Dec 2014

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • December 2014 • Vol. 9, No. 12

SOLID TUMORS

Report From ESMO Everolimus yields OS benefit in patients with advanced pancreatic neuroendocrine tumors ........

Partisanship killed 2014 federal bill; states still active 4

CURRENT PRACTICE Early progress seen in pediatric immunotherapy ....................

13

What do you do when a patient refuses care? ...........

19

HEMATOLOGIC DISEASE Florent Malard, MD, and Mohamad Mohty, MD: How I manage relapsed and refractory MM ................

New recommendations reflect advances for HL and NHL ....................................

by the

IMAGES in ONCOLOGY

Parity for Oral Chemotherapy On 2015 Agenda

INSIDE

King of Prussia, Pa.—Federal oral chemotherapy parity legislation is dead, at least for this year, according to Matt Farber, MA, the director of provider economics and public policy at the Association of Community Cancer Centers (ACCC). However, this and other bills will be reintroduced next year.

Part of the reason that it was so difficult to get legislation passed is the “hyper” partisanship of legislators today, Mr. Farber explained at see CHEMO PARITY, Y page 14

22

Alarming Trend:

27

Colorectal Cancer Rates Are Surging In Younger Patients

numbers

Changing rates of colorectal cancer: younger vs older

EDITORIAL BOARD COMMENTARY

Philadelphia—A growing number of younger patients are being diagnosed with aggressive colorectal cancer, even as the incidence of the disease among older patients is declining, new research shows.

The incidence of early-onset colorectal cancer (CRC) among patients younger than age 50 has been rising at an annual rate of 1.5% per year, compared with an annual decrease of 3.1% among older individuals over the past decade, according to the study. Individuals with early-onset disease tend to have larger tumors that are more likely to metastasize. see COLORECTAL, page 9

Prostate cancer cells. New analysis of CHAARTED presented at the ESMO 2014 Congress shows the relative benefit of docetaxel increases in high-volume disease; story on page 8.

Are We Ready for a Paradigm Shift in Cancer Investigation?

A

t times it appears that a week does not go by without a report in a high-impact journal strongly suggesting that the “standard of care” for a cancer in a particular clinical setting must change based on the unique molecular biology in a subset of patients.

Of course, any reported finding requires confirmation, and some have questioned the overall clinical impact of this ongoing evolution in the understanding of the role of “driver abnormalities” in individuMaurie al cancers; however, in my opinion, the acceleration in the rate of disMarkman, MD covery of useful (“actionable”) data that can be employed in routine cancer care is simply staggering.

With this background in mind, this commentary poses a provocative question that potentially has high clinical relevance. It is recognized that a number of molecularly “targeted” antineoplastic agents approved by drug regulatory agencies and commercially available in a specific clinical setting were previously examined in clinical trials in tumor types outside of existing regulatory approval, based, at that time, on rational hypotheses suggesting that the “target” could be affected favorably. see PARADIGM SHIFT, T page 20

Pancreatic Cancer Research Update: Advancements in Diagnosis and Immunotherapy See page 10.

FO L NEW RM IQ — UL UID AT IO N

Single-agent TREANDA® (bendamustine HCl) Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months

All responders (n=74)

(95% CI: 7.1, 10.8)

Patients who achieved a CR/CRu

10.4 months

1

(95% CI: 9.3, 13.6)

8.3 months

Patients who achieved a PR

1

(95% CI: 6.3, 10.8)

0

2

4

6

8

10

12

Months The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

Indication TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions.

Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels.

There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia.

Please see accompanying brief summary of Full Prescribing Information on the following pages.

Learn more at TREANDAHCP.com Reference: 1. Data on file. Teva Pharmaceuticals.

of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40367 November 2014

™

Brief Summary of Prescribing Information for Indolent B-cell NonHodgkin Lymphoma That Has Progressed 1 INDICATIONS AND USAGE 1.2 Non-Hodgkin Lymphoma (NHL) TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHL Recommended Dosage: g The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.

Dose Delays, y , Dose Modifications and Reinitiation of Therapy py for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant * Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ) Grade 1 and/ or the blood counts have improved [Absolute Neutrophil Count (ANC) * 1 x 109/L, platelets * 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution.

Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/ 0.45% Sodium Chloride Injection, USP, for dilution, as outlined above.

No other diluents have been shown to be compatible.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be * 1 x 109/L and the platelet count should be * 75 x 109/L. [See Dosage and Administration (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

TREANDA® (bendamustine hydrochloride) Injection

TREANDA® (bendamustine hydrochloride) Injection

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain.

Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions]] of the label: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (* 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).

The most common non-hematologic Grade 3 or 4 adverse reactions (* 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100)

94 (53)

13 (7)

0

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

Number (%) of patients* All Grades Grade 3/4

System organ class Preferred term

continued Infections and infestations 5 (3) 18 (10) Herpes zoster 0 18 (10) Upper respiratory tract infection 4 (2) 17 (10) Urinary tract infection 0 15 (9) Sinusitis 9 (5) 14 (8) Pneumonia 11 (6) 11 (6) Febrile neutropenia 2 (1) 11 (6) Oral candidiasis 0 11 (6) Nasopharyngitis Investigations 3 (2) 31 (18) Weight decreased Metabolism and nutrition disorders 3 (2) 40 (23) Anorexia 8 (5) 24 (14) Dehydration 1 (<1) 22 (13) Decreased appetite 9 (5) 15 (9) Hypokalemia Musculoskeletal and connective tissue disorders 5 (3) 25 (14) Back pain 0 11 (6) Arthralgia 2 (1) 8 (5) Pain in extremity 0 8 (5) Bone pain Nervous system disorders 0 36 (21) Headache 0 25 (14) Dizziness 0 13 (7) Dysgeusia Psychiatric disorders 0 23 (13) Insomnia 1 (<1) 14 (8) Anxiety 0 10 (6) Depression Respiratory, thoracic and mediastinal disorders 1 (<1) 38 (22) Cough 3 (2) 28 (16) Dyspnea 1 (<1) 14 (8) Pharyngolaryngeal pain 0 8 (5) Wheezing 0 8 (5) Nasal congestion Skin and subcutaneous tissue disorders 1 (<1) 28 (16) Rash 0 11 (6) Pruritus 0 9 (5) Dry skin 0 9 (5) Night sweats 0 8 (5) Hyperhidrosis Vascular disorders 2 (1) 10 (6) Hypotension *Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology variable

All Grades

Grades 3/4

Lymphocytes Decreased

99

94

Leukocytes Decreased

94

56

Hemoglobin Decreased

88

11

Neutrophils Decreased

86

60

Platelets Decreased

86

25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in * 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.

4

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Report From ESMO

Everolimus Yields Some OS Benefit in Advanced pNET Madrid—Everolimus provided a meaningful, albeit not statistically significant, gain in overall survival (OS) compared with placebo for patients with advanced pancreatic neuroendocrine tumors (pNET), according to final results from the RADIANT-3 trial presented at the European Society for Medical Oncology (ESMO) 2014 Congress.

Although the difference in OS did not reach statistical significance in a conventional intention-to-treat analysis, 85% of placebo patients crossed over, and the median six-month OS advantage was reinforced by a methodology suggesting that the difference might be greater after compensating for the crossover.

Patients randomized to everolimus (Afinitor, Novartis) in this Phase III trial achieved a median OS of 44 months, which exceeds the median OS reported in previous studies with alternative agents, including sunitinib (Sutent, Pfizer) and streptozocin (Zanosar, Teva)-based chemotherapy, according to James Yao, MD, a professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer

Center, in Houston, who presented the results at the meeting (abstract 1132O).

In this international study, 410 patients with advanced pNET were randomized to best supportive care plus everolimus 10 mg daily or placebo. The progressionfree survival (PFS) advantage of everolimus of more than six months (hazard ratio, [HR], 0.35; P<0.001) was previously reported ((N Engl J Med d 2011;364[6]:514523, PMID: 21306238).

The most recent analysis evaluated OS from randomization to the final data analysis in March 2014. By that time, 61% of everolimus and 64% of placebo patients had died. Since initial randomization, 85% of patients originally assigned to placebo had taken everolimus. Those initially randomized to everolimus had a median OS of 6.3 months longer than those initially randomized to placebo. Although this difference did not reach statistical significance (HR, 0.94; P=0.3), rates of survival were consistently greater among patients treated with everolimus when the two groups were compared at 12, 24, 36 and 48 months of follow-up. When evaluated with the

TREANDA® (bendamustine hydrochloride) Injection Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.

No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons.

16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°46°F). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved.

9/2013 (Label Code: 00016287.06) TRE-40366 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

Rank-Preserving Structural Failure Time (RPSFT) method of adjusting for crossover, the analysis indicated a high probability of a meaningful OS advantage.

The ESMO-invited discussant, Alexandria T. Phan, MD, a gastrointestinal medical oncologist at Methodist Cancer Center, in Houston, said that using the RPSFT to adjust for the crossover, “the take-home for clinical practice is that the median survival is at least 6.3 months longer on everolimus relative to placebo and at most 23.4 months longer.”

However, Dr. Phan suggested that a similar crossover phenomenon also is likely to have obscured the OS advantage of sunitinib, which was evaluated in a Phase III trial published simultaneously with RADIANT-3 ((N Engl J Med 2011;364[6]:501-513). Although the median OS was approximately 10 months longer in RADIANT-3 than in the Phase III trial with sunitinib, a cross-trial comparison ignores potential differences in the populations enrolled. Using the same RPSFT analysis, Dr. Phan noted that the range of probable OS benefit for everolimus and

sunitinib, which also achieved about a six-month PFS advantage over placebo (HR, 0.42; P<0.001), overlapped.

In the absence of direct evidence that survival is longer with everolimus, tolerability may be relevant. In the RADIANT-3 study, stomatitis was the most common adverse event (AE) overall and also the most common AE requiring dose modification. For sunitinib, diarrhea and hematologic AEs were the most frequently reported AEs, with about 30% of patients requiring some dose modification.

As for selecting between everolimus and sunitinib as first-line therapy, Dr. Phan said that, after adjusting for crossovers, “clearly both drugs, especially everolimus, demonstrate overall survival improvement.” In clinical practice, selection of one treatment over another may be best done on an individual basis.

—Ted Bosworth Dr. Yao reported financial relationships with Ipsen, Novartis and Pfizer. Dr. Phan reported financial relationships with Ipsen and Novartis.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD, PhD University of California San Diego, CA

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Hematologic Malignancies Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Texas, MD Anderson Cancer Center Houston, TX

University of Alabama Birmingham, AL

Pharmacy Shaji Kumar, MD

Gastrointestinal Cancer

Mayo Clinic Rochester, MN

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Mitchell Cancer Institute Mobile, AL The Pritchard Group, Rockville, MD

Matt Brow

University of Colorado Cancer Center Denver, CO

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Genitourinary y Cancer Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Sara S. Kim, PharmD

Richard Stone, MD

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Policy and Management

Cindy O’Bryant, PharmD

Edward Chu, MD University of Pittsburgh Cancer Institute Pittsburgh, PA

Cleveland State University Cleveland, OH

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Joseph P. DeMarco, PhD

Oncology Nursing

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

Steven Vogl, MD

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists providing the best possible care for their patients.

Medical Oncologist New York, NY

Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings, such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members also are consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc.

Lung g and Head and Neck Cancers Edward S. Kim, MD

Steven D. Passik, PhD

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Lung g Cancer,, Emesis Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

How I Manage articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Report From ESMO

In Relapsed Ovarian Cancer, Cediranib Sustains QoL Results add to earlier data showing survival benefit with this VEGF inhibitor Madrid—Expanding on last year’s Phase III trial evidence that the experimental tyrosine kinase inhibitor cediranib in combination with chemotherapy improves survival over chemotherapy alone in relapsed platinum-sensitive ovarian cancer, a new substudy has found that it also sustains patient quality of life (QoL). These and other data have rekindled interest in an agent for which development had once been abandoned.

In the QoL substudy of the ICON6 Phase III trial, “there was no global quality-of-life difference at 12 months that would offset the potential survival advantage,” reported Daniel Stark, MD, a senior lecturer at St. James Institute of Oncology, in Leeds, United Kingdom.

Presenting the preplanned substudy data at the European Society for Medical Oncology (ESMO) 2014 Congress (abstract 875O), Dr. Stark acknowledged that the substudy hypothesis—that cediranib would provide a QoL advantage— was not observed, but he said that QoL was reasonably good in both arms of the study once patients reached the maintenance phase.

In this study, 456 patients with ovarian cancer who were relapse-free for at least six months after first-line chemotherapy were randomized at the time of relapse to one of three arms. Patients in arm A received six cycles of a platinum-based chemotherapy followed by placebo maintenance. Those in arm B received the same chemotherapy plus cediranib followed by placebo maintenance. Arm C patients received chemotherapy plus cediranib followed by

The ‘well-developed blood supply’ of cervical cancers makes novel inhibitors of the VEGF pathway attractive in cancer control.

—Paul Symonds, MD cediranib maintenance. In results initially presented at the 2013 ESMO, arm C yielded a significant advantage for median progression-free survival (PFS; 12.5 vs. 9.4 months; P<0.001) and median overall survival (20.2 vs. 17.6 months; P=0.042) relative to arm A. The activity of cediranib in ovarian cancer came after its manufacturer, AstraZeneca, had announced plans to abandon further development of this agent, which targets the vascular endothelial growth factor (VEGF) pathway.

The decision was based on disappointing activity with this agent in lung and colorectal cancers.

However, this decision is being reconsidered based on mounting evidence that cediranib is active in highly vascularized cancers. In a Phase II

trial presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA5500) and recently published findings ((Lancet Oncol 2014;15[11]:1207-1214, PMID: 25218906), cediranib provided a PFS advantage when combined with olaparib (AstraZeneca) compared with olaparib alone in platinum-sensitive, relapsed ovarian, fallopian or peritoneal cancers.

The conclusion of the study was that a Phase III trial is warranted.

Data on other highly vascularized cancers also support substantial activity with cediranib. In the Phase II CIRCCa trial presented at the ESMO 2014 Congress (abstract LBA25-PR), cediranib was associated with substantial increases in overall response rate (66% vs. 42%; P<0.03) and PFS (median 35

vs. 30 weeks; HR, 0.61; P<0.046) compared with placebo in a randomized trial of patients with metastatic or recurrent cervical cancer. In this study of 69 patients, cediranib was tested on top of carboplatin plus paclitaxel.

The Phase II cervical data also encourage Phase III studies, according to the first author of the study, Paul Symonds, MD, from the Department of Cancer Studies and Molecular Medicine at the University of Leicester, in the United Kingdom. He indicated that the “welldeveloped blood supply” of cervical cancers makes novel inhibitors of the VEGF pathway attractive in cancer control.

Following the release of the Phase II data at ASCO and referencing the ICON6 trial, AstraZeneca issued a press release stating its interest in rekindling efforts to develop cediranib “with a view to potential regulatory submissions later this year.”

When contacted for her perspective, Joyce F. Liu, MD, a specialist in gynecologic cancers at Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, agreed that further exploration of cediranib in the treatment of highly vascularized tissues of the female reproductive tract “is of great interest” based on the series of completed studies showing “encouraging” potential.

—Ted Bosworth Drs. Stark and Symonds reported no relevant financial relationships.

Dr. Liu reported a financial relationship with Genentech.

Final Analysis Confirms:

Sustained OS Benefit From Bevacizumab in Cervical Cancer MNQrpQ—When bevacizumab is added to chemotherapy in patients with advanced cervical cancer, a relative overall survival (OS) advantage over chemotherapy alone continues to be observed after a median follow-up of 24 months and maximum followup of more than four years, according to the most recent and final analysis of a Phase III study. The finding, in the context of acceptable safety, reconfirms the clinical efficacy of this approach.

“The survival curves have remained separated in favor of bevacizumab through 50 months of followup,” reported Krishnansu S. Tewari, MD, a professor of obstetrics and gynecology at the University of California, Irvine. The data, presented at the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract LBA26), suggest that inhibition of the vascular endothelial growth factor (VEGF) pathway, the mechanism of action of bevacizumab (Avastin, Genentech), inhibits the growth of cervical cancer.

The primary results of this study were published earlier this year (N Engl J Med d 2014;370[8]:734-743, PMID: 24552320). In this trial, a 2×2 factorial design was used to evaluate both chemotherapy—comparing topotecan with paclitaxel when each is added to cisplatin—and the effect of adding bevacizumab relative to placebo. The topotecan and paclitaxel regimens did not yield in different OS results, but the addition of the VEGF inhibitor increased median OS by more than three months in the published report (17 vs. 13.3 months; P=0.004) as well as in the protocol-specified final analysis presented at ESMO 2014 (16.8 vs. 13.3 months; P=0.0068).

The major adverse events that were more common with bevacizumab included gastrointestinal (GI) or vaginal fistulae (8.2% vs. 0.9%), thromboembolic episodes (10.6% vs. 5.4%) and GI perforations (3.2% vs.

0%). It was noted that all GI perforations occurred in patients who had prior radiotherapy. Hypertension and neutropenia also were significantly more

common in patients who received bevacizumab relative to those who did not, but data presented in the original publication suggested that bevacizumab did not significantly diminish quality of life.

In August, bevacizumab became the first VEGF inhibitor to receive an indication for treatment of cervical cancer, a role reinforced by these OS data. This is consistent with Phase II trial data on cediranib, another VEGF inhibitor, which were presented at the ESMO 2014 Congress (abstract LBA25-PR; see story above). Overall, these data suggest that VEGF inhibition is a highly appealing target for recurrent cervical cancer due to the apparent importance of neovascularization in cervical tumor growth.

—Ted Bosworth

Dr. Tewari reported no relevant financial relationships.

It takes a compassionate heart and an analytical mind to get new therapies through the rigors of trials as well as developing business strategies to bring them to market. It takes a global healthcare solutions leader dedicated to enhancing patient care through end-to-end solutions for manufacturers, pharmacies and providers.

It takes AmerisourceBergen.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Report From ESMO: Early Docetaxel for Metastatic Prostate Cancer

Relative Benefit Increases With High-Volume Disease Madrid—In a new analysis of the practice-changing CHAARTED study, the relative benefit of early use of docetaxel for control of metastatic castrationsensitive prostate cancer (mCSPC) was found to be even greater in the subgroup of men with high-volume disease. Compared with the total population, all of the advantages, including median overall survival (OS), increased in the presence of greater disease burden.

The initial results of CHAARTED, also known as the E3805 trial, were presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA2; see http:// goo.gl/xUjltl). The new subgroup analysis in patients with high-volume disease was presented at the European Society for Medical Oncology (ESMO) 2014 Congress (abstract 756O). The data are mutually reinforcing.

In the completed trial, 790 patients with mCSPC were randomized to a standard course of androgen deprivation therapy (ADT) with or without six cycles of docetaxel (75 mg/m2 every three weeks), starting within four months of ADT. The most important result, reported at ASCO, was a more than one-year increase in overall survival (OS) (57.6 vs. 44.0 months; P=0.0003) in the group receiving docetaxel. In the retrospective analysis

presented at ESMO, the median OS in the 514 men with high-volume disease climbed from 32.2 months in the group receiving ADT alone to 49.2 months ( =0.0006) in those also receiving (P docetaxel (Figure).

Relative improvements in other measures, such as time to clinical progression, also were greater in the subgroup with high-volume disease compared with the overall study population, reported Christopher Sweeney, MD, a medical oncologist at DanaFarber Cancer Institute’s Lank Center for Genitourinary Oncology, in Boston.

Dr. Sweeney presented both the full CHAARTED results at ASCO and the subgroup analyses at ESMO. Docetaxel was associated with very

many experts to consider CHAARTED to provide practice-changing information, the substudy results provided an even stronger rationale for early docetaxel in patients with high-volume disease.

Commenting on the findings in an interview, Steven Vogl, MD, an oncologist in private practice in White Plains and the Bronx, New York, called the CHAARTED data “very important” and said “they should change practice.” But he said that the subgroup analysis does not yield any new

50

30

32.2

20 10 0 ADT OS

ADT + docetaxel OS

Figure. OS in patients with high-volume disease.

ADT, androgen deprivation therapy; OS, overall survival

Relative improvements in other measures, such as time to clinical progression, also were greater in the subgroup with high-volume disease compared with the overall study population.

—Christopher Sweeney, MD low rates of grade 3 or higher side effects and was well tolerated in the overall population and in those with high-volume disease.

Although the main results led

49.2

P=0.0006

40

Months

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perspective on the main results. Dr. Vogl, who provided a comment on CHAARTED for Clinical Oncology News (http:// goo.gl/H4ipcI) after the data were initially presented at ASCO, noted that

hazard ratios to calculate relative benefit were about the same in high- and low-volume patients, even though there were fewer events in the low-volume subgroup. The sub-analysis supports the previous results, he said, but “there is not much new” relative to the conclusions already reached.

—Ted Bosworth Dr. Sweeney reported financial relationships with Astella, BD Biosciences, BIND, Bionomics, Exelixis, Genentech, Janssen, Roche and Sanofi. Dr. Vogl reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Report From ESMO:

Biomarker Can Predict Benefit From Cetuximab in CRC

COLORECTAL continued from page 1

“Although the incidence in younger patients is still low compared with colorectal cancers in older populations, the trend is alarming and calls for more investigation and appropriate intervention,” said investigator Xi Emily Zheng, MD, PhD, a fellow in the Department of Healthcare Policy and Research at Weill Cornell Medical College, in New York City. Dr. Zheng’s group presented its findings at the 2014 annual meeting of the American College of Gastroenterology (abstract 7).

Using the Surveillance, Epidemiology, and End Results database from 2000 to 2011, the researchers compared the incidence and characteristics of CRC among patients younger than age 50 (n=39,787) with those of CRC patients who were older than 50 (n=330,009; Figure).

The New York researchers also found that younger CRC patients were more likely to be male (odds ratio, 1.13; 95% confidence interval [CI], 1.11-1.16) and black or Hispanic rather than white. Blacks had a 1.6-fold higher risk for CRC than whites (95% CI, 1.57-1.67) and Hispanics had a 2.1-fold higher risk than whites (95% CI, 2.07-2.21), Dr. Zheng said.

In addition to the trends in cancer incidence, Dr. Zheng and her colleagues also found that the rate of distant disease has increased 3% per year, whereas cases of localized or regional tumors have risen 1%.

This trend, which is being seen in clinical practice, is disturbing, said Al B. Benson III, MD, a professor of medicine and

randomized patients to receive chemotherapy alone or chemotherapy plus cetuximab before and after resection of colorectal liver metastasis. The trial results, published last spring in The Lancet Oncology (15[6]:601-611, PMID: 24717919), had showed that KRAS exon 2 wild-type patients who received cetuximab along with standard chemotherapy and surgery for operable colorectal liver metastases had significantly reduced progression-free survival (PFS) compared with patients who did not receive cetuximab. Surprisingly, the greatest detriment was seen in patients with better prognoses and occurred even in those who responded to treatment, leaving investigators searching for a biological explanation.

Dr. Primrose and his colleagues conducted the post-hoc analysis to look at biomarkers that could identify patients who benefit from treatments targeting epidermal growth factor receptor

Rate of Onset of CRC (per 100,000 population)

Madrid—The biomarker miR-31-3p predicts cetuximab’s efficacy in patients with all-RAS wild-type metastatic colorectal cancer, according to research presented during the European Society for Medical Oncology (ESMO) 2014 Congress.

This is the first biomarker that pinpoints a patient population likely to experience detriment from cetuximab, according to post-hoc analyses from New EPOC Study.

“The results of our study demonstrate that all-RAS wild-type metastatic colorectal cancer patients with high expression levels of miR-31-3p experience inferior progression-free survival when treated with the combination of chemotherapy plus cetuximab,” said study co-author John Primrose, MD, a professor of surgery at the University of Southampton, in England, and the chief investigator for the study.

The finding comes from post-hoc analysis of the Phase III trial, which had

(EGFR). They focused on patients without a KRAS or NRAS mutation.

The analysis revealed a strong relationship between miR-31-3p expression and patients’ outcome after treatment with chemotherapy plus cetuximab. Among patients with high expression of miR31-3p, those who received the combination of chemotherapy plus cetuximab had just over one-third of the median PFS of patients treated with chemotherapy alone (13 vs. more than 35 months; hazard ratio, 2.7; 95% confidence interval, 1.1-6.4; P=0.02). However, when only patients with low levels of miR-31-3p were evaluated, PFS was no worse with the addition of cetuximab.

In addition, the study identified a correlation between miR-31-3p expression in primary tumors and metastases in patients receiving chemotherapy alone but not in those receiving chemotherapy plus cetuximab, suggesting that miR-31-3p affects the EGFR

20-49 years regional localized distant

pathway, Dr. Primrose said.

“MiR-31-3p is a biomarker of harm from cetuximab, but we need to now understand the pathways involved and which genes are being regulated,” he said.

Co-investigator John Bridgewater, MD, a gastrointestinal oncologist at the University College London Hospitals, in London, England, said oncologists should take two key messages from the results. “Do not use EGFR inhibitors in a neoadjuvant setting, and there are complex molecular events about which we still understand very little.”

Investigators called for thorough testing of RAS status in all patients before giving an anti-EGFR antibody.

—Christina Frangou Dr. Primrose reported financial relationships with Bayer, Merck, Roche and Sanofi-Aventis. Dr. Bridgewater reported financial relationships with AstraZeneca, Merck, Roche and Sanofi.

50+ years 100

Overall: 1.5% increase

Overall: 3.1% decrease 75

4 50 2 25

0 2000

0 2001 2002 2003 2004 2005 2006

2007 2008

2009 2010

2011

2000

2001 2002 2003 2004 2005 2006

2007 2008

2009 2010

2011

Figure. Opposite trends of colorectal cancer incidence among younger vs. older patients at all stages, 2000-2011.

‘We are seeing increasing numbers of younger patients, and many are presenting with more advanced disease.’

—Al B. Benson III, MD the associate director for clinical investigations at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, in Chicago. “We are seeing increasing numbers of younger patients, and many are presenting with more advanced disease,” said Dr. Benson, who was not part of the study.

The tumors are more advanced in stage, of higher grade, larger size with more neural invasion compared with CRC in older patients. And they are more likely to metastasize, according to Dr. Zheng.

“The young-onset CRC is more likely to present with aggressive clinicopathologic characteristics compared with old-onset CRC. And the rising

incidence of young-onset CRC stratified by stage shows greatest up-trend for the advanced/distant disease,” Dr Zheng said, postulating that it could be due to the distinct underlying biology of this cancer in younger patients and/or a delay in diagnosis.

“It is not clear why this is happening and whether any of the associated risks for developing colon cancer are an issue, including diet, exercise, obesity, etc. This will have potential impact on how we screen patients for colorectal cancer and push a research agenda to find out how to identify patients at risk to inform screening strategies,” Dr. Benson added.

Both Dr. Zheng and Dr. Benson said

more data are needed before baselinescreening policies can be changed butsaid it would be reasonable to consider colonoscopy in younger black or Hispanic individuals with a family history of CRC. “Screening colonoscopies and removing polyps starting at a younger age would undoubtedly be helpful if we set aside cost,” Dr. Zheng told Clinical Oncology News. “Our study shows CRC diagnosed between 40 and 50 years of age accounts for more than 50% of young-onset CRC.” However, expanding screening to this population would not be cost-effective for our society, said Dr. Zheng, and risk stratification would be needed to determine which people should be screened earlier.

Dr. Zheng and her colleagues are trying to determine if young-onset CRC has a unique genetic profile.

—Marie Rosenthal

9

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Pancreatic Cancer Research Update: Advancements in Diagnosis and Immunotherapy Michel Kahaleh, MD, AGAF, FACG, FASGE Chief of Endoscopy and Medical Director, Pancreas Program Division of Gastroenterology and Hepatology Department of Medicine NewYork-Presbyterian/Weill Cornell Medical Center Center for Advanced Digestive Care, and Professor of Medicine, Weill Cornell Medical College

Yvonne Saenger, MD Director, Melanoma Immunotherapy Department of Medicine NewYork-Presbyterian/Columbia University Medical Center NCI-Designated Herbert Irving Comprehensive Cancer Center, and Assistant Professor, Columbia University College of Physicians and Surgeons

The Target: Pancreatic Cancer Pancreatic cancer typically develops without early symptoms and presents no dependable, clinically available means of early detection, so diagnosis is often delayed until an advanced stage and lethality is heightened.1 Surgical resection of the tumor, radiation therapy, and chemotherapy may prolong survival but rarely produce a cure.1 Novel, molecularly targeted therapies have generally failed to improve survival2 when added to chemotherapy (with the possible exception of the addition of the epidermal growth factor receptor [EGFR] inhibitor erlotinib to gemcitabine3).

The result: Pancreatic cancer, with a projected incidence of 46,420 new cases in 2014, will cause 39,590 deaths.1 Relative 5-year survival rate is a scant 6%.4 Clearly there are vast, unmet needs in the diagnosis and management of pancreatic cancer. The challenge is considerable, but two research teams at NewYork-Presbyterian Hospital are advancing the medical science in two key areas: definitive diagnosis, via the use of sophisticated imaging technology, and the development of immunotherapy to combat pancreatic cancer. The goal: improve clinical outcomes.

Reimagining the Workup Michel Kahaleh, MD, leads a team investigating the imaging of pancreatic cancer with probe-based confocal laser endomicroscopy (pCLE).5,6 This technique is especially suited to visualize difficult-to-access visceral regions, such as bile and pancreatic ducts.5 Therefore, pCLE has important applications for pancreatic cancer, which typically involves pancreatic ductal tissues and may extend to the bile duct.2 “Until the advent of pCLE,” Dr. Kahaleh said, “we were not always able to image pancreaticobiliary areas as thoroughly as we would like for definitive diagnosis and surgical planning.” A number of imaging modalities are used in the workup of pancreatic cancer—including computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography (ERCP)5,7—but

10

CLINICAL ONCOLOGY NEWS • DECEMBER 2014

definitive diagnosis, even with a combination of techniques, tissue pathology.5 When ERCP and pCLE were combined, is difficult.8 accuracy was 90%—significantly higher than the 73% accuFor example,ERCP provides valuable, direct visualization of racy of ERCP plus tissue acquisition (P=0.001). ductal epithelium but cannot offer images of sufficient preThis research led to the so-called Miami Classification—a cision for planning surgery, radiation therapy, or chemother- uniform and reproducible description of findings from panapy.5 The clinician is often compelled to round out the profile creaticobiliary pCLE.9 Miami criteria most suggestive of canwith histologic confirmation, a technique that cer on pCLE include thick dark bands, thick white itself confers limited accuracy.5 bands, dark clumps, or epithelial struc“pCLE The use of pCLE resolves this tures.9 A further classification problem; it verifies the presence schema—the Paris Classificais a way to confirm of pancreatic cancer while tion— expanded the criteria diagnosis, but even more, it is generating distinct images to improve pCLE accuracy in a technique that beautifully maps of great utility to the surdistinguishing benign from geon contemplating resecinflammatory pathology.10 pancreatic cancer, telling the surgeon tion. Dr. Kahaleh described A study conducted by Dr. exactly what to remove.” pCLE as “a way to confirm diagKahaleh and his team showed —Michel Kahaleh, MD nosis, but even more, a technique the importance of proper training that beautifully maps the cancer, tellto ensure interrater reliability when ing the surgeon exactly what to remove.” using pCLE.11 Because NewYork-Presbyterian/ Weill Cornell Medical Center is one of the first centers in the pCLE Methodology United States to use pCLE actively, affiliated clinicians are pCLE employs a miniaturized probe designed for use dur- among the best trained in the technology. ing the ERCP procedure.5 By funneling light through a confocal opening, the pCLE probe views the tissue subsurface with pCLE Linked to Better Management no interference from solid residues or secretion (bile or panDr. Kahaleh and his team recently completed a study of the creatic juice).5 For convenience, the probe can be inserted utility of pCLE of the pancreatic duct compared with cytologic via catheter or cholangioscope as a standard ERCP accessory and histologic results.6 The study has been accepted for pubdevice.5 lication in Digestive and Liver Disease. An important finding of Once the probe is placed in direct contact with the mucosa the study was that pCLE resulted in a favorable change in surat a selected pancreaticobiliary site, a solution of 10% fluo- gical management from total resection to partial resection.6 rescein sodium (2.5 mL) is injected intravenously.5 A scanning The study was conducted at 2 tertiary care centers: laser is then activated, and the site is microscopically evalu- NewYork-Presbyterian/Weill Cornell in New York City and Instiated, generating real-time, microscopic video sequences. tut Paoli-Calmettes in Marseilles, France. Clinicians conducted Images produced by pCLE are remarkably informative. “On pCLE via placement of the confocal probe through a pancrepCLE,” Dr. Kahaleh noted, “normal cells look organized and atoscope or catheter, advancing the probe into the pancreatic clear, but cancer is disorganized and dark. The images are duct. After obtaining real-time video images, endoscopists high contrast.” performed immediate interpretation according to the Miami Prior comparative research demonstrated that, in the Classification. These pCLE interpretations were compared detection of cancerous pancreaticobiliary strictures, pCLE with available cytologic and histopathologic material. attained an overall accuracy of 81% versus 75% for index Use of pCLE differentiated cases of benign (ie, inflammatory) disease, malignant neoplasm, intraductal papillary mucinous neoplasm of the pancreas, and normal tissue.

Agreement between the cytology/histopathology and pCLE results was nearly perfect. Most importantly, pancreatic pCLE altered management for some patients in this study, changing the choice of surgery from total resection to partial resection (pancreaticoduodenectomy).

“The study shows we can confirm cancer with pCLE,” Dr. Kahaleh said. “But in some patients, pCLE enabled us to guide the surgeon to a partial resection of the pancreas, sparing the patient a more extensive procedure. This is a meaningful clinical advance.”

Immunotherapy: The New Frontier Confocal imaging in pancreas cancer: Dark cells with disorganized architecture confirm the diagnosis of pancreatic cancer.

Courtesy of Dr. Michel Kahaleh

NewYork-Presbyterian/Columbia University Medical Center is participating in ECLIPSE (Efficacy of Combination Listeria/ GVAX Immunotