

GENERIC NAME The active ingredients and strengths are listed under the name of each dosage form. If the product contains tartrazine, alcohol, flavors, or is alcohol-, sugar-, or dye-free, it is noted. Abbreviations are used to describe the dosage form and its formulation, e.g.: tabs = tablets caps = capsules e-c = enteric coated sust rel = sustained-release ext rel = extended-release

BRAND NAME The main name under which the product and all other dosage forms in the monograph are marketed.

LEGAL CATEGORY Federal schedule. The laws governing the prescribing/dispensing of products vary from state to state.

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DRUG MONOGRAPHS

GENITOURINARY CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: In adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily; continue until disease progression or unacceptable toxicity. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risks.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor.

Concomitant strong CYP3A4/PgP inducers: avoid; if required, consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines.

Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation.

Elderly. Embryo-fetal toxicity. Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir,

fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); see Adult.

Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

How supplied: Tabs—28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic renal cell carcinoma (mRCC) in combination with interferon alfa.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins.

10mg/kg every 2 weeks with interferon alfa.

Children: Not established.

Warnings/Precautions: Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). History of hemoptysis of ≥ ½-teaspoon of red blood: do not administer.

Discontinue if GI perforation, non-GI fistula formation, wound healing complications, serious hemorrhage, severe arterial or Grade 4 venous thromboembolic events, hypertensive crisis, nephrotic syndrome, or posterior reversible encephalopathy syndrome occurs; suspend therapy if severe hypertension, moderate to severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Cardiovascular disease. Diabetes. Monitor BP every 2–3 weeks.

Monitor proteinuria by dipstick urine analysis.

Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure.

How supplied: Single-use vial—1

BAVENCIO EMD Serono

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Avelumab 20mg/mL; soln for IV infusion after dilution; preservative-free; contains mannitol.

Indications: Treatment of locally advanced or metastatic urothelial carcinoma (UC) in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinumcontaining chemotherapy.

Adults: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; then subsequent doses as clinically indicated. Give as IV infusion over 60mins. 10mg/kg every 2 weeks until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: <12yrs: not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event.

Permanently discontinue for Grade 3/4 pneumonitis or recurrent Grade 2 pneumonitis, Grade 4 diarrhea or colitis or recurrent Grade 3 diarrhea or colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, any life-threatening (Grade 4) or recurrent severe (Grade 3) immune-mediated adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2/3 immune-mediated adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2/3 diarrhea or colitis, Grade 3/4 adrenal insufficiency, Grade 3/4 thyroid disorders, Grade 3/4 hyperglycemia, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN; withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if Grade 1/2 infusion-related reactions occur; permanently discontinue if Grade 3/4. Monitor for abnormal liver tests, adrenal insufficiency, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for ≥1 month after final dose. Pregnancy. Nursing mothers: not recommended (during and for ≥1 month after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, peripheral edema, UTI; other immune-mediated adverse reactions (may be fatal).

How supplied: Single-dose vial (10mL)—1

CABOMETYX Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 40mg, 60mg; tabs.

Indications: Advanced renal cell carcinoma (RCC).

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DRUG MONOGRAPHS

GENITOURINARY CANCER Adults: Do not substitute with cabozantinib caps. Do not eat at least 2hrs before and 1hr after dose. Swallow whole. 60mg once daily until disease progression or unacceptable toxicity. Stop treatment at least 28 days prior to scheduled surgery (including dental). Withhold for Grade 4 adverse reactions, Grade 3 or intolerable Grade 2 adverse reactions that are unmanageable with dose reduction or supportive care. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 60mg daily, resume at 40mg daily; previously on 40mg daily, resume at 20mg daily; previously on 20mg daily, resume at 20mg if tolerated, otherwise discontinue.

Concomitant strong CYP3A4 inhibitor: reduce daily dose by 20mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor.

Concomitant strong CYP3A4 inducer: increase daily dose by 20mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 80mg. Mild or moderate hepatic impairment: initially 40mg once daily.

Children: Not established.

Warnings/Precautions: Permanently discontinue if the following occurs: unmanageable GI perforation/fistula, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome. Recent history or risk of severe hemorrhage: do not administer. Monitor for GI perforations/fistulas. Monitor BP regularly; withhold for hypertension inadequately controlled with medical management; resume at reduced dose when resolved. Withhold therapy if intolerable Grade 2 diarrhea, unmanageable Grade 3/4 diarrhea, or intolerable Grade 2/3 palmar-plantar erythrodysesthesia (PPE) develops until improvement to Grade 1; resume at reduced dose. Discontinue if reversible posterior leukoencephalopathy syndrome develops. Severe hepatic impairment: not recommended. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after final dose. Pregnancy. Nursing mothers: not recommended (during and for 4 months after final dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, St. John’s wort); if unavoidable, see Adult dose.

Adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, stomatitis; lab abnormalities.

How supplied: Tabs—30

CASODEX AstraZeneca

℞

Antiandrogen. Bicalutamide 50mg; tabs.

Indications: In combination with luteinizing hormone-releasing hormone (LHRH) analogue in stage D2 metastatic prostate carcinoma.

Adults: Take at the same time each day. 50mg daily. Start treatment at same time as starting LHRH analogue.

Children: Not applicable.

Contraindications: Women. Pregnancy.

Warnings/Precautions: Moderate to severe hepatic impairment. Monitor prostate specific antigen and hepatic function (discontinue if ALT >2xULN or if jaundice occurs). Males with female partners of reproductive potential should use effective contraception during therapy and for 130 days after final dose. Nursing mothers.

Interactions: Monitor oral anticoagulants.

Adverse reactions: Hot flashes, gynecomastia, breast pain, diarrhea, pain, asthenia, infection, dyspnea, impotence, loss of libido, others (see full labeling); rare: hepatitis.

How supplied: Tabs—30, 100

ELIGARD Tolmar

℞

GnRH analogue. Leuprolide acetate 7.5mg, 22.5mg, 30mg, 45mg; per inj; ext-rel susp for SC inj.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Allow product to reach room temperature before using; inject within 30 minutes of mixing.

Use correct formulation. Rotate inj sites. 7.5mg SC once per month; or 22.5mg SC once every 3 months; or 30mg SC once every 4 months; or 45mg SC once every 6 months.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: May worsen metastatic vertebral lesions and/or urinary tract obstruction; monitor closely during first few weeks. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/symptoms of CVD during therapy. Risk of QT prolongation in patients with congenital long QT syndrome, CHF, or frequent electrolyte abnormalities. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Monitor serum testosterone, PSA periodically. Nursing mothers: not recommended.

Interactions: Caution with concomitant drugs known to prolong the QT interval. May interfere with pituitary-gonadal diagnostic tests.

Adverse reactions: Malaise, fatigue, hot flashes/sweats, testicular atrophy, local reactions (eg, burning/stinging, pain, erythema, bruising, pruritus); transient worsening of signs/symptoms (eg, bone pain, neuropathy, hematuria, bladder outlet obstruction), spinal cord compression, hyperglycemia, decreased bone density; rare: pituitary apoplexy.

How supplied: Single-use kit—1 (with sterile or sterile safety needle)

IFEX Baxter

℞

Alkylating agent. Ifosfamide 1g, 3g; per vial; pwd for IV infusion after reconstitution.

Indications: Third-line adjunctive treatment of germ cell testicular cancer.

Adults: Give by slow IV infusion over at least 30 mins. 1.2g/m2 per day for 5 consecutive days; repeat every 3 weeks or after hematological recovery (platelets ≥100000/μL, WBC ≥4000/μL).

Children: Not recommended.

Contraindications: Urinary outflow obstruction.

Warnings/Precautions: Risk of myelosuppression, immunosuppression, and infections. Do hematologic profile before each dose; discontinue if WBCs <2000/μL or platelets <50000/μL. Risk of CNS toxicity and other neurotoxic effects. Discontinue if encephalopathy develops. Do urinalysis before each dose, postpone dose if hematuria occurs.

Give mesna and at least 2L fluids daily. Active urinary tract infections. Impaired hepatic, renal, or hematopoetic function. Preexisting cardiac disease. May interfere with wound healing. Prior radiation therapy or other cytotoxic agents. Ensure adequate hydration. Pregnancy (Cat.D); avoid.

Nursing mothers: not recommended.

Interactions: Increased risk of myelosuppression with other chemotherapy agents. Caution with drugs acting on the CNS (eg, antiemetics, sedatives, narcotics, antihistamines).

Adverse reactions: Alopecia, nausea, vomiting, leukopenia, anemia, CNS toxicity, hematuria, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), thrombocytopenia, pulmonary toxicity, secondary malignancies.

How supplied: Single-dose vials—1

IMFINZI AstraZeneca

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Durvalumab 50mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Adults: Give as IV infusion over 60mins.

10mg/kg every 2 weeks until disease progression or unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or ALT >8×ULN or total bilirubin >5×ULN, concurrent AST or ALT >3×ULN and total bilirubin >2×ULN (with no other cause), Grade 3/4 colitis or diarrhea, creatinine ≥3×ULN, Grade 3/4 infusion-related reactions, or Grade 4 rash/dermatitis. Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5–3×ULN, AST or ALT ≤8×ULN or total bilirubin ≤5×ULN, Grade 2 colitis or diarrhea, Grade ≥2 hypophysitis/hypopituitarism,

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DRUG MONOGRAPHS

GENITOURINARY CANCER Grade ≥2 adrenal insufficiency, Grade ≥2 hyperthyroidism, Grade ≥2 type 1 diabetes, creatinine >1.5–3×ULN, Grade 3/4 infection, Grade 2 (if >1 week) or Grade 3 rash. Monitor for immune-related pneumonitis, hepatitis (obtain LFTs each cycle), colitis/diarrhea, endocrinopathies (thyroid disorders, adrenal insufficiency, diabetes, hypophysitis/hypopituitarism), rash, thrombocytopenia purpura, nephritis; see full labeling for adverse reaction management details.

Monitor for signs/symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions.

Embryo-fetal toxicity. Pregnancy. Females of reproductive potential should use effective contraception during therapy and for ≥3 months after final dose. Nursing mothers: not recommended (during and for ≥3 months after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infection; other immune-related reactions (eg, aseptic meningitis, hemolytic anemia), infusion-related reactions, lab abnormalities.

How supplied: Single-dose vial (2.4mL, 10mL)—1

INLYTA Pfizer

℞

Kinase inhibitor. Axitinib 1mg, 5mg; tabs.

Indications: Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Adults: Take 12hrs apart. Swallow whole with a glass of water. Initially 5mg twice daily. If tolerated for at least two consecutive weeks with no adverse reactions >Grade 2, normotensive, and not receiving antihypertensives, may increase dose to 7mg twice daily, then 10mg twice daily. May reduce dose from 5mg twice daily to 3mg twice daily, then 2mg twice daily if additional dose reduction required. Concomitant strong CYP3A4/5 inhibitors: avoid; if warranted, decrease Inlyta dose by approximately ½. If strong CYP3A4/5 inhibitor discontinued, return Inlyta dose (after 3–5 half-lives of the inhibitor) to that used prior to CYP3A4/5 inhibitor initiation. Moderate hepatic impairment: decrease dose by approximately ½.

Children: Not studied.

Warnings/Precautions: Control and monitor BP prior to and during therapy; discontinue if severe and persistent hypertension (despite antihypertensive therapy and dose reduction).

Risk of thromboembolic events. Untreated brain metastasis, recent active GI bleed: not recommended. Interrupt therapy if bleeding requires medical intervention. Monitor for signs/symptoms of cardiac failure during therapy; permanently discontinue if occurs. GI perforation and fistula formation; monitor. Monitor thyroid, liver function (ALT, AST, bilirubin), and for proteinuria before starting therapy, then periodically. Reduce dose or temporarily interrupt for moderate-tosevere proteinuria. Risk of reversible posterior leukoencephalopathy syndrome (discontinue if

occurs). Stop treatment at least 24hrs prior to scheduled surgery. Severe hepatic impairment.

End-stage renal disease. Pregnancy (Cat.D); avoid.

Use adequate contraception during therapy.

Nursing mothers: not recommended.

Interactions: See Adult dose. Avoid strong CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort), moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin).

Adverse reactions: Diarrhea, nausea, vomiting, hypertension, fatigue, decreased appetite, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, asthenia, constipation.

How supplied: Tabs 1mg—180; 5mg—60

JEVTANA Sanofi Aventis

℞

Antimicrotubule agent. Cabazitaxel 60mg/1.5mL; soln for IV infusion after dilution; contains polysorbate 80, diluent contains ethanol.

Indications: In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen.

Adults: Premedicate with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). Infuse over 1hr. 20mg/m2 every 3 weeks, with oral prednisone 10mg/day during treatment; 25mg/m2 may be used in select patients.

Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea, grade 2 peripheral neuropathy: delay treatment and/or reduce by one dose level (see full labeling). Discontinue if grade ≥3 peripheral neuropathy. Hepatic impairment: (mild): 20mg/m2; (moderate): 15mg/m2. If concomitant strong CYP3A inhibitor necessary, consider a 25% cabazitaxel dose reduction.

Children: Not established.

Contraindications: Neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80.

Severe hepatic impairment (total bilirubin >3xULN). Pregnancy.

Warnings/Precautions: Increased risk of neutropenia complications; consider G-CSF prophylaxis (recommended in high risk patients). Monitor CBC weekly in 1st cycle and before each subsequent cycle. Patients with hemoglobin <10g/dL; monitor closely. Monitor for hypersensitivity reactions esp. during 1st and 2nd infusions; discontinue if occur. Increased risk of GI disorders in patients with neutropenia, age, or history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Evaluate and treat if serious GI toxicity occurs; treatment delay or discontinuation may be needed. Underlying lung disease. Monitor closely for respiratory disorders; interrupt if new or worsening pulmonary

symptoms develop. Monitor for cystitis in patients who previously received pelvic radiation; interrupt or discontinue if severe hemorrhagic cystitis occurs. Hepatic impairment (monitor). ESRD (CrCl <15mL/min). Elderly (increased susceptibility to adverse reactions); monitor closely. Males with female partners of reproductive potential must use effective contraception during and for 3 months after last dose. Nursing mothers.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); avoid. May be antagonized by rifampin. Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants.

Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), diarrhea (may be fatal), fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; febrile neutropenia, renal failure, hypersensitivity reactions.

How supplied: Kit (single-use vial + diluent)—1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free.

Indications: Locally advanced or metastatic urothelial carcinoma in patients who are ineligible for cisplatin-containing chemotherapy, or in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 develops. Monitor for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor

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DRUG MONOGRAPHS

GENITOURINARY CANCER for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops.

Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others.

Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

LENVIMA Eisai

℞

Kinase inhibitor. Lenvatinib 4mg, 10mg; capsules.

Indications: In combination with everolimus, for treatment of advanced renal cell carcinoma, following one prior anti-angiogenic therapy.

Adults: Swallow whole or may dissolve capsule contents into liquid. 18mg (in combination with everolimus 5mg) once daily until disease progression or unacceptable toxicity occurs.

Severe renal impairment (CrCl <30mL/min) or severe hepatic impairment (Child-Pugh C): 10mg once daily. Dose modifications for adverse reactions or lab abnormalities: see full labeling.

Children: Not established.

Warnings/Precautions: Control blood pressure prior to treatment; monitor after 1 week, every 2 weeks for the first 2 months, and then at least monthly thereafter during therapy. Discontinue if life-threatening hypertension, Grade 4 cardiac dysfunction or hemorrhage, arterial thrombotic event, hepatic failure, nephrotic syndrome, GI perforation or life-threatening fistula, or severe and persistent neurologic symptoms occur. Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation >500ms, Grade 3 or 4 renal failure/impairment,

≥2g of proteinuria/24hrs, or reversible posterior leukoencephalopathy syndrome (RPLS) occurs. Monitor for signs/symptoms of cardiac decompensation. Monitor liver function prior to treatment, every 2 weeks for the first 2 months, then at least monthly during treatment. Monitor for proteinuria prior to, and periodically during treatment. Monitor for dehydration and treat if diarrhea develops; interrupt if Grade 3 or 4 and permanently discontinue if Grade 4 diarrhea persists despite therapy. Hypovolemia. Congenital long QT syndrome, CHF, bradyarrhythmias, or those taking Class Ia or III antiarrhythmic drugs; monitor ECGs. Monitor and correct electrolyte abnormalities. Monitor blood calcium levels at least monthly; replace as needed during treatment.

Monitor thyroid function prior to initiation and at least monthly thereafter; treat hypothyroidism as needed. ESRD. Embryo-fetal toxicity. Pregnancy: avoid. Use effective contraception during and for at least 2 weeks after treatment completion. Nursing mothers: not recommended.

Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia.

How supplied: Blister cards—6

MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1.25–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X).

Warnings/Precautions: Hepatic dysfunction.

Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia.

Discontinue if jaundice occurs. Nursing mothers.

Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence.

How supplied: Tabs 2.5mg—50; 0.3mg, 0.625mg, 1.25mg—100

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated.

Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy.

Adults: Give as IV infusion over 30mins. 240mg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5xULN (non-HCC) or AST/ALT >10xULN (HCC) or total bilirubin >3xULN, SCr >6xULN, Grade 4 hypophysitis, Grade 3 or

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DRUG MONOGRAPHS

GENITOURINARY CANCER 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immunemediated encephalitis, recurring Grade 3 adverse reactions, Grade 3 myocarditis, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5xULN or total bilirubin >1.5–3xULN, SCr >1.5–6xULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening.

Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Monitor for transplantrelated complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose. Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI, pyrexia, headache, abdominal pain; also with ipilimumab: vomiting; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL, 24mL)—1

PROVENGE Dendreon

℞

Autologous cellular immunotherapy. Sipuleucel-T (autologous CD54+ cells activated with PAP-GMCSF); minimum 50 million cells/dose; suspension for IV infusion.

Indications: Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer.

Adults: Autologous use only. Obtain product release from manufacturer, match patient identity on product and Cell Product Disposition form, check expiration date and time on product before infusing. Premedicate 30 minutes before infusion with acetaminophen and antihistamine. Give three doses at 2-week intervals. For each dose: give entire contents of bag by IV infusion over 60 minutes; do not use filter; do not use if clumps do not disperse with gentle mixing. Observe patient for at least 30 minutes after infusion. May interrupt or slow infusion if acute transfusion reaction occurs; do not restart if product at room temp for >3 hours.

Children: Not applicable.

Warnings/Precautions: Cardiac or pulmonary conditions. Each dose requires a standard

leukapheresis procedure about 3 days before infusion. If scheduled infusion is missed, do an additional leukapheresis procedure if treatment course is to be continued. Risk of disease transmission. Pregnancy, lactation: not applicable.

Interactions: May be antagonized by concomitant chemotherapy or immunosuppressive therapy.

Adverse reactions: Infusion reactions (eg, chills, fever, respiratory events, GI upset, hypertension, tachycardia), fatigue, back pain, joint ache, headache.

Note: If product sterility tests indicate microbial contamination, manufacturer will contact physician (tests are incomplete at time of infusion).

How supplied: Patient-specific bag (250mL)—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; hard gel caps.

Indications: Advanced renal cell carcinoma (RCC). Adjuvant treatment of patients at high risk of recurrent RCC following nephrectomy.

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). Adjuvant: treat for nine 6-week cycles. May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Risk of hepatotoxicity (may be severe or fatal). Monitor LFTs before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart.

Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or pre-existing cardiac disease, bradycardia, electrolyte disturbances; perform periodic ECG, monitor electrolytes. Monitor BP; suspend if severe hypertension develops until controlled. Not for use in lung cancer patients.

Perform serial CBCs and physical exams.

Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment.

Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden.

Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation.

Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists.

Temporary interrupt if undergoing major surgery.

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not

restart if diagnosis suspected. ESRD on dialysis.

Severe hepatic impairment. Embryo-fetal toxicity.

Use effective contraception during and for ≥4 weeks (females) or 7 weeks (males) after last dose. Pregnancy; exclude status prior to initiation.

Nursing mothers: not recommended (during and for ≥4 weeks after last dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider alternatives or reduce dose if needed (see Adult).

May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider alternatives or increase dose if needed (see Adult). Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysguesia/altered taste, dyspepsia, thrombocytopenia; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs).

How supplied: Caps—28

TECENTRIQ Genentech

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Atezolizumab 60mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Locally advanced or metastatic urothelial carcinoma in patients who are ineligible for cisplatin-containing chemotherapy, or who have disease progression during or after any platinumcontaining chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy.

Adults: Give as IV infusion over 60mins. 1200mg every 3 weeks until disease progression or unacceptable toxicity. May give subsequent infusions over 30mins if first infusion tolerated.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or ALT >5×ULN or total bilirubin >3×ULN, Grade 4 diarrhea or colitis, Grade 4 hypophysitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre or meningoencephalitis, Grade 3/4 ocular inflammatory toxicity, Grade 4 or recurrent pancreatitis, Grade 3/4 infusion-related reactions, or Grade 4 rash. Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5–3×ULN, Grade 2/3 diarrhea or colitis, symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, Grade 3/4 hyperglycemia, Grade 2 ocular inflammatory toxicity, Grade 2/3 pancreatitis or Grade 3/4 increases in amylase or

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DRUG MONOGRAPHS

GENITOURINARY CANCER lipase levels (>2×ULN), Grade 3/4 infection, Grade 2 infusion-related reactions, or Grade 3 rash; may be resumed when recover to Grade 0–1. Monitor for immune-related pneumonitis, hepatitis (obtain AST, ALT, bilirubin prior to and during treatment), diarrhea/colitis, endocrinopathies (hypophysitis, thyroid function, adrenal insufficiency, diabetes), meningitis or encephalitis, motor and sensory neuropathy, and acute pancreatitis; see full labeling for adverse reaction management details.

Monitor for signs/symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Pregnancy.

Use effective contraception during and for ≥5 months after final dose. Nursing mothers: not recommended (during and for ≥5 months after final dose).

Adverse reactions: Fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, constipation; immune-related reactions, lab abnormalities.

How supplied: Single-dose vial (20mL)—1

TRELSTAR Allergan

℞

GnRH analogue. Triptorelin pamoate 3.75mg, 11.25mg, 22.5mg; lyophilized microgranules for IM inj after reconstitution; contains mannitol.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Give by IM inj in buttock. 3.75mg every 4 weeks, or 11.25mg every 12 weeks, or 22.5mg every 24 weeks.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Not for use in women.

Must administer under physician supervision.

Discontinue if hypersensitivity occurs. Initial transient increase in serum testosterone may result in worsening of signs/symptoms including bone pain, neuropathy, hematuria, or urethral/bladder obstruction. Spinal cord compression. Renal or hepatic impairment. Metastatic vertebral lesions. Upper or lower urinary tract obstruction.

May prolong QT/QTc interval in patients with congenital long QT syndrome, CHF, frequent electrolyte abnormalities. Correct any electrolyte abnormalities; monitor ECGs and electrolytes periodically. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and/or HbA1c, and for signs/symptoms of cardiovascular disease. Measure serum testosterone periodically.

Nursing mothers: not recommended.

Interactions: Concomitant hyperprolactinemic drugs: not recommended. Avoid concomitant drugs that are known to prolong the QT interval. May interfere with pituitary gonadotropic function tests.

Adverse reactions: Inj site reactions, hot flushes, skeletal pain, impotence, headache, leg edema/pain, erectile dysfunction, testicular atrophy; hyperglycemia.

How supplied: Single-dose vial—1; MixJect system—1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free.

Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void.

Children: Not recommended.

Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation).

Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised. Delay administration for at least 2 weeks after transurethral resection and/or fulguration. Maintain adequate hydration.

Pregnancy (Cat. C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended.

Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI).

How supplied: Single-use vials—4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Insert 1 implant SC in the inner aspect of the upper arm. Remove after 12 months; may replace.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X). Nursing mothers. Not for use in women or children.

Warnings/Precautions: Initial transient increase in serum testosterone may result in worsening signs/symptoms (eg, bone pain, neuropathy, hematuria). Metastatic vertebral lesions, urinary tract obstruction (monitor closely in 1st few weeks). Avoid wetting inserted arm for 24hrs and heavy lifting or strenuous exertion for 1st week. Increased risk of developing diabetes; monitor blood glucose and HbA1c periodically; treat if occurs. Increased risk of developing MI, sudden cardiac death, stroke; monitor for signs/symptoms of cardiovascular disease. May prolong QT/QTc interval in patients with congenital long QT syndrome,

CHF, electrolyte abnormalities; monitor ECGs. If electrolyte abnormalities occur, correct and monitor. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray.

Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Hot flashes, fatigue, implant site reactions, testicular atrophy, renal impairment; hyperglycemia, diabetes, cardiovascular disease.

How supplied: Kit—1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Limitation of use: not for treating adipocytic soft tissue sarcoma or gastrointestinal stromal tumors.

Adults: Take on an empty stomach. Swallow whole.

800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended. Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin): avoid and consider alternate drug; if warranted, reduce dose of pazopanib to 400mg; may reduce further if toxicity occurs. Concomitant strong CYP3A4 inducers (eg, rifampin): avoid and consider alternate drug.

Children: Not established.

Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity (esp. ≥65yrs old).

Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3xULN and 8xULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8xULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3xULN recurs, permanently discontinue. Permanently discontinue if ALT>3xULN and bilirubin >2xULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk (including previous anthracycline exposure): evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid function. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended).

Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, interstitial lung disease (ILD)/pneumonitis, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, serious infection, ILD or pneumonitis occurs.

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DRUG MONOGRAPHS

GENITOURINARY CANCER Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence.

Embryo-fetal toxicity. Pregnancy: exclude status prior to starting. Females of reproductive potential must use effective contraception and males (use condoms) during therapy and for ≥2 weeks after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors.

Antagonized by strong CYP3A4 inducers.

Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops. Avoid concomitant drugs that raise gastric pH (eg, PPIs, H2-blockers). Separate antacids by several hours.

Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics).

Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatotoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, ILD/pneumonitis, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs).

How supplied: Tabs—120

XOFIGO Bayer

℞

Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection.

Indications: Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections.

Children: <18yrs: not established.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat. X).

Warnings/Precautions: Not for use in women.

Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose.

Before 1st dose, the ANC should be ≥1.5 X 109/L, platelets ≥100 X 109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 X 109/L and platelets ≥50 X 109/L; discontinue if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely

if evidence of compromised bone marrow reserve.

Discontinue if life-threatening complications occur despite supportive care for bone marrow failure. Monitor oral intake and fluid status carefully. Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended.

Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with chemotherapy, other systemic radioisotopes or hemibody external radiotherapy.

Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia.

How supplied: Single-use vials (6mL)—1

XTANDI Astellas

℞

Androgen receptor inhibitor. Enzalutamide 40mg; soft gelatin caps.

Indications: Treatment of metastatic castrationresistant prostate cancer.

Adults: Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable side effect: withhold dosing for 1 week or until symptoms improve to ≤Grade 2, then resume at same or reduced dose (120mg or 80mg), if warranted. Concomitant strong CYP2C8 inhibitors: avoid if possible. If co-administration necessary, reduce enzalutamide dose to 80mg once daily; if inhibitor is discontinued, return enzalutamide dose to the dose used prior to initiation of inhibitor.

Children: Not established.

Contraindications: Pregnancy.

Warnings/Precautions: Risk of seizure; permanently discontinue if develops during treatment. Severe renal or hepatic impairment.

Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP2C8 inhibitors (eg, gemfibrozil) if possible; reduce enzalutamide dose if cannot be avoided.

Avoid concomitant CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin), and St. John’s Wort if possible.

Potentiated by CYP3A4 inhibitors (itraconazole).

Antagonizes midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid concomitant drugs with narrow therapeutic indexes metabolized

by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), CYP2C19 (eg, S-mephenytoin); enzalutamide may decrease their exposure. Caution with concomitant drugs that may lower the seizure threshold. Conduct more INR monitoring if concomitant warfarin cannot be avoided.

Adverse reactions: Asthenia/fatigue, back pain, decreased appetite, constipation,

arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, dizziness/vertigo.

How supplied: Caps—120

ZYTIGA Janssen Biotech

℞

CYP17 inhibitor. Abiraterone acetate 250mg, 500mg; tabs.

Indications: In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.

Adults: Take on empty stomach (no food ≥2hrs before or ≥1hr after administration). Swallow whole with water. 1g once daily (in combination with prednisone 5mg twice daily). Moderate hepatic impairment (Child-Pugh Class B): 250mg once daily; monitor frequently. If hepatotoxicity occurs: interrupt, then restart at reduced dose; discontinue if severe (see full labeling). If concomitant strong CYP3A4 inducer necessary, increase abiraterone dose frequency to twice daily during co-administration period (eg, from 1g once daily to 1g twice daily); reduce back to previous dose/frequency when CYP3A4 inducer is discontinued.

Children: Not recommended.

Contraindications: Pregnancy (Cat.X). Women who may become pregnant.

Warnings/Precautions: Risk of mineralocorticoid excess: patients with history of cardiovascular disease, LVEF <50%, Class II-IV heart failure, recent MI, ventricular arrhythmias.

Monitor BP, serum potassium, and for fluid retention monthly. Control hypertension and correct hypokalemia before and during treatment.

Monitor for adrenocortical insufficiency. Stress (may need higher corticosteroid dose). Baseline severe hepatic impairment (Child-Pugh Class C); avoid. Monitor liver function (ALT/AST, bilirubin) prior to starting treatment, every 2 weeks for the first 3 months, and monthly thereafter; interrupt, reduce dose, or discontinue if hepatotoxicity occurs. Permanently discontinue if concurrent ALT elevation >3xULN and total bilirubin >2xULN develops without biliary obstruction or other causes of elevation. Nursing mothers: not recommended.

Interactions: CYP2D6 substrates with narrow therapeutic index (eg, thioridazine); avoid.

Potentiates dextromethorphan. May affect, or be affected by, strong inhibitors or inducers of CYP3A4; avoid or use caution. Concomitant CYP2C8 substrates: monitor closely for signs of toxicity.

Adverse reactions: Joint swelling or discomfort, hypokalemia, edema, myalgia, hot flush, GI upset, UTI, cough, hypertension, arrhythmias, urinary frequency, nocturia, URI, adrenocortical insufficiency, hepatotoxicity.

Note: Pregnant women and those of childbearing potential should not handle Zytiga tablets without protection (eg, gloves). Partners must use appropriate barrier contraception.

How supplied: Tabs 250mg—120; 500mg—60

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CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Head and Neck Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Squamous Cell Cancers1,a Principle of Systemic Therapy Systemic therapy should be individualized based on patient characteristics (performance status, goals of therapy).

Note: All recommendations are category 2A unless otherwise indicated.

REGIMEN

DOSING

Primary Systemic Therapy + Concurrent Radiotherapy1 High-dose cisplatin (preferred; Category 1)2,3

Days 1, 22, and 43: Cisplatin 100mg/m2 IV + concurrent radiotherapy 2Gy/day to a total of 70Gy.

Cetuximab (Category 1 for Day 1: Cetuximab 400mg/m2 loading dose over 2 hours, 1 week before radiotherapy, plus oropharynx, hypopharynx, or larynx; Day 7: Begin radiotherapy with 7 weekly infusions of cetuximab 250mg/m2.

Category 2B for lip, oral cavity, ethmoid sinus, maxillary sinus, occult primary)4 Carboplatin + infusional 5-FU (Category 1)5,6

Days 1–4: 5-FU 600mg/m2/day as continuous IV infusion for 4 days + carboplatin 70mg/m2/day IV bolus.

Repeat every 3 weeks for 3 cycles (given concurrently with radiotherapy).

5-FU + hydroxyurea7

Day 1: Hydroxyurea 1,000mg orally every 12 hours (11 doses/cycle) + 5-FU 800mg/m2/day continuous IV infusion, plus radiotherapy: 70Gy, delivered in 35 fractions; 1 fraction delivered daily Monday–Friday.

Concurrent radiotherapy and chemotherapy every other week for total treatment duration of 13 weeks.

Cisplatin + paclitaxel7

Day 1: Paclitaxel 30mg/m2 IV (every Monday), plus Day 2: Cisplatin 20mg/m2 IV (every Tuesday).

Repeat cycle every week for 7 cycles, plus radiotherapy: 70Gy, delivered in 35 fractions; 1 fraction delivered daily Monday–Friday.

Cisplatin + infusional 5-FU8

Day 1: Cisplatin 60mg/m2 over 15 minutes; plus Days 1–5: 5-FU 800mg/m2/day by continuous infusion for 5 days; plus Days 1–5: Radiotherapy: 2Gy repeated every other week for 7 cycles.

Carboplatin + paclitaxel (Category 2B)9

Day 1: Paclitaxel 40–45mg/m2/week and carboplatin 100mg/m2/week; prior to radiotherapy: 70.2Gy at 1.8Gy/fraction/day for 5 days/week.

Weekly cisplatin (Category 2B)10,11

Day 1–28: Cisplatin 40mg/mg2 IV over 30 minutes weekly; plus Days 1–38: Radiotherapy (5 fractions/week): 1.8Gy single dose (up to total dose of 50.4Gy); plus Days 22–38: Boost radiotherapy: 1.5Gy/day (up to 19.5Gy) in addition to regular dose. Booster doses to be given at least 6-hours after regular dose (total tumor dose of 69.9Gy).

OR Day 1–28: Cisplatin 40mg/mg2 IV weekly; plus Days 1–40: Radiotherapy: five fractions of 1.8Gy/week (up to total dose of 54Gy); plus Days 25–40: Boost radiotherapy: 1.5Gy/day (up to 19.5Gy) in addition to regular dose. Booster doses to be given at least 6-hours after regular dose.

Primary Chemotherapy With Postoperative Chemoradiation1 Cisplatin (Category 1 for high-risk non-oropharyngeal cancers)12–16

Days 1, 22, and 43: Cisplatin 100mg/m2 IV + radiotherapy.

Induction Chemotherapyb/Sequential Chemotherapy1, c Docetaxel + cisplatin + 5-FU (Category 1 if induction is chosen)17-19

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV, plus Days 1–5: 5-FU 750mg/m2/day continuous IV infusion for 5 days.

Repeat every 3 weeks for up to 4 cycles.

22 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Squamous Cell Cancers1,a REGIMEN

DOSING

Induction Chemotherapy /Sequential chemotherapy1, c b

Paclitaxel + cisplatin+ infusional 5-FU20,d

Day 1: Paclitaxel 175mg/m2 over 3 hours Day 2: Cisplatin 100mg/m2; plus Day 2–6: 5-FU 500mg/m2/day continuous IV infusion for 5 days.

Repeat every 3 weeks for 3 cycles.

Nasopharynx Cancer1 Chemoradiation Followed by Adjuvant Chemotherapy1 Cisplatin + radiotherapy + cisplatin + 5-FU21,22

Cycles 1–3 Day 1: Cisplatin 100mg/m2 IV; plus radiotherapy.

Repeat cycle every 3 weeks; followed by Cycles 4–6 Days 1: Cisplatin 80mg/m2 IV over 1 hour plus Days 1-4: 5-FU 1,000mg/m2 continuous IV infusion daily.

Repeat cycle every 4 weeks for 3 cycles.

Carboplatin + radiotherapy + carboplatin + 5-FU (Category 2B)23

Cycles 1–3 Day 1: Carboplatin AUC 6mg·min/mL IV over 1 hour; plus radiotherapy: 200cGy/fraction with 5 daily fractions/week (to a total dose of 6600–7000cGy).

Repeat cycle every 3 weeks for 3 cycles; followed by Cycles 4–6 Day 1: Carboplatin AUC 5mg·min/mL IV over 1 hour Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion over 24 hours Repeat cycle every 3 weeks for 2 cycles.

Cisplatin + radiotherapy without adjuvant chemotherapy (Category 2B)24

Cisplatin 40mg/m2 weekly for up to 7 weeks, concurrently with radiotherapy at a dose of 2.0 to 2.27Gy per fraction with 5 daily fractions per week for 6 to 7 weeks to a total dose of 66Gy or greater to the primary tumor and 60 to 66Gy to the involved neck area.

Induction Chemotherapyb/Sequential Chemotherapy1,e Docetaxel + cisplatin + 5-FU (Category 1 if induction is chosen)25

Day 1: Docetaxel 70mg/m2 IV over 1 hour and cisplatin 75mg/m2 IV over 3 hours; followed by Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion for 4 days.

Repeat every week for 3 cycles; followed by Cisplatin 100mg/m2; plus radiotherapy: 5 daily fractions of 1.8 or 2Gy/ day (total dose of 68.4Gy) Repeat every 3 weeks.

Docetaxel + cisplatin (Category 2B)26

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV every 3 weeks for two cycles, followed by Cisplatin 40mg/m2 IV weekly concurrent with radiotherapy.

Cisplatin + 5-FU18

Day 1: Cisplatin 100mg/m2/day IV. Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion for 4 days.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

Cisplatin + epirubicin + paclitaxel

This regimen was included in the NCCN guidelines but no reference was provided to indicate appropriate dosage.

Following induction, agents to be used with concurrent chemoradiation typically include weekly cisplatin or carboplatin.22,50 Principles of Systemic Therapy1 • The choice of systemic therapy should be individualized based on patient characteristics (performance status, goals of therapy).

• Unless otherwise specified, regimens listed below can be used for either nasopharyngeal or non-nasopharyngeal cancer.

Combination Therapy for Recurrent, Unresectable, or Metastatic Disease (With No Surgery or RT Option)1 Cisplatin or carboplatin + 5-FU + cetuximab (Category 1)27 (non-nasopharyngeal)

Day 1: Cisplatin 100mg/m2 IV or carboplatin AUC 5mg·min/mL 1 hour IV infusion, plus Day 1: Cetuximab 400mg/m2 IV over 2 hours (initial dose), followed by 250mg/m2 IV over 1 hour once weekly Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion for 4 days.

Repeat cycle every 3 weeks for a maximum of 6 cycles.

Cisplatin or carboplatin + docetaxel28 Day 1: Docetaxel 75mg/m2 IV over 1 hour; followed immediately by cisplatin 75mg/m2 IV. OR Day 1: Docetaxel 65mg/m2 IV over 1 hour; followed immediately by carboplatin AUC 6mg·min/mL IV. Repeat cycle every 3 weeks. continued

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CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Head And Neck Cancer Treatment Regimens Nasopharynx Cancer1 (continued) REGIMEN

DOSING

Combination Therapy for Recurrent, Unresectable, or Metastatic Disease (With No Surgery or RT Option)1 (continued) Cisplatin or carboplatin + paclitaxel29 Day 1: Cisplatin 75mg/m2/day IV + paclitaxel 175mg/m2 IV over 3 hours.

OR Day 1: Carboplatin AUC 6mg·min/mL IV + paclitaxel 200mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

Cisplatin + cetuximab30 (non-nasopharyngeal)

Day 1: Cetuximab 200mg/m2 IV over 120 minutes for 1 cycle, then cetuximab 125mg/m2/week IV over 60 minutes for subsequent cycles Repeat once weekly, plus Day 1: Cisplatin 100mg/m2 IV. Repeat every 4 weeks.

Cisplatin + 5-FU29,31

Day 1: Cisplatin 100mg/m2/day IV Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion for 4 days.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

Cisplatin or carboplatin + docetaxel + Day 1: Cisplatin 75mg/m2 IV or carboplatin 5mg·min/mL IV cetuximab32 (non-nasopharyngeal) Day 1: Docetaxel 75mg/m2 IV + cetuximab (400mg/m2 on day 1 of cycle 1, then 250mg/m2 weekly).

Repeat cycle every 21 days for 4 cycles, followed by cetuximab 500mg/m2 IV every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity.

Cisplatin or carboplatin + paclitaxel + Day 1: Cisplatin 75 or 100mg/m2 IV or carboplatin AUC 6mg·min/mL IV cetuximab33,34 (non-nasopharyngeal) Day 1: Paclitaxel 175mg/m2 IV. Repeat every 3 weeks for 2 cycles, followed by Day 1: Cisplatin 75 or 100mg/m2 IV or carboplatin AUC 6mg·min/mL every 3 weeks + cetuximab (400mg/m2 IV on day 1, then 250mg/m2 weekly) for 4 cycles.

Carboplatin + cetuximab35 (nasopharyngeal)

Day 1: Cetuximab initial dose of 400mg/m2 IV over 2 hours; followed by weekly doses of cetuximab 250mg/m2 IV over 1 hour; followed by carboplatin AUC 5mg·min/mL IV. Repeat every 3 weeks for a maximum of 8 cycles.

Cisplatin + gemcitabine36 (nasopharyngeal)

Days 1 and 8: Gemcitabine 1,000mg/m2 IV Days 1–3: Cisplatin 80mg/m2 IV in divided doses.

Repeat cycle every 3 weeks.

Gemcitabine + vinorelbine40 (nasopharyngeal)

Day 1 and 8: Vinorelbine 25mg/m2 IV; followed by gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat every 3 weeks.

Single Agents for Recurrent, Unresectable, or Metastatic Disease (With No Surgery or RT Option)1 Cisplatin30,38

Day 1: Cisplatin 100mg/m2 IV over 15–20 minutes.

Repeat every 3–4 weeks.

Carboplatin39

Day 1: 25mg/m2 daily followed by radiotherapy: 5 daily fractions of 1.8 or 2Gy.

Paclitaxel40

Day 1: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat every 6 weeks.

Docetaxel41,42

Day 1: Docetaxel 40–100mg/m2 IV over 1 hour.

Repeat every 3 weeks.

5-FU38

Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion for 4 days.

Repeat every 3 weeks.

Methotrexate31,43

Day 1: Methotrexate 40mg/m2 IV weekly, with progressive increase to 60mg/m2, if tolerated.

Cetuximab (non-nasopharyngeal)

Day 1: Cetuximab 400mg/m2 over 2 hours as a loading dose (including a 20mg test dose); followed by cetuximab 250mg/m2 IV over 1 hour weekly.

Repeat for at least 6 weeks. If treatment response or stable disease, continue until progressive disease or unacceptable toxicity.

Gemcitabine45 (nasopharyngeal)

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat every 4 weeks.

Capecitabine46

Days 1–14: Capecitabine 1250mg/m2 orally twice daily; followed by a 1-week rest period.

Repeat every 3 weeks for at least two cycles.

44

24 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Nasopharynx Cancer1 (continued) REGIMEN

DOSING

Single Agents for Recurrent, Unresectable, or Metastatic Disease (With No Surgery or RT Option)1 (continued) Afatinib (Category 2B)47,f (non-nasopharyngeal; second-line)

Day 1: Afatinib 40 mg orally daily until disease progression or unacceptable toxicity.

Pembrolizumab51,52,f (non-nasopharyngeal)

Day 1: Pembrolizumab 10mg/kg IV. Repeat cycle every 2 weeks.

Nivolumab (Category 1)53,f (non-nasopharyngeal)

Day 1: Nivolumab 3mg/kg IV. Repeat cycle every 2 weeks.

c

d

Includes lip, oral cavity, oropharynx, hypopharynx, glottic larynx, supraglottic larynx, ethmoid sinus, maxillary sinus, occult primary.

Induction chemotherapy should only be done in a tertiary setting.

Following induction, agents to be used with concurrent chemoradiation typically include weekly carboplatin or cetuximab.48-50 Patients with complete partial response of greater than 80% in primary tumor received additional chemoradiation therapy (ie, cisplatin 100mg/m2 on days 1, 22, and 43 plus 70Gy). Radiotherapy was administered in 35 fractions of 2Gy each over a 7-week period. e Following induction, agents to be used with concurrent chemoradiation typically include weekly cisplatin22 or carboplatin.48 f If disease progression on or after platinum-containing chemotherapy. a

b

References 1. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™.

Bladder Cancer. v 2.2017. Available at: http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed December 26, 2017.

2. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol.

2003;21(1):92–98.

3. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845–852.

4. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomized trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010; 11(1):21–28.

5. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.

J Clin Oncol. 2004;22(1):69–76.

6. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13(2):145–153.

7. Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol. 2004;22(14):2856–2864.

8. Taylor 5, Murthy A, Vannetzel J, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol. 1994;12(2):385–395.

9. Suntharalingam M, Haas ML, Conley BA, et al. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2000;47:49–56.

10. Beckmann GK, Hoppe F, Pfreundner L, et al. Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer. Head Neck. 2005;27(1):36–43.

11. Medina JA, Rueda A, de Pasos AS, et al. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas. Radiother Oncol. 2006;79(1):34–38.

12. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N EngI J Med. 2004;350(19): 1937–1944.

13. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

concomitant chemotherapy for locally ­advanced head and neck cancer. N EngI J Med. 2004;350(19):1945–1952.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843–850.

Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined post­operative radiotherapy and weekly cisplatin infusion for locally ­advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996;36(5):999–1004.

Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck.

Int J Radiat Oncol Biol Phys. 2012;84(5):1198–1205.

Vermorken JB, Remenar E, van Herpen C, et al; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.

N EngI J Med. 2007;357(17):1695–1704.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N EngI J Med. 2007;357(17):1705–1715.

Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation.

J NatI Cancer Inst. 2009;101(7):498–506.

Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005;23(34):8636–8645.

Al-Sarraf M, LeBlanc M, Gin PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasophanyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16(4):1310–1317.

Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J NatI Cancer Inst. 2005;97(7):536–539.

Dechaphunkul T, Pruegsanusak K, Sangthawan D, et al. Concurrent chemoradiotherapy with carboplatin followed by carboplatin and 5-fluorouracil in locally advanced nasopharyngeal carcinoma. Head Neck Oncol. 2011;3:30.

Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012;13:163–171.

Bae WK, Hwang JE, Shim HJ, et al. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. Cancer Chemother Pharmacol. 2010;65(3):589–595.

Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of concurrent cisplatin-

continued

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CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Head And Neck Cancer Treatment Regimens References (continued)

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27(2):242–249.

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–1127.

Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of docetaxel/carboplatin in patients with meta- static or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest. 2007;25(3):182–188.

Gibson MK, Li Y, Murphy B, et al. Eastern Cooperative Oncology Group. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23(15): 3562–3567.

Burtness B, Goldwasser MA, Flood W, et al. Eastern Cooperative Oncology Group.

Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23(34):8646–8654. Erratum in: J Clin Oncol. 2006;24(4):724.

Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus flurouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol. 1992;10(8):1245–1251.

Guigay J, Fayette J, Dillies AF, et al. Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study. Ann Oncol. 2015;26(9): 1941–1947.

Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005; 23(24):5578–5587.

Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol. 2012; 13(1):35–46.

Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol. 2005;23(15):3568–3576.

Jin Y, Cai XY, Shi YX, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 2012;138(10):1717–1725.

Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol. 2012;48(11):1146–1151.

Jacobs C, Lyman G, Velez-GarcIa E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;1O:257–263.

Al-Sarraf M, Metch B, Kish J, et al. Platinum analogs in recurrent and advanced head and neck cancer: a Southwest Oncology Group and Wayne State University Study. Cancer Treat Rep. 1987;71(7-8):723–726.

Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol. 2009;129(11):1294–1299.

41. Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol. 1994;5(6):533–537.

42. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer. 2004;40(14):2071–2076.

43. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009;27(11):1864–1871. Erratum in: J Clin Oncol.

2009;27(20):3410.

44. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol.

2007;25(16):2171–2177.

45. Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2008;61(1):33–38.

46. Martinez-Trufero J, Isla D, Adansa JC, et al. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer.2010;102(12):1687–1691.

47. Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUXHead & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol.

2015;16(5):583–594.

48. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer. 2007;43(9):1399–1406.

49. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14(3):257–264.

50. Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol. 2013;31(7):853–859.

51. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol.

2016;17:956-965.

52. Chow LQ, Hadded R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort.

J Clin Oncol. 2016.

53. Ferris R, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856-1867.

(Revised 1/2018) © 2018 by Haymarket Media, Inc.

Clinical Treatment Regimens Visit Cancer Therapy Advisor and review disease-specific treatment regimens that outline the most up-to-date therapeutic strategies based on guidance from the US Food and Drug Administration and the National Comprehensive Cancer Network.

Review all regimens at www.CancerTherapyAdvisor.com/TreatmentRegimens.

26 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

DRUG MONOGRAPHS

HEAD AND NECK CANCER ERBITUX Lilly

℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: In combination with radiation therapy for treating locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). In combination with platinum-based therapy with 5-fluorouracil (5-FU) for first-line treatment of recurrent locoregional disease or metastatic SCCHN. As a single agent for recurrent or metastatic SCCHN after failure of prior platinum-based therapy.

Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour. Combination therapy: Give initial dose 1 week prior to initiation of radiation therapy. Complete administration 1 hour prior to platinum-based therapy with 5-FU. Give subsequent weekly dose for duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity. Permanently reduce infusion rate by 50% if Grade 1 or 2 and nonserious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr post-infusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for serious infusion reactions; immediately interrupt and permanently discontinue if occur. Risk of cardiopulmonary arrest and/or sudden death; carefully consider use (w. irradiation or platinumbased therapy with 5-FU) in coronary artery disease, CHF, or arrhythmias. Monitor electrolytes (eg, magnesium, potassium, calcium) during and for ≥8wks after cetuximab therapy. Interrupt for acute onset or worsening pulmonary symptoms; permanently discontinue if interstitial lung disease confirmed. Monitor for dermatologic toxicities (eg, acneiform rash) and infection; avoid sun exposure. Additive cutaneous reactions with irradiation. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin.

Adverse reactions: Cutaneous reactions (eg, rash, pruritus, nail changes), headache, diarrhea, infection; infusion reactions (may be severe), cardiopulmonary arrest, interstitial lung disease, dermatologic toxicities, electrolyte abnormalities (eg, hypomagnesemia), sepsis, renal failure, pulmonary embolus.

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb Antimetabolite. Hydroxyurea 500mg; caps.

Indications: Adjunct with irradiation therapy in locally advanced squamous cell

℞

carcinomas of the head and neck, excluding the lip.

Adults: Base dose on ideal or actual weight, whichever is less. Individualize. Initially 15mg/kg/day. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of severe myelosuppression; reduce dose or discontinue if necessary. Monitor blood counts at baseline and at least once a week during therapy. Correct severe anemia before starting. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Previous irradiation therapy (monitor for skin erythema) or chemotherapy. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment. Elderly.

Embryo-fetal toxicity. Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy.

Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays.

Adverse reactions: Leukopenia, thrombocytopenia, anemia, GI upset, anorexia; secondary malignancies, macrocytosis.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free.

Indications: Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinumcontaining chemotherapy.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 develops. Monitor

for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops.

Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity.

Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose.

Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinumbased therapy.

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DRUG MONOGRAPHS

HEAD AND NECK CANCER Adults: Give as IV infusion over 30mins.

3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5xULN (non-HCC) or AST/ALT >10xULN (HCC) or total bilirubin >3xULN, SCr >6xULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, Grade 3 myocarditis, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5xULN or total bilirubin >1.5–3xULN, SCr >1.5–6xULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD,

steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI, pyrexia, headache, abdominal pain; also with ipilimumab: vomiting; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL, 24mL)—1

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Epidermoid cancers of the head and neck.

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat. X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor

hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer.

Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, nonabsorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, StevensJohnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

<2

2–3

>3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

INTERPRETATION OF CHILD-PUGH SCORES Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

28 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

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CANCER TREATMENT REGIMEN

LUNG CANCER Small Cell Lung Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Small Cell Lung Cancer (SCLC) Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Principles of Systemic Therapy Response Assessment for Limited-stage • For patients receiving adjuvant therapy, response assessment should occur only after completion of adjuvant therapy; do not repeat scans to assess response during adjuvant treatment.

• For patients receiving systemic therapy + concurrent radiotherapy, response assessment should only occur after completion of initial therapy; do not repeat scans to assess response during initial treatment.

• For patients receiving systemic therapy alone or sequential systemic therapy followed by radiotherapy, response assessment by chest/abdomen CT with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy.

Response Assessment for Extensive-stage • During systemic therapy, response assessment by chest/abdomen CT with contrast should occur every 2–3 cycles of systemic therapy and at completion of therapy.

• For patients with asymptomatic brain metastases receiving systemic therapy before whole-brain radiotherapy, brain MRI (preferred) or CT with contrast should be repeated after every 2 cycles of systemic therapy and at completion of therapy.

Response Assessment of Subsequent Systemic therapy • Response assessment by chest/abdomen CT with contrast should occur after every 2–3 cycles of systemic therapy.

Systemic Therapy as Primary or Adjuvant Therapy1,a Limited Stage (maximum of 4–6 cycles)1,b,c Cisplatin + etoposide2,3

Day 1: Cisplatin 60mg/m2 IV Days 1–3: Etoposide 120mg/m2 IV. Repeat cycle every 3 weeks for at least 4 cycles.

OR Day 1: Cisplatin 80mg/m2 IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Carboplatin + etoposide4

Day 1: Carboplatin AUC 5–6mg • min/mL IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

Extensive Stage (maximum of 4–6 cycles)1 Carboplatin + etoposide5

Day 1: Carboplatin AUC 5–6mg • min/mL IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Cisplatin + etoposide6-8

Day 1: Cisplatin 75mg/m2 IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

OR Day 1: Cisplatin 80mg/m2 IV Days 1–3: Etoposide 80mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

OR Days 1–3: Cisplatin 25mg/m2 IV + etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4-6 cycles.

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CANCER TREATMENT REGIMEN

LUNG CANCER Small Cell Lung Cancer Treatment Regimens Small Cell Lung Cancer (SCLC) (continued) REGIMEN

DOSING

Extensive Stage (maximum of 4–6 cycles)1,d (continued) Carboplatin + irinotecan9

Day 1: Carboplatin AUC 5mg • min/mL IV Days 1, 8, and 15: Irinotecan 50mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Cisplatin + irinotecan10,11

Day 1: Cisplatin 60mg/m2 IV Days 1, 8, and 15: Irinotecan 60mg/m2 IV. Repeat cycle every 4 weeks for 4 cycles.

OR Day 1 and 8: Cisplatin 30mg/m2 IV + irinotecan 65mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

Subsequent Systemic Therapy1,e Relapse ≤6 months, PS 0-21 Topotecan12-14

Days 1–5: Topotecan 1.5mg/m2 IV daily over 30 minutes.

Repeat cycle every 3 weeks.

OR Days 1–5: Topotecan 2.3mg/m2 orally once daily.

Repeat cycle every 3 weeks.

Irinotecan15

Day 1: Irinotecan 100mg/m2 IV over 90 minutes.

Repeat cycle every week.

Paclitaxel16,17

Day 1: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat every week for 6 weeks, followed by a 2-week break.

Docetaxel18

Day 1: Docetaxel 100 mg/m2 IV over 1 hour.

Repeat cycle every 3 weeks.

Temozolomide19,20

Day 1–21: Temozolomide 75mg/m2 orally.

Repeat cycle every 4 weeks.

Nivolumab ± ipilimumab21,22

Day 1: Nivolumab 3mg/kg IV. Repeat cycle every 2 weeks until disease progression or unacceptable toxicity.

OR Day 1: Nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV. Repeat cycle every 3 weeks for 4 cycles, followed by nivolumab 3mg/kg IV every 2 weeks.

OR Nivolumab 3mg/kg IV + ipilimumab 1mg/kg IV. Repeat cycle every 3 weeks for 4 cycles, followed by nivolumab 3mg/kg IV every 2 weeks.

Vinorelbine23,24

Day 1: Vinorelbine 25–30mg/m2 IV. Repeat cycle every week.

Etoposide25,26

Day 1–21: Etoposide 50mg/m2 orally.

Repeat cycle every 4 to 5 weeks.

Gemcitabine27,28

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV. Repeat cycle every 4 weeks.

Cyclophosphamide + doxorubicin + vincristine (CAV)12

Day 1: Cyclophosphamide 1,000mg/m2 IV + doxorubicin 45mg/m2 IV + vincristine 2mg IV. Repeat cycle every 3 weeks.

Bendamustine (Category 2B)29

Days 1 and 2: Bendamustine 120mg/m2 IV. Repeat cycle every 3 weeks for up to 6 cycles.

Relapse >6 months1 • Original regimen29,30 The regimens included are representative of the more commonly used regimens for small cell lung cancer.

Other regimens may be acceptable. b During systemic therapy + radiotherapy, cisplatin/etoposide is recommended (category 1). c The use of myeloid growth factors is not recommended during concurrent systemic therapy plus radiotherapy (category 1 for not using GM-CSF).32 d If not used as original regimen, may be used as therapy for primary progressive disease. e Subsequent systemic therapy refers to second-line and beyond therapy. a

30 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

LUNG CANCER References 1.

2.

3.

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12.

13.

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15.

Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™ Small Cell Lung Cancer. v 2.2018. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/sclc.pdf. Accessed January 12, 2018.

Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265–271.

Saito H, Takada Y, Ichinose Y, et al. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol. 2006;24(33): 5247–5252.

Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2001;12(9):1231–1238.

Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small cell lung cancer. J Clin Oncol.

1999;17(11): 3540–3545.

Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011;29:2215–2222.

Niell HB, Herndon JE, Miller AA, et al. Randomized phase III Intergroup trial of etoposide with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol. 2005;23:3752–3759.

Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985;3(11): 1471–1477.

Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol. 006;17:663–667.

Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002; 346(2):85–91.

Hanna N, Bunn Jr. PA, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24(13):2038–2043. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658–667.

O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441–5447.

Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol.

2007;25(15):2086–2092.

Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin

16.

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for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol.

1992; 10:1225–1229.

Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer. 1998;77:347–351.

Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res. 2006;26: 777–781.

Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. Eur J Cancer. 1994; 30A:1058–1060.

Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res. 2012;18:1138–1145.

Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase. Lung Cancer. 2014;86:237–240.

Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label phase 1/2 trial. Lancet Oncol. 2016;17:883–895.

Hellmann MD, Ott PA, Zugazagoitia J, et al. First report of a randomized expansion cohort from CheckMate 032 [abstract]. J Clin Oncol. 2017;35: Abstract 8503.

Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. Eur J Cancer. 1993;29A: 1720–1722.

Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Oncology. 1996;53:169–172.

Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer. Semin Oncol. 1990;17:32–35.

Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol. 1990; 8:1613–1617.

Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol. 2001;12:557–561.

Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer. J Clin Oncol. 2003;21:1550–1555.

Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol.

2014;9:559–562.

Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987;23:1409–1411.

Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol. 1987;23: 1697–1699.

Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol. 1995;13:1632–1641.

(Revised 1/2018) © 2018 by Haymarket Media, Inc.

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CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR 31

DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 mins on Days 1, 8, and 15 of each 21-day cycle.

Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5XULN or AST >10XULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis. Renal dysfunction.

Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/ asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

ALECENSA Genentech

℞

Kinase inhibitor. Alectinib 150mg; caps.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Adults: Swallow whole. Take with food.

600mg twice daily until disease progression or unacceptable toxicity. Dose modifications or dose reduction schedule: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor liver function tests (eg, ALT, AST, total bilirubin) every 2 weeks

℞

Children: Not established.

Warnings/Precautions: See full labeling.

Increased risk of myelosuppression without vitamin supplementation. Permanently discontinue if Grade 3 or 4 neurologic toxicity, recurrent Grade 3 or 4 non-hematologic toxicity after two dose reductions, severe/life-threatening skin toxicity, interstitial pneumonitis, or signs of radiation recall occur. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min.

Monitor CBCs, platelets, renal and hepatic function. Renal impairment (CrCl <45mL/min).

Severe third space fluid. Embryo-fetal toxicity.

Pregnancy; avoid. Use effective contraception during treatment and for 6 months (females) or 3 months (males) after final dose. Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Increased risk of toxicity with concomitant ibuprofen in renal impairment (CrCl 45–79mL/min): avoid for 2 days before, the day of, and 2 days following pemetrexed dose; if unavoidable, monitor more frequently for effects.

Adverse reactions: Fatigue, nausea, anorexia, vomiting, fatigue, stomatitis/pharyngitis, constipation, rash/desquamation, neutropenia, anemia, thrombocytopenia, elevated creatinine, sensory neuropathy; rare: renal failure.

Testing considerations: TS (thymidylate synthase) expression for response and toxicity.

How supplied: Single-use vial—1

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free.

Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of platinum-based 1st-line chemotherapy, as a single agent. Treatment of patients with recurrent, metastatic nonsquamous, NSCLC after prior chemotherapy, as a single agent. Limitations of use: not for the treatment of squamous cell NSCLC. Malignant pleural mesothelioma (MPM): in combination with cisplatin, for the initial treatment of patients whose disease is either unresectable or who are otherwise not candidates for curative surgery.

Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle. Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion.

Supplement with oral folic acid and intramuscular vitamin B12 one week prior to 1st pemetrexed dose, continue during treatment, and for 21 days after the last dose. Pretreat with dexamethasone for 3 consecutive days, beginning the day before each pemetrexed dose. Dose modifications: see full labeling.

Kinase inhibitor. Brigatinib 30mg; tabs.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Adults: Swallow whole. Initially 90mg once daily for first 7 days; if tolerated, increase to 180mg once daily until disease progression or unacceptable toxicity. Dose modifications or dose reduction levels: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms esp. during 1st week of initiation; if occurs, withhold and evaluate for ILD/pneumonitis; resume at same dose for Grade 1 or reduced dose for Grade 2 severity; permanently discontinue for Grade 3/4 or recurrent Grade 1/2 ILD/pneumonitis.

Monitor BP after 2 weeks and at least monthly thereafter; withhold for Grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose upon improvement to Grade 1 severity; consider permanent discontinuation for Grade 4 or recurrent Grade 3 hypertension. Monitor HR and BP regularly; if symptomatic bradycardia occurs, withhold and evaluate any concomitant drugs that are known

for the first 3 months, then monthly and as clinically indicated; test more frequently if transaminase and bilirubin elevated; withhold, resume at reduced dose, or permanently discontinue based on severity. Evaluate if presence of worsening respiratory symptoms; withhold if ILD/pneumonitis diagnosed; permanently discontinue if no other cause identified. Withhold for Grade 3 renal toxicity until recovery to ≤1.5×ULN, then resume at reduced dose; permanently discontinue if Grade 4 occurs.

Monitor HR, BP regularly. If non-life-threatening symptomatic bradycardia occurs, withhold until asymptomatic or HR ≥60bpm; permanently discontinue in case(s) of recurrence or lifethreatening bradycardia if no contributing concomitant medication identified. Assess CPK every 2 weeks for the first month and as clinically indicated; withhold, resume, or reduce dose based on severity. Embryo-fetal toxicity. Pregnancy: avoid. Use effective contraception during and for 1 week (females) or 3 months (males) after final dose. Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Increased bradycardia with concomitant antihypertensives or other drugs known to cause bradycardia.

Adverse reactions: Fatigue, constipation, edema, myalgia, anemia; hepatotoxicity, ILD/pneumonitis, renal impairment, bradycardia, CPK elevation.

How supplied: Caps—240

ALIMTA Lilly

ALUNBRIG Takeda

℞

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DRUG MONOGRAPHS

LUNG CANCER to cause bradycardia; resume at same or reduced dose after resolution; discontinue for life-threatening bradycardia if no contributing concomitant medication identified. Withhold and evaluate for new or worsening visual symptoms of Grade ≥2 severity; resume at reduced doses upon recovery to Grade 1 or baseline; permanently discontinue for Grade 4 visual disturbances. Monitor CPK, lipase, and amylase levels during treatment; withhold for Grade 3/4 elevation; resume at same or reduced dose upon recovery to Grade 1 or baseline.

Assess fasting serum glucose prior to initiation and periodically thereafter; if not adequately controlled with optimal antihyperglycemics, withhold then consider dose reduction, or permanently discontinue based on severity.

Embryo-fetal toxicity. Pregnancy: avoid. Females of reproductive potential should use effective non-hormonal contraception during treatment and for at least 4 months after final dose; males should use effective contraception during treatment and for at least 3 months after final dose. Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan); if unavoidable, reduce Alunbrig dose by ~50%. Avoid grapefruit or grapefruit juice. Avoid concomitant strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin, St. John’s wort).

May reduce efficacy of CYP3A substrates (eg, hormonal contraceptives). Caution with antihypertensives that cause bradycardia.

Adverse reactions: Nausea, diarrhea, fatigue, cough, headache; ILD/pneumonitis, hypertension, bradycardia, visual disturbances, CPK elevation, pancreatic enzyme elevation, hyperglycemia, possible infertility in males.

How supplied: Tabs 30mg—21, 180

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 15mg/kg every 3 weeks with carboplatin/paclitaxel.

Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full

labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event.

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome (PRES), or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, PRES, infusion reactions, ovarian failure, neutropenia, infection.

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: In combination with docetaxel, for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDAapproved therapy for these aberrations prior to initiation.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. 10mg/kg on Day 1 of a 21-day cycle prior to docetaxel; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery; resume based on adequate healing; discontinue if complications develops during therapy until wound is fully healed. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusionrelated reactions.

How supplied: Single-dose vial (10mL, 50mL)—1

GILOTRIF Boehringer Ingelheim

℞

Tyrosine kinase inhibitor. Afatinib 20mg, 30mg, 40mg; tabs.

Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test. Limitations of use: safety and efficacy have not been established in patients whose tumors have resistant EGFR mutations. Treatment of patients with metastatic squamous NSCLC progressing after platinumbased chemotherapy.

Adults: Take on an empty stomach at least 1 hr before or 2 hrs after a meal. 40mg once daily until disease progression or not tolerated. Severe renal impairment (CrCl 15–29mL/min): 30mg once daily. Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the inhibitor.

Concomitant P-gp inducers: increase afatinib daily dose by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the inducer.

Dose modifications: see full labeling.

Children: Not established.

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DRUG MONOGRAPHS

LUNG CANCER Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease (ILD), severe druginduced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, during evaluation of suspected ILD, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Obtain LFTs periodically during treatment. Severe renal or hepatic impairment; monitor and adjust dose (see Adults). Embryo-fetal toxicity. Pregnancy (avoid).

Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: See Adults. Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized by P-gp inducers (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

Adverse reactions: Diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus; bullous/exfoliative skin disorders, ILD, hepatotoxicity, keratitis.

How supplied: Tabs—30

IRESSA AstraZeneca

℞

Tyrosine kinase inhibitor. Gefitinib 250mg; tabs.

Indications: First-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitations of use: not established in metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.

Adults: May disperse tabs in water; drink immediately or give via NG tube. Give 250mg once daily until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling.

Concomitant strong CYP3A4 inducers: increase to 500mg daily; resume at 250mg seven days after discontinuation of the CYP3A4 inducer.

Children: Not established.

Warnings/Precautions: Permanently discontinue if confirmed interstitial lung disease (ILD), severe hepatic impairment, GI perforation, or persistent ulcerative keratitis occurs. Withhold for up to 14 days if acute onset or worsening pulmonary symptoms, NCI CTCAE Grade ≥2 ALT and/or AST elevations, Grade ≥3 diarrhea or skin reactions, or severe or worsening ocular

disorders (including keratitis) occurs. Interrupt or discontinue therapy if severe bullous and exfoliative skin disorders develop. Obtain periodic LFTs. Moderate and severe hepatic impairment; monitor. Use effective contraception during treatment and for at least 2 weeks after completion. Pregnancy, nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole); monitor. Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, tricyclics); see Adults. May be antagonized by drugs that increase gastric pH (eg, H2-blockers, antacids); take gefitinib 6 hours after or 6 hours before an H2-blocker or antacid. Avoid concomitant PPIs; if necessary, take gefitinib 12 hours after last dose or 12 hours before next PPI dose. May potentiate warfarin; monitor INR. Adverse reactions: Skin reactions, diarrhea, vomiting, decreased appetite, stomatitis; ILD, hepatotoxicity, GI perforation, ocular disorders.

Testing considerations: EGFR mutation analysis.

How supplied: Tabs—30

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free.

Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

Treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinumcontaining chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda.

First-line treatment of patients with metastatic nonsquamous NSCLC, in combination with pemetrexed and carboplatin.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In combination with pemetrexed/carboplatin: give prior to chemotherapy when given on the same day (see full labeling). Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade

2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 develops.

Monitor for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity.

Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

MEKINIST Novartis

℞

Kinase inhibitor. Trametinib 0.5mg, 2mg; tabs.

Indications: In combination with dabrafenib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test.

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DRUG MONOGRAPHS

LUNG CANCER Adults: Confirm presence of BRAF V600E mutation prior to initiation. Take at same time each day, at least 1hr before or 2hrs after a meal.

Monotherapy or in combination with dabrafenib: 2mg once daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for dabrafenib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation.

Monitor for non-cutaneous malignancies, pulmonary embolism (permanently discontinue if life-threatening), colitis, GI perforations, skin toxicities and secondary infections. Permanently discontinue for all Grade 4 hemorrhagic events or any Grade 3 events that do not improve.

Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from baseline and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction is unresolved within 4wks. Perform eye exam periodically and at any time for visual disturbances; permanently discontinue if retinal vein occlusion develops or retinal pigment epithelial detachment persists. Permanently discontinue if interstitial lung disease or pneumonitis occurs. Withhold if fever >104°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels.

Severe renal or moderate-to-severe hepatic impairment. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after treatment. Pregnancy. Nursing mothers: not recommended (during and for 4 months after last dose).

Adverse reactions: Rash, diarrhea, lymphedema. In combination with dabrafenib: also pyrexia, chills, fatigue, nausea, vomiting, hypertension, peripheral edema, dry skin, decreased appetite, hemorrhage, cough, dyspnea.

How supplied: Tabs—30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Adults: Give as IV infusion over 30mins. 240mg every 2 weeks until disease progression or

unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5xULN (non-HCC) or AST/ALT >10xULN (HCC) or total bilirubin >3xULN, SCr >6xULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immunemediated encephalitis, recurring Grade 3 adverse reactions, Grade 3 myocarditis, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks.

Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5xULN or total bilirubin >1.5–3xULN, SCr >1.5–6xULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity.

Females of reproductive potential should use effective contraception during and for ≥5 months after final dose. Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI, pyrexia, headache, abdominal pain; also with ipilimumab: vomiting; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL, 24mL)—1

PORTRAZZA Lilly

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Necitumumab 800mg/50mL; soln for IV infusion after dilution; preservativefree.

Indications: In combination with gemcitabine and cisplatin, for first-line treatment of metastatic squamous non-small cell lung cancer. Limitations of use: not for treatment of non-squamous nonsmall cell lung cancer.

Adults: Give by IV infusion over 60 mins prior to gemcitabine and cisplatin infusion. 800mg on Days 1 and 8 of each 3-week cycle; continue until disease progression or unacceptable toxicity.

May premedicate with diphenhydramine HCl (or equivalent) if previously experienced a Grade 1/2 infusion-related reaction. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of cardiopulmonary arrest and/or sudden death, hypomagnesemia. History of coronary artery disease, CHF, or arrhythmias. Monitor serum electrolytes (eg, magnesium, potassium, calcium) prior to each infusion during therapy and for at least 8 weeks after last dose; withhold for Grade 3/4 electrolyte abnormalities and may resume once improved to Grade ≤2. Replete electrolytes as medically appropriate. Discontinue if serious or life-threatening venous/arterial thromboembolic events or infusion-related reactions occur.

Discontinue if Grade 4 skin reactions or Grade 3 skin induration/fibrosis occurs. Limit sun exposure. Embryo-fetal toxicity. Pregnancy; avoid.

Use effective contraception during treatment and for 3 months after last dose. Nursing mothers: not recommended (during therapy and for 3 months after last dose).

Adverse reactions: Rash, dermatitis acneiform, vomiting, diarrhea, thromboembolic events, hypomagnesemia, hypocalcemia, hypokalemia; cardiopulmonary arrest, dermatologic toxicities, infusion reactions.

How supplied: Single-use vial—1

TAFINLAR Novartis

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps.

Indications: In combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of wild-type BRAF NSCLC. Adults: Confirm presence of BRAF V600E mutation prior to initiation. Swallow whole.

Take at least 1hr before or 2hrs after a meal. Monotherapy or in combination with trametinib: 150mg twice daily (approx. 12hrs apart); continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

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DRUG MONOGRAPHS

LUNG CANCER Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Monitor for non-cutaneous malignancies; permanently discontinue if RAS mutation-positive malignancy occurs. Permanently discontinue for all Grade 4 hemorrhagic events or any persistent Grade 3 events. Risk of cardiomyopathy with trametinib; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal. Withhold if fever ≥101.3°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels.

Monitor for visual signs/symptoms of uveitis; permanently discontinue for persistent Grade ≥2 lasting >6wks. G6PD deficiency: monitor for hemolytic anemia. Severe renal or moderate-tosevere hepatic impairment. Embryo-fetal toxicity.

Females of reproductive potential should use highly effective non-hormonal contraception during and for 2wks after last dose. Pregnancy.

Nursing mothers: not recommended (during and for 2wks after last dose).

Interactions: Avoid concomitant strong CYP3A4 or CYP2C8 inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil); if unavoidable, monitor closely. May antagonize effects of CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6 substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives); consider alternatives or monitor.

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmarplantar erythrodysesthesia syndrome; skin toxicity (may be serious). In combination with trametinib: also chills, fatigue, rash, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, hemorrhage, cough, dyspnea.

How supplied: Caps—120

TAGRISSO AstraZeneca

℞

Kinase inhibitor. Osimertinib 40mg, 80mg; tabs.

Indications: Treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDAapproved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy.

Adults: 80mg once daily until disease progression or unacceptable toxicity. If swallowing difficulty, may disperse tab in 2oz (60mL) of non-carbonated water only; stir and swallow immediately, then rinse container with 4–8oz water and drink immediately; or if administration via NG tube is required, disperse tab in 15mL of non-carbonated water and use an additional 15mL

of water to transfer any residues to the syringe; give resulting 30mL via NG tube as instructed with appropriate water flushes (~30mL).

Concomitant strong CYP3A4 inducers (if use is unavoidable): increase dose to 160mg daily; resume at 80mg 3 weeks after discontinuing CYP3A4 inducer. Dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm presence of T790M mutation prior to treatment initiation.

Permanently discontinue if interstitial lung disease (ILD)/pneumonitis is confirmed; QTc interval prolongation with signs/symptoms of life-threatening arrhythmia; symptomatic CHF or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks; or if no improvement within 3 weeks. Withhold dose if worsening respiratory symptoms indicative of ILD occur; if QTc interval >500msec on ≥2 separate ECGs; or adverse reactions of Grade ≥3 severity.

Monitor ECGs and electrolytes periodically in patients with congenital long QTc syndrome, CHF, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval. Conduct cardiac monitoring (including LVEF at baseline and during treatment in patients with cardiac risk factors). Evaluate if signs/symptoms of keratitis occur. ESRD. Severe hepatic impairment. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for 6 weeks after final dose; males (with female partners of reproductive potential) should use effective contraception during and for 4 months after final dose. Pregnancy. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Antagonized by strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s Wort); avoid; if use is unavoidable, increase Tagrisso dose (see Adults).

Potentiates BCRP substrates (eg, rosuvastatin, sulfasalazine, topotecan); monitor closely for related toxicity.

Adverse reactions: Diarrhea, rash, dry skin, nail toxicity, fatigue, lab abnormalities; possibly infertility.

How supplied: Tabs—30

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: Treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen. Limitations of use: not established in patients with NSCLC whose tumors have other EGFR mutations. Not recommended

for use in combination with platinum-based chemotherapy.

Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling.

Concomitant strong CYP3A4 inhibitors (see Interactions): reduce by 50mg decrements; avoid use if possible. Concomitant CYP3A4 inducers (see Interactions): increase by 50mg increments at 2-week intervals (max 450mg); avoid use if possible. Concurrent cigarette smoking: increase by 50mg increments at 2-week intervals (max 300mg); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3XULN or transaminases >5XULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for acute onset of unexplained pulmonary symptoms pending evaluation, persistent severe diarrhea unresponsive to loperamide, severe rash, grade 3–4 keratitis or grade 2 lasting ≥2 weeks.

Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time.

History of peptic ulcers or diverticular disease.

Embryo-fetal toxicity. Pregnancy: avoid. Females of reproductive potential should use effective contraception during therapy and at least 1 month after the last dose. Nursing mothers: not recommended (during and for 2 weeks after the last dose).

Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) or a combined CYP3A4 and CYP1A2 inhibitor (eg, ciprofloxacin); reduce dose if unavoidable.

Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort); increase dose if unavoidable. Avoid concomitant moderate CYP1A2 inducers (eg, teriflunomide, rifampin, phenytoin) or smoking tobacco; increase dose if unavoidable. Avoid concomitant proton pump inhibitors if possible. Separate dosing of antacids by several hours or for H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose). Increased risk of GI perforation with concomitant anti-angiogenic

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DRUG MONOGRAPHS

LUNG CANCER agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia with thrombocytopenia, cerebrovascular accident (in pancreatic cancer), interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs—30

TECENTRIQ Genentech

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Atezolizumab 60mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic non-small cell lung cancer (NSCLC) in patients with disease progression during or after platinum-containing chemotherapy.

Adults: Give as IV infusion over 60mins. 1200mg every 3 weeks until disease progression or unacceptable toxicity. May give subsequent infusions over 30mins if first infusion tolerated.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or ALT >5×ULN or total bilirubin >3×ULN, Grade 4 diarrhea or colitis, Grade 4 hypophysitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre or meningoencephalitis, Grade 3/4 ocular inflammatory toxicity, Grade 4 or recurrent pancreatitis, Grade 3/4 infusion-related reactions, or Grade 4 rash. Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5– 3×ULN, Grade 2/3 diarrhea or colitis, symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, Grade 3/4 hyperglycemia, Grade 2 ocular inflammatory toxicity, Grade 2/3 pancreatitis or Grade 3/4 increases in amylase or lipase levels (>2×ULN), Grade 3/4 infection, Grade 2 infusion-related reactions, or Grade 3 rash; may be resumed when recover to Grade 0–1. Monitor for immune-related pneumonitis, hepatitis (obtain AST, ALT, bilirubin prior to and during treatment), diarrhea/colitis, endocrinopathies (hypophysitis, thyroid function, adrenal insufficiency, diabetes), meningitis or encephalitis, motor and sensory neuropathy, and acute pancreatitis; see full labeling for adverse reaction management details.

Monitor for signs/symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions. Moderate or severe hepatic impairment:

not studied. Embryo-fetal toxicity. Pregnancy.

Use effective contraception during and for ≥5 months after final dose. Nursing mothers: not recommended (during and for ≥5 months after final dose).

Adverse reactions: Fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, constipation; immune-related reactions, lab abnormalities.

How supplied: Single-dose vial (20mL)—1

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Lung cancer (squamous cell and small cell types).

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat. X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer.

Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

XALKORI Pfizer

℞

Tyrosine kinase inhibitor. Crizotinib 200mg, 250mg; hard gel caps.

Indications: Treatment of metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. Treatment of metastatic NSCLC that is ROS1-positive.

Adults: Confirm ALK-positive NSCLC with an FDA-approved test before treating. Swallow whole. 250mg twice daily until disease progression or intolerance. Dose modification and/or dose reduction to 200mg twice daily may be required based on Grade 3 or 4 severity, then to 250mg once daily, or permanently discontinue if intolerable. Severe renal impairment (CrCl <30mL/min) not requiring dialysis: 250mg once daily. Dose reduction for hematologic and non-hematologic toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor ALT, AST and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated. Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Congenital long QT syndrome; avoid.

History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QT interval): consider monitoring ECG, electrolytes periodically.

Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or ≥60ms change from baseline.

Monitor HR and BP regularly; discontinue if life-threatening bradycardia occurs. Discontinue if onset of severe visual loss; perform eye evaluation. Hepatic impairment. Severe renal impairment. Embryo-fetal toxicity. Pregnancy; avoid. Use effective contraception during therapy and for at least 45 days (females) or 90 days (males) after final dose. Nursing mothers: not recommended (during therapy and for 45 days after final dose).

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DRUG MONOGRAPHS

LUNG CANCER Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue. Caution with moderate CYP3A inhibitors. Dose reduction may be needed with coadministered drugs metabolized

by CYP3A. Adverse reactions: Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper RTI, dizziness, neuropathy, neutropenia; hepatotoxicity (may be fatal), pneumonitis (may be fatal), QT prolongation, bradycardia.

How supplied: Caps—60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps.

Indications: Treatment of patients with metastatic non-small cell lung cancer (NSCLC)

whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDAapproved test.

Adults: Take with food. 450mg once daily until disease progression or unacceptable toxicity. Discontinue if 150mg once daily with food not tolerated. Severe hepatic impairment or if concomitant use of strong CYP3A4 inhibitors unavoidable: reduce ceritinib dose by ⅓. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose.

Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue if ALT/AST elevation >3xULN with total bilirubin >2xULN in the absence of cholestasis or hemolysis. Congenital long QT syndrome; avoid. Patients with CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval; monitor ECG, electrolytes periodically.

Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhy thmia develop. Monitor HR and BP regularly; fasting serum glucose, lipase, amylase prior to initiation and periodically thereafter. Monitor for pulmonary

symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Severe hepatic impairment.

Embryo-fetal toxicity. Pregnancy. Use effective contraception during treatment and for 6 months (females) or 3 months (males) after completion. Nursing mothers: not recommended (during and for 2 weeks after completion).

Interactions: See Adults. Potentiated by strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; avoid. Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates with narrow therapeutic indices (eg, phenytoin, warfarin); if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, betablockers, non-dihydropyridine CCBs, clonidine, digoxin).

Adverse reactions: Diarrhea, nausea, fatigue, vomiting, abdominal pain, decreased appetite, weight loss; hepatotoxicity, ILD/pneumonitis, QT prolongation, hyperglycemia, bradycardia, pancreatitis.

How supplied: Caps—70

ERROR-PRONE SYMBOLS The symbols found in this table have been reported to the Institute for Safe Medical Practices (ISMP) through the ISMP Medication Error Reporting Program as being frequently misinterpreted and involved in harmful medication errors. These symbols should never be used when communicating medical information.

Symbol

Intended Meaning

Misinterpretation

Correction

ʒ c x3d > and <

Dram Minim For three days Greater than and less than

Use the metric system Use the metric system Use “for three days” Use “greater than” or “less than”

/ (slash mark)

Separates two doses or indicates “per”

@ & + °

At And Plus or and Hour

Mistaken as “3” Mistaken as “mL” Mistaken as “3 doses” Mistaken as opposite of intended; incorrect symbol used mistakenly; “<10” mistaken as “40” (forty) Mistaken as the number 1 (eg, “25 units/10units” misread as “25 units and 110 units”) Mistaken as “2” Mistaken as “2” Mistaken as “4” Mistaken as a zero (eg, q2° seen as q 20)

Φ or ∅

Zero, null sign

Mistaken as numerals 4, 6, 8, and 9

Use 0 or zero, or describe intent using whole words

Use “per” rather than a slash mark to separate doses Use “at” Use “and” Use “and” Use “hr”, “h”, or “hour”

References Source: Institute for Safe Medication Practices. Error-Prone Abbreviations, Symbols, and Dose Designations. 2015.

Available at: http://www.ismp.org/Tools/errorproneabbreviations.pdf.

(Rev. 7/2016)

38 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

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3/3/18 11:24 AM

CANCER TREATMENT REGIMEN

SKIN CANCER Melanoma Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Systemic Therapy Options for Metastatic or Unresectable Melanoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

First-line Immunotherapy Regimens Nivolumab (Category 1)2,3abcd

Nivolumab 3mg/kg IV every 2 weeks.

Nivolumab + ipilimumab

Day 1: Nivolumab 1mg/kg followed by ipilimumab 3mg/kg IV every 3 weeks for 4 cycles; then, nivolumab 3mg/kg every 2 weeks.

4,5abcdef

Pembrolizumab (Category 1)6-9acd

Pembrolizumab 2mg/kg IV every 3 weeks.

First-line Targeted Therapy for BRAF-Mutant Melanoma Preferred Regimens Dabrafenib + trametinib (Category 1)10-13ghi

Dabrafenib 150mg orally twice daily + trametinib 2mg/day orally.

Vemurafenib + cobimetinib (Category 1)14-16ghij

Vemurafenib 960mg orally twice daily on days 1–28 + cobimetinib 60mg/day orally on days 1–21.

Repeat cycle every 28 days.

Other Active Regimens Vemurafenib (Category 1)17,18ghi

Vemurafenib 960mg orally twice daily.

Dabrafenib (Category 1)

Dabrafenib 150mg orally twice daily.

19,20ghi

Second-line or Subsequent Therapyk Pembrolizumab6-9acdl

Pembrolizumab 2mg/kg IV every 3 weeks.

Nivolumab2,3abcd

Nivolumab 3mg/kg IV every 2 weeks.

Nivolumab + ipilimumab4,5abcdefl

Day 1: Nivolumab 1mg/kg followed by ipilimumab 3mg/kg IV every 3 weeks for 4 cycles; then, nivolumab 3mg/kg every 2 weeks.

Ipilimumab (Category 1)21-24cdelm

Day 1: Ipilimumab 3mg/kg IV. Repeat cycle every 3 weeks for 4 cycles.

High-dose IL-225-28,n,o

Days 1–5: IL-2 22mcg/kg (360,000 IU/kg), 33mcg/kg (540,000 IU/kg), 36mcg/kg (600,000 IU/kg), or 44mcg/kg (720,000mcg/kg) IV every 8 hours for up to 14 consecutive doses as clinically tolerated.

Dacarbazine29

Day 1: Dacarbazine 2–4.5mg/kg/day IV for 10 days.

Repeat cycle every 4 weeks.

OR Days 1–5: Dacarbazine 250mg/m2/day IV. Repeat cycle every 3 weeks.

Temozolomide30

Days 1–5: Temozolomide 200mg/m2/day orally for 5 days.

Repeat cycle every 4 weeks. continued

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR 39

CANCER TREATMENT REGIMEN

SKIN CANCER Melanoma Treatment Regimens Systemic Therapy Options for Metastatic or Unresectable Melanoma1 (continued) REGIMEN

DOSING

Second-line or Subsequent Therapyk (continued) Paclitaxel31

Paclitaxel 250mg/m2 continuous IV infusion for 24 hours.

Repeat cycle every 21 days.

Albumin-bound paclitaxel32,33

Nab-paclitaxel 100mg/m2 (in previously treated patients) or 150mg/m2 (in chemotherapy-naive patients) IV. Repeat every week for 3–4 cycles.

Carboplatin + paclitaxel34-37

Days 1, 8, and 15: Paclitaxel 100mg/m2 IV + carboplatin AUC 2mg·min/mL IV. Repeat cycle every 4 weeks until disease progression

Biochemotherapy for adjuvant treatment of high-risk disease (Category 2B)38,o

Dacarbazine, cisplatin, vinblastine, IL-2, and interferon alfa-2b

Imatinib39,40,p

Imatinib 400mg orally twice daily.

Second-Line or Subsequent Therapy for BRAF-Mutant Melanoma Preferred Regimens Dabrafenib + trametinib10-13ghi

Dabrafenib 150mg orally twice daily + trametinib 2mg/day orally.

Vemurafenib + cobimetinib14-16ghij

Vemurafenib 960mg orally twice daily on days 1–28 + cobimetinib 60mg/day orally on days 1–21.

Repeat cycle every 28 days.

Other Active Regimens Vemurafenib17,18ghi

Vemurafenib 960mg orally twice daily.

Dabrafenib19,20ghi

Dabrafenib 150mg orally twice daily.

Local Therapy for Stage III Disease (Unresectable, incomplete resection, progression or recurrent) Intralesional Injections Talimogene laherparepvac (T-VEC) (Category 1)q,41,42

Day 1: Inject up to 4mL at concentration of 106 (1 million) plaque-forming units (PFU)/mL in multiple injections starting with the largest lesions for one 3-week cycle, followed by: Day 1: Inject up to 4mL at concentration of 108 (100 million) plaque-forming units (PFU)/mL in multiple injections starting with any new lesions that have developed.

Repeat cycle every 2 weeks.

Bacillus Calmette-Guerin (BCG) (Category 2)43-45

Day 1: Inject 0.1mL intralesionally.

Repeat 4-6 week cycle for 1–2 cycles.

Interferon alfa-2b (Category 2)46

Day 1: Inject 1.36–3.4 million units/m2 (6-15mcg) intralesionally.

Repeat cycle every 4 weeks.

Aldesleukin (IL-2) (Category 2)47,48

Inject 0.6–6 million units intralesionally 3 times a week.

Repeat cycle every week.

Topical Imiquimod for superficial dermal lesions (Category 2B)49,50

Days 1–28: Apply 5% cream topically twice daily.

Repeat cycle every 4 weeks.

Consider radiation therapy for unresectable disease (Category 2B) Regional Therapy Isolated limb infusion/perfusion (ILI/ILP) with melphalan51,52 a

Nivolumab or pembrolizumab may cause immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, ­hypophysitis, ­nephritis, and hyperthyroidism. For moderate to severe immune-mediated toxicities, discontinue therapy and administer systemic steroids. b Clinically significant (grade 3 and 4) immune-related adverse events are seen more commonly with nivolumab/ipilimumab combination therapy compared with iplimumab or

nivolumab monotherapy. This emphasizes the need for careful patient ­education, selection, and monitoring.

Immune-mediated dermatitis sometimes responds to topical corticosteroids. For patients who do not respond, consider ­referral to a dermatologist or provider experienced in diagnosing and management cutaneous manifestations of immunotherapy.

c

40 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

SKIN CANCER Notes d

Infliximab 5 mg/kg is preferred for treatment of severe immune- related colitis that does not resolve with high-dose steroids. A single dose of infliximab is sufficient to resolve immune-related colitis in most patients. e Ipilimumab has the potential for significant immune-mediated complications. Although no longer required by the FDA, the Risk Evaluation and Mitigation Strategy program and/or experience in use of the drug as well as resources to follow the p ­ atient closely are essential for safe use of ipilimumab. It should be used with extreme caution, if at all, in patients with underlying immune disorders. f Nivolumab/ipilimumab combination therapy was associated with improved ORR and PFS compared with single agent ipilimumab, at the expense of significantly increased toxicity.

Compared to single-agent therapy, the impact of nivolumab/ipilimumab combination therapy on overall survival is not known. The phase III trial of nivolumab/ipilimumab or nivolumab monotherapy versus ipilimumab monotherapy was conducted in previously untreated patients with unresectable stage III or IV melanoma. g Vemurafenib, dabrafenib, and trametinib are recommended only for patients with V600 mutation of the BRAF gene documented by an FDA-approved or Clinical Laboratory Improvement Amendments (CLIA)-approved facility. h Regular dermatologic evaluation and referral to a dermatologist or provider experienced in the diagnosis and management of cutaneous manifestations of targeted therapy is recommended. BRAF inhibitors are associated with cutaneous squamous cell carcinoma, extreme photosensitivity, and other dermatologic toxicities, which occur much less often with concurrent MEK inhibitors. i Pyrexia (defined as a temperature of 38.5°C or greater) is a common (~55%) side effect of combining BRAF and MEK inhibitors and occurs less frequently with BRAF monotherapy (~20%). The pyrexia is episodic, and onset is often 2 to 4 weeks following the start of therapy with a median duration of 9 days. Pyrexia may be associated with chills, night sweats, rash, dehydration, electrolyte abnormalities, and hypotension. Stopping or holding dab-

rafenib and trametinib at the onset of pyrexia will often interrupt the episode, and treatment can be resumed with full-dose dabrafenib and trametinib upon cessation of pyrexia and pyrexia-related symptoms. Upon re-exposure to dabrafenib and trametinib, repeat pyrexia events can occur, but grade >3 events are uncommon (21%). In occasional instances of prolonged or severe pyrexia not responsive to discontinuation of dabrafenib and trametinib, low-dose steroids (prednisone 10 mg/day) can be used. Patients with pyrexia should be advised to use antipyretics as needed and increase fluid intake. j Vemurafenib/cobimetinib combination therapy was associated with better PFS and a better response rate than vemurafenib monotherapy in previously untreated patients with unresectable stage IIIC or stage IV disease. The combination’s effect on OS compared to single-agent vemurafenib is unknown. k Consider second-line agents that were not used in first-line therapy and that are not of the same class. l For patients with preexistent hypophysitis due to iplimumab, pembrolizumab may be administered if patients are on appropriate physiologic replacement endocrine therapy. m Ipilimumab reintroduction may be considered for select patients who did not experience significant systemic toxicity during prior ipilimumab therapy and who relapse after initial clinical response or have progression after stable disease > 3 months. n High-dose IL should not be used in patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases. IL-2 may be considered for patients with small brain metastases and without significant peritumoral edema. o Administration of multiagent regimens and high-dose IL-2 is complex and associated with significant toxicities. Therapy should only be administered at an institution with medical staff experienced in the administration and management of these regimens. p For tumors with activating mutations of C-KIT. q Also indicated for extracranial lesions.

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Melanoma. v 1.2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed January 8, 2018.

2. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus c­ hemotherapy in patients with advanced melanoma who p ­ rogressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–384.

3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–330.

4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

5. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017.

6. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–918.

7. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–2532.

8. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–1117.

9. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (Anti-PD-1) in Melanoma. N Eng J Med. 2013;369:134–144.

10. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015; 386:444–451.

11. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–39.

12. Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAF V600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014;32:3697–3704.

13. Sanlorenzo M, Choudhry A, Vujic I, et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014;71:1102–1109;e1101.

14. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–1876.

15. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15:954–965.

16. Pavlick AC, Ribas A, Gonzalez R, et al. Extended follow-up ­results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol. 2015;33:(suppl; abstr 9020).

17. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–714.

18. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15:323–332.

19. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAKMB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–1095.

20. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-­mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet.

2012;380:358–365.

21. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–465.

22. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697.

23. Hodi FS, O’Day SJ, McDermott DF, Weber RW, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med. 2010;363:711–723.

24. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011;364:2517–2526.

25. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.

J Am Med Assoc. 1994;271:907–913.

26. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–2116.

27. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6 Suppl 1:S11–14.

28. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610–5618.

29. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21–34.

30. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolo-

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SKIN CANCER References (continued)

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mide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.J Clin Oncol. 2000;18:158–166.

Wiernik PH, Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst Monogr.

1993;15:185–187.

Hersh EM, O’Day SJ, Ribas A, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer.

2010;116:155–163.

Kottschade LA, Suman VJ, Amatruda T, et al. A phase II trial of nabpaclitaxel (ABI007) and carboplatin in patients with unresectable stage IV melanoma: a North Central cancer treatment group study, N057E(1). Cancer. 2011;117:1704–1710.

Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer.

2006;106:375–382.

Agarwala SS, Keilholz U, Hogg D, et al. Randomized phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma. J Clin Oncol. 2007;25(18_suppl):8510.

Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823–2830.

Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of E2603: A double-blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma. J Clin Oncol. 2010. 28:(suppl; abstr 8511).

Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma—an intergroup study of cancer and leukemia Group B, Children’s Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol.

2014;32:3771–3778.

Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182–3190.

Carvajal RD, Antonescu CR, Wolchok, JD, et al. KIT as a therapeutic target in metastatic melanoma. J Am Med Assoc. 2011;395:2327–2334.

Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol.

2015;33:2780–2788. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 26014293.

Andtbacka RH, Chastain M, Li A, et al. Phase 2, multicenter, randomized, open-label trial assessing efficacy and safety of talimogene laherparepvec (T-VEC) neoad-

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Tan JK, Ho VC. Pooled analysis of the efficacy of Bacille Calmette-Guerin (BCG) immunotherapy in malignant melanoma. J Dermatol Surg Oncol. 1993;19:985–990.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/8245304 Mastrangelo MJ, Sulit HL, Prehn LM, et al. Intralesional BCG in the treatment of metastatic malignant melanoma. Cancer. 1976;37:684-692. Available at: https:// www.ncbi.nlm.nih.gov/pubmed/766947.

Cohen MH, Jessup JM, Felix EL, et al. Intralesional treatment of recurrent metastatic cutaneous malignant melanoma: a randomized prospective study of intralesional Bacillus Calmette-Guerin versus intralesional dinitrochlorobenzene. Cancer.

1978;41:2456–2463. Available at: http://www.ncbi.nlm.nih.gov/pubmed/657108.

Ikic D, Spaventi S, Padovan I, et al. Local interferon therapy for melanoma patients.

Int J Dermatol. 1995;34:872-874. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/8647672.

Weide B, Derhovanessian E, Pflugfelder A, et al. High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer. 2010;116:4139–4146. Available at: https://www. ncbi.nlm.nih.gov/pubmed/20564107.

Radny P, Caroli UM, Bauer J, et al. Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer. 2003;89:1620–1626.

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Bong AB, Bonnekoh B, Franke I, et al. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology. 2002;205:135–138. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/12218228.

Miller AK, Dusing R, Meggison A, Aires D. Regression of internal melanoma metastases following application of topical imiquimod to overlying skin. J Drugs Dermatol. 2011;10:302–305. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/21369648.

Cornett WR, McCall LM, Petersen RP, et al. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol. 2006;24:4196-4201. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/16943537.

Kroon HM, Huismans AM, Kam PC, Thompson JF. Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review. J Surg Oncol.

2014;109: 348–351. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24522939.

(Revised 1/2018) © 2018 by Haymarket Media, Inc.

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Skin Cancer Advisor

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A section of Cancer Therapy Advisor that features exclusive news and clinical content for oncologists who specialize in the treatment of patients with skin cancer.

Visit CancerTherapyAdvisor.com/SkinCancer to access the following and more:

DRUG MONOGRAPHS

SKIN CANCER BAVENCIO EMD Serono

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Avelumab 20mg/mL; soln for IV infusion after dilution; preservative-free; contains mannitol.

Indications: Treatment of metastatic Merkel cell carcinoma (MCC).

Adults: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; then subsequent doses as clinically indicated.

Give as IV infusion over 60mins. 10mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: <12yrs: not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for Grade 3/4 pneumonitis or recurrent Grade 2 pneumonitis, Grade 4 diarrhea or colitis or recurrent Grade 3 diarrhea or colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, any life-threatening (Grade 4) or recurrent severe (Grade 3) immune-mediated adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2/3 immune-mediated adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2/3 diarrhea or colitis, Grade 3/4 adrenal insufficiency, Grade 3/4 thyroid disorders, Grade 3/4 hyperglycemia, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN; withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if Grade 1/2 infusion-related reactions occur; permanently discontinue if Grade 3/4. Monitor for abnormal liver tests, adrenal insufficiency, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥1 month after final dose. Pregnancy. Nursing mothers: not recommended (during and for ≥1 month after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, peripheral edema, UTI; other immune-mediated adverse reactions (may be fatal).

How supplied: Single-dose vial (10mL)—1

COTELLIC Genentech Kinase inhibitor. Cobimetinib 20mg; tabs.

Indications: In combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

℞

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. In combination with vemurafenib: 60mg once daily for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Concomitant CYP3A inhibitors: see Interactions.

Other dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Review full labeling for vemurafenib prior to initiation. Monitor for new malignancies (cutaneous and non-cutaneous); perform skin evaluations prior to initiation, every 2 months during therapy, and for 6 months after discontinuation. Monitor for signs/symptoms of bleeding; withhold if Grade 3 hemorrhagic events occur; resume at lower dose if improved to Grade 0/1 within 4 weeks; discontinue if no improvement. Risk of cardiomyopathy; assess LVEF prior to initiation, after 1 month, and then every 3 months thereafter until discontinuation.

Patients with baseline LVEF below institutional lower limit of normal or <50%: not established.

Interrupt, reduce dose, or discontinue if severe skin reactions occur. Perform eye exams at regular intervals and for any visual disturbances. Manage serous retinopathy with treatment interruption, dose reduction, or discontinuation. Permanently discontinue if retinal vein occlusion occurs.

Monitor liver tests prior to initiation, monthly during treatment, or more frequently as indicated; dose interruption, reduction, or discontinuation if Grade 3/4 abnormalities occur. Obtain baseline CPK and creatinine levels prior to initiation, periodically during treatment, and as clinically indicated for signs/symptoms of rhabdomyolysis.

Avoid sun exposure. Severe renal impairment.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during therapy and for 2 weeks after final dose.

Pregnancy. Nursing mothers: not recommended (during therapy and for 2 weeks after final dose).

Interactions: Avoid concomitant strong or moderate CYP3A inhibitors (eg, itraconazole, erythromycin, ciprofloxacin). If short-term (≤14 days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60mg, reduce to 20mg and resume at previous dose upon discontinuing the CYP3A inhibitor; for patients taking cobimetinib 20mg or 40mg, use alternative. Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, phenytoin, rifampin, St. John’s wort).

Adverse reactions: Diarrhea, photosensitivity, nausea, pyrexia, vomiting, increased GGT, CPK, ALT/AST and alkaline phosphatase, hypophosphatemia, lymphopenia, hyponatremia.

How supplied: Tabs—63

EFUDEX Valeant

℞

Antimetabolite. Fluorouracil 2%, 5%; soln. ℞ Also: EFUDEX CREAM Fluorouracil 5%.

Indications: Multiple actinic or solar keratoses.

Superficial basal cell carcinoma when

conventional therapy is impractical (5% only); see literature.

Adults: Keratoses: Apply twice daily until erosion occurs (usually 2–4 wks). Basal cell carcinoma (5% only): Apply twice daily, usually for 3–6 weeks (obliteration may take 10–12 weeks).

Children: Not recommended.

Contraindications: Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy (Cat.X).

Warnings/Precautions: Apply cautiously near eyes, nose, mouth. Avoid mucous membranes, occlusion, ulcerated/inflamed skin, exposure to UV light. Wash hands after application if fingers were used. Notify patients of expected skin reaction. Biopsy unresponsive lesions. Nursing mothers: not recommended.

Adverse reactions: Pain or burning at application site, pruritus, irritation, hyperpigmentation.

How supplied: Soln—10mL (w. drop dispenser); Crm—25g

ERIVEDGE Genentech

℞

Hedgehog pathway inhibitor. Vismodegib 150mg; caps.

Indications: Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Adults: Swallow whole. 150mg once daily, until disease progression or unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Risk of embryo-fetal death and severe birth defects in pregnant women. Verify pregnancy status within 7 days prior to initiation of therapy. Females of reproductive potential should use effective contraception during therapy and for 24 months after final dose; male patients should use condoms (even after a vasectomy) during and for 3 months after final dose. Advise patients not to donate blood or blood products during therapy and for 24 months after final dose. Advise male patients not to donate semen during and for 3 months after final dose. Premature fusion of the epiphyses may occur in pediatrics if exposed. Pregnancy: avoid. Nursing mothers: not recommended (during and for 24 months after final dose).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, vomiting, decreased appetite, constipation, arthralgias, ageusia; amenorrhea.

Note: Report immediately exposure to Erivedge during pregnancy by contacting the Genentech Adverse Event Line at (888) 835-2555.

How supplied: Caps—28

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DRUG MONOGRAPHS

SKIN CANCER GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Adults with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation as determined with an FDA-approved test or with c-Kit mutational status unknown.

Adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: ASM without D816V c-Kit mutation or status unknown (determine D816V c-Kit mutation status prior to initiation): 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. DFSP: 400mg twice daily. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling.

Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Not recommended.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; renal function at baseline and during therapy; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Diabetes. Hypertension. CHF. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use.

Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy.

Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Embryo-fetal toxicity. Pregnancy (avoid); exclude status prior to initiation. Females of reproductive potential should use highly effective contraception during treatment and for 14 days after cessation. Nursing mothers: not recommended (during and for 1 month after final dose).

Interactions: Avoid grapefruit juice.

Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin);

consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus) or CYP2C9 (use heparin instead of warfarin). Caution with concomitant CYP2D6 substrates that have a narrow therapeutic window.

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, StevensJohnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

IMLYGIC Amgen

site. Underlying autoimmune disease. Multiple myeloma or plasmacytoma. Pregnancy. Women of childbearing potential should use effective method of contraception. Nursing mothers: not recommended.

Interactions: Acyclovir or other antiherpetic viral agents may interfere with efficacy.

Adverse reactions: Fatigue, chills, pyrexia, nausea, influenza-like illness, inj site pain; immune-mediated events.

Note: Report suspected herpetic lesions to Amgen at (855) 465-9442.

How supplied: Single-use vial (1mL)—1

KEYTRUDA Merck

℞

Genetically modified oncolytic viral therapy.

Talimogene laherparepvec 106 (1 million) PFU/mL, 108 (100 million) PFU/mL; susp for intralesional inj; preservative-free.

Indications: Treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use: not shown to improve overall survival or have an effect on visceral metastases.

Adults: See full labeling. Inject intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. Total inj volume per treatment visit: max 4mL for all injected lesions combined. Initial dose: up to 4mL of 106 (1 million) PFU/mL. 2nd dose: up to 4mL of 108 (100 million) PFU/mL given 3 weeks later. All subsequent doses (including reinitiation): up to 4mL of 108 (100 million) PFU/mL given 2 weeks apart.

Continue for ≥6 months unless other treatment required or until no injectable lesions to treat; reinitiate if new lesions appear after a complete response.

Children: Not established.

Contraindications: Immunocompromised or pregnant patients.

Warnings/Precautions: For intralesional inj only. Avoid accidental exposure (esp. skin, eyes, mucous membranes) and direct contact with patient’s injected lesions, dressings, or body fluids. Advise patients to avoid inadvertent transfer of drug to other areas of the body (eg, touching/scratching inj sites or occlusive dressings). Evaluate lesions if suspected herpetic infection occurs. Inj site complications (eg, necrosis or ulceration of tumor tissue, cellulitis, systemic bacterial infection).

Persistent infection or delayed healing of inj

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free.

Indications: Unresectable or metastatic melanoma.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 develops.

Monitor for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related

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DRUG MONOGRAPHS

SKIN CANCER reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

MEKINIST Novartis

℞

Kinase inhibitor. Trametinib 0.5mg, 2mg; tabs.

Indications: As monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDAapproved test. Limitation of use: not indicated for treatment of patients who have progressed on prior BRAF-inhibitor therapy.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at same time each day, at least 1hr before or 2hrs after a meal. Monotherapy or in combination with dabrafenib: 2mg once daily; continue until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for dabrafenib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Monitor for non-cutaneous malignancies, pulmonary embolism (permanently discontinue if lifethreatening), colitis, GI perforations, skin toxicities and secondary infections. Permanently discontinue for all Grade 4 hemorrhagic events or any Grade 3 events that do not improve.

Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from baseline and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction is unresolved within 4wks. Perform eye exam periodically and at any time for visual disturbances; permanently discontinue if retinal vein occlusion develops or retinal pigment epithelial detachment persists. Permanently

discontinue if interstitial lung disease or pneumonitis occurs. Withhold if fever >104°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels.

Severe renal or moderate-to-severe hepatic impairment. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after treatment. Pregnancy. Nursing mothers: not recommended (during and for 4 months after last dose).

Adverse reactions: Rash, diarrhea, lymphedema. In combination with dabrafenib: also pyrexia, chills, fatigue, nausea, vomiting, hypertension, peripheral edema, dry skin, decreased appetite, hemorrhage, cough, dyspnea.

How supplied: Tabs—30

ODOMZO Novartis

℞

Hedgehog pathway inhibitor. Sonidegib 200mg; caps.

Indications: Treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation, or those who are not candidates for surgery or radiation therapy.

Adults: Take on empty stomach. 200mg once daily until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of embryofetal death or severe birth defects in pregnant women. Verify pregnancy status of females of reproductive potential prior to initiation. Advise females to use effective contraception during therapy and for at least 20 months after the last dose; male patients must use condoms and not to donate semen during therapy and for at least 8 months after last dose. Advise patients not to donate blood or blood products during therapy and for at least 20 months after last dose. Risk of musculoskeletal adverse reactions accompanied by serum creatine kinase (CK) elevations; temporarily interrupt or discontinue based on severity of reactions.

Obtain baseline serum CK and creatinine (SCr) levels prior to initiation; periodically during treatment and as clinically indicated. Obtain serum CK and SCr levels at least weekly in those with musculoskeletal adverse reactions with concurrent serum CK elevation >2.5XULN until symptoms resolve. Pregnancy. Nursing mothers: not recommended during therapy and for 20 months after last dose.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) or moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole); if moderate CYP3A inhibitor use necessary,

administer for <14 days and monitor closely.

Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, pruritus; anemia, hyperglycemia, increased SCr, CK, and LFTs. Note: To report exposure to Odomzo during pregnancy, call Novartis at (888) 669-6682.

How supplied: Caps—30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: As a single agent for patients with BRAF V600 wild-type or BRAF V600 mutation (+) unresectable or metastatic melanoma. In combination with ipilimumab for unresectable or metastatic melanoma. Adjuvant treatment for melanoma in patients with involvement of lymph nodes or metastatic disease who have undergone complete resection.

Adults: Give as an IV infusion. Single agent: 240mg over 30mins every 2 weeks until disease progression or unacceptable toxicity.

In combination with ipilimumab: 1mg/kg over 30mins (followed by ipilimumab on the same day) every 3 weeks for 4 doses, then followed by 240mg over 30mins every 2 weeks (as single agent) until disease progression or unacceptable toxicity. Adjuvant: 240mg over 60mins every 2 weeks until disease recurrence or unacceptable toxicity for up to 1 year. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5xULN (non-HCC) or AST/ALT >10xULN (HCC) or total bilirubin >3xULN, SCr >6xULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immunemediated encephalitis, recurring Grade 3 adverse reactions, Grade 3 myocarditis, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5xULN or total bilirubin >1.5–3xULN, SCr >1.5–6xULN, Grade 2 or

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DRUG MONOGRAPHS

SKIN CANCER 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderateto-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or lifethreatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI, pyrexia, headache, abdominal pain; also with ipilimumab: vomiting; immunemediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL, 24mL)—1

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic melanoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/course), as tolerated.

Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature.

History of cardiac or pulmonary disease.

Renal, hepatic, or CNS impairment. Seizure disorder. Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion

is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-tosevere lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment. Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur. Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases. Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

TAFINLAR Novartis

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps.

Indications: As monotherapy for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDA-approved test. In combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of wild-type BRAF melanoma.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Swallow whole.

Take at least 1hr before or 2hrs after a meal.

Monotherapy or in combination with trametinib: 150mg twice daily (approx. 12hrs apart); continue until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation.

Monitor for non-cutaneous malignancies; permanently discontinue if RAS mutationpositive malignancy occurs. Permanently discontinue for all Grade 4 hemorrhagic events or any persistent Grade 3 events. Risk of cardiomyopathy with trametinib; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal. Withhold if fever ≥101.3°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels.

Monitor for visual signs/symptoms of uveitis; permanently discontinue for persistent Grade ≥2 lasting >6wks. G6PD deficiency: monitor for hemolytic anemia. Severe renal or moderate-tosevere hepatic impairment. Embryo-fetal toxicity.

Females of reproductive potential should use highly effective non-hormonal contraception during and for 2wks after last dose. Pregnancy.

Nursing mothers: not recommended (during and for 2wks after last dose).

Interactions: Avoid concomitant strong CYP3A4 or CYP2C8 inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil); if unavoidable, monitor closely.

May antagonize effects of CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6 substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives); consider alternatives or monitor.

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome; skin toxicity (may be serious).

In combination with trametinib: also chills, fatigue, rash, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, hemorrhage, cough, dyspnea.

How supplied: Caps—120

YERVOY Bristol-Myers Squibb

℞

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocking antibody. Ipilimumab 5mg/mL; soln for IV infusion; preservative-free.

Indications: Treatment of unresectable or metastatic melanoma in patients ≥12yrs.

Adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes >1mm who have undergone complete resection, including total lymphadenectomy.

Adults: Give by IV infusion over 90 mins.

Unresectable, metastatic: 3mg/kg every 3 weeks

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DRUG MONOGRAPHS

SKIN CANCER for a maximum of 4 doses; may delay doses if toxicity occurs, but all treatment must be given within 16 weeks of the first dose. Adjuvant: 10mg/kg every 3 weeks for 4 doses, followed by 10mg/kg every 12 weeks for up to 3 years; may omit doses if toxicity occurs. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Severe and fatal immune-mediated adverse reactions can develop. Permanently discontinue therapy and initiate systemic high-dose corticosteroids for severe, persistent, or recurring immunemediated reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5mg prednisone or equivalent per day. Monitor for enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, and others including ocular manifestations; perform clinical chemistries including LFTs, ACTH levels, and thyroid tests at baseline and before each dose. Give steroid eye drops if uveitis, iritis, or episcleritis develops (may need systemic treatment if a Vogt-Koyanagi-Harada-like syndrome develops); permanently discontinue if unresponsive to local therapy. Moderate or severe hepatic impairment. Embryo-fetal toxicity.

Females of reproductive potential should use effective contraception during and for 3 months after final dose. Pregnancy. Nursing mothers: not recommended (during and for 3 months after final dose).

Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis, headache, weight loss, nausea, pyrexia, decreased appetite, vomiting, insomnia; immune-mediated reactions.

Note: To enroll pregnant patients in the Pregnancy Safety Surveillance Study, call (844) 593-7869.

How supplied: Single-use vial (50mg, 200mg)—1

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs.

Indications: Treatment of unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma.

Adults: Confirm BRAF V600E mutation-positive melanoma with FDA-approved test before initiating. Swallow whole. ≥18yrs: 960mg every 12hrs; continue until disease progression or unacceptable toxicity. Concomitant strong CYP3A4 inducer: avoid; if unavoidable, increase dose by 240mg as tolerated (see full labeling).

Dose modifications for adverse reactions: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65yrs, prior skin cancer, chronic sun exposure; if occurs, do excision and evaluate. Perform dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after discontinuation. Monitor for signs/symptoms of new non-cutaneous SCC and other malignancies. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Prior to and following initiation or after dose adjustment for QTc prolongation, evaluate ECG and electrolytes after 15 days, monthly during the 1st 3 months, then every 3 months thereafter, or more as

clinically indicated. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before initiating and monthly during treatment, or as needed. Measure SCr before initiating and periodically during treatment. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Pregnancy. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, saquinavir, ritonavir, indinavir, nelfinavir); consider alternatives. Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin); consider alternatives, or increase dose (see Adult). Avoid concomitant CYP1A2 (eg, tizanidine) and P-gp (eg, digoxin) substrates with narrow therapeutic indices; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab. Concomitant or sequential administration with radiation treatment; monitor closely.

Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occur), QT prolongation, hepatotoxicity, uveitis, blurry vision, photophobia, other malignancies, radiation sensitization and recall, renal failure, Dupuytren’s contracture (may be severe), plantar fascial fibromatosis.

How supplied: Tabs—112, 120

DOSAGES FOR THE ELDERLY Special caution is advised when prescribing drugs for elderly patients. Keep the following points in mind when prescribing drugs for patients of approximately 60 years or older:

1. Renal Function: Glomerular filtration rate, renal tubular secretion and blood flow tend to decrease with advancing age, while the incidence of renal pathology increases.

2. Drug Sensitivity: Elderly patients may show unusual sensitivity or paradoxical reactions to a number of drugs. Refer to the complete prescribing information.

3. Drug Distribution: The ratio of fat to lean body weight may increase in the elderly, which affects the volume of distribution of fat-soluble drugs. Plasma albumin concentrations may be decreased in the elderly. This potentiates plasma-protein bound drugs and increases the potential for drug interactions caused by plasma-protein displacement.

4. Polypharmacy: It is important to determine the patient’s current medication use, including nonprescription products, before adding any medication to determine any possible interactions.

5. Hepatic Function: Reduced function of metabolic enzymes in the liver may occur in the elderly.

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ALPHABETICAL INDEX A Abemaciclib Verzenio Abiraterone Zytiga

Bevacizumab Avastin (inj) 7 21

Abraxane (inj) cancer, breast non-small cell lung cancer

1 32

Actinic keratoses

43

Ado-trastuzumab Kadcyla

4

Afatinib Gilotrif

33

Afinitor cancer, breast cancer, renal

1 15

Aldesleukin Proleukin (inj)

Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

9, 15, 33

Bicalutamide Casodex

16

Breast cancer

5, 7

Brigatinib Alunbrig

32

C Cabazitaxel Jevtana (inj)

17

Cabometyx

15

Cabozantinib Cabometyx

15

Cancer, bladder Cancer, breast

46 Cancer, cervical

Alecensa

32

Alectinib Alecensa

32

Alimta (inj)

32

Cancer, GI

Alunbrig

32

Cancer, head and neck

Cancer, colorectal

15–17, 19–20, 37

7, 10, 27–28, 37

Cancer, pancreatic

Axitinib Inlyta

15, 43 17

B Basal cell carcinoma Bavencio (inj) cancer, bladder cancer, renal melanoma

43, 45 15 15 43

16

E

21

1

Avelumab Bavencio (inj)

10, 44

Durvalumab Imfinzi (inj)

Enzalutamide Xtandi

3, 9, 11

Aromasin

9, 15, 33

Dermatofibrosarcoma protuberans

9

7, 28, 32–37 5, 9, 33 2, 10, 13, 19, 36 16–21 9, 12, 15, 17–20, 33, 37, 46

Cancer, stomach

2, 10

Cancer, testicular Cancer, thyroid

35, 46

Eloxatin (inj)

2, 8–10, 12–15, 27, 33

Cancer, ovarian

9, 15, 33 9, 15, 33 9, 33 9, 15, 33 9, 15, 33

Dabrafenib Tafinlar

16

Cancer, lung

Avastin (inj) cancer, cervical cancer, colorectal cancer, ovarian cancer, renal glioblastoma non-small cell lung cancer

D

43

1

Cancer, renal

9 33

Eligard (inj)

Arimidex

Cancer, prostate

Cyramza (inj) cancer, GI cancer, lung

Efudex (ext)

1

19, 37

37

9, 15, 33

12, 18

Atezolizumab Tecentriq (inj)

43

Crizotinib Xalkori

1–8, 10–11, 14, 28, 37

Cancer, liver

Anastrozole Arimidex

Cotellic

16 12, 18

Capecitabine Xeloda

8, 14

Erbitux (inj) cancer, colorectal cancer, head and neck Eribulin Halaven (inj)

10, 27 10, 27 2

Erivedge

43

Erlotinib Tarceva

36

Estrogens, esterified Menest

18

Everolimus Afinitor Exemestane Aromasin

1, 15 1

Casodex

16

Ceritinib Zykadia

F

38

Faslodex (inj)

2

Femara

2

Cetuximab Erbitux (inj)

10, 27

Chorioadenoma destruens

7, 28, 37

Choriocarcinoma, gestational

7, 28, 37

Cobimetinib Cotellic Colorectal cancer

43 10–11

Fluorouracil Efudex (ext) Fluorouracil

43 2, 10

Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach

2, 10 2, 10 2, 10 2, 10

48 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

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Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

Fulvestrant Faslodex (inj) Fusilev (inj)

2

Imatinib Gleevec

10

Imfinzi (inj)

16

Imlygic (inj)

44

G Gefitinib Iressa GI stromal tumors Gilotrif Gleevec dermatofibrosarcoma protuberans GI stromal tumors hypereosinophilic syndrome leukemia, acute myeloid leukemia, chronic eosinophilic leukemia, chronic myelogenous mastocytosis myelodysplastic syndromes Glioblastoma

34 10, 13, 19, 44 33

10, 44 10, 44 10, 44 10, 44 10, 44 10, 44 10, 44 10, 44 9, 15, 33

H Halaven (inj) Herceptin (inj) cancer, breast cancer, GI Histrelin Vantas Hydatidiform mole Hydrea Hydroxyurea Hydrea Hypereosinophilic syndrome

ALPHABETICAL INDEX

2 3, 11 3, 11 20 7, 28, 37

10, 44

Inlyta

17

Ipilimumab Yervoy (inj)

46

Iressa

34

Ixabepilone Ixempra (inj)

3

Ixempra (inj)

3

J Jevtana (inj)

17

K

Leuprolide Eligard (inj)

16

Levoleucovorin Fusilev (inj)

10

Lonsurf

12

Lynparza

5

M Malignant pleural mesothelioma

32

Kadcyla Keytruda (inj) cancer, bladder cancer, head and neck cancer, renal colorectal cancer melanoma non-small cell lung cancer

4

45 34 43–47

Melanoma, metastatic

46

Menest

18

Methotrexate Trexall

7, 28, 37

Mycosis fungoides

7, 28, 37

34

N

4

Kisqali Femara Co-Pack

4

L

27

Lenvatinib Lenvima

18

Lenvima

18

Leucovorin

Mekinist melanoma non-small cell lung cancer

17 27 17 11 44

Kisqali

Letrozole Femara Kisqali Femara Co-Pack*

10, 44

Melanoma

27

I

10, 44

Mastocytosis

Lapatinib Tykerb

10, 44

Leukemia, chronic myelogenous

7

2 4 12

Myelodysplastic syndromes

10, 44

Necitumumab Portrazza (inj)

35

Neoplasms

20

Neratinib Nerlynx

5

Nerlynx

5

Neuroendocrine tumors

13, 19

Nexavar cancer, liver cancer, renal cancer, thyroid

12, 18 12, 18 12, 18

Nivolumab Opdivo (inj)

Ibrance

3

Ifex (inj)

16

Leukemia, acute myeloid

10, 44

Non-Hodgkin’s lymphoma

Ifosfamide Ifex (inj)

16

Leukemia, chronic eosinophilic

10, 44

Non-small cell lung cancer

12, 18, 27, 35, 45 7, 28, 37 9, 15, 32–38

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

CancerTherapyAdvisor.com | MARCH/APRIL 2018 | CANCER THERAPY ADVISOR 49

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ALPHABETICAL INDEX O

S

Odomzo

45

Olaparib Lynparza

5

Opdivo (inj) cancer, colorectal cancer, head and neck cancer, lung cancer, renal melanoma

12 27 35 18 45

Osimertinib Tagrisso

36

Oxaliplatin Eloxatin (inj)

9

P Paclitaxel, protein-bound Abraxane (inj)

Sipuleucel-T Provenge (inj)

19

Soltamox

6

Sonidegib Odomzo

45

Sorafenib Nexavar

12, 18

Stivarga

13

3

Panitumumab Vectibix (inj)

13

Pazopanib Votrient

20 11, 17, 27, 34, 44

Pemetrexed Alimta (inj) Perjeta (inj)

32 6

43 13, 19 13, 19 13, 19

6

Portrazza (inj)

35

Proleukin (inj)

46

Provenge (inj)

19

R Radium Ra 223 dichloride Xofigo (inj) Ramucirumab Cyramza (inj) Regorafenib Stivarga Ribociclib Kisqali Kisqali Femara Co-Pack*

T Tafinlar melanoma non-small cell lung cancer

46

21

13 4 4

Trifluridine Lonsurf*

12

Triptorelin Trelstar (inj)

20 7

V Valrubicin Valstar

20

Valstar

20

Vantas

20

Vectibix (inj)

13

Vemurafenib Zelboraf

47

Verzenio

7

Vismodegib Erivedge

43

Tagrisso

36

Votrient

20

Talimogene laherparepvec Imlygic (inj)

44

X

6 6

Xalkori

Tamoxifen Soltamox Tamoxifen Tecentriq (inj) cancer, bladder cancer, renal

36 19, 37 19, 37

Tipiracil Lonsurf*

12

Trametinib Mekinist

34, 45

Trastuzumab Herceptin (inj)

3, 11

Trelstar (inj) 9, 33

7, 28, 37

35

Tarceva

Pertuzumab Perjeta (inj)

7, 28, 37 7, 28, 37 7, 28, 37

13, 19

Superficial basal cell carcinoma Sutent cancer, pancreatic GI stromal tumors neuroendocrine tumors

choriocarcinoma, gestational hydatidiform mole mycosis fungoides non-Hodgkin’s lymphoma

Tykerb

Sunitinib Sutent

1, 32

Palbociclib Ibrance

Pembrolizumab Keytruda (inj)

Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

Trexall cancer, breast cancer, head and neck cancer, lung chorioadenoma destruens

20 7, 28, 37 7, 28, 37 7, 28, 37 7, 28, 37

Xeloda cancer, breast cancer, colorectal

37 8, 14 8, 14

Xofigo (inj)

21

Xtandi

21

Y Yervoy (inj)

46

Z Zaltrap (inj)

14

Zelboraf

47

Ziv-aflibercept Zaltrap (inj)

14

Zykadia

38

Zytiga

21

50 CANCER THERAPY ADVISOR | MARCH/APRIL 2018 | CancerTherapyAdvisor.com

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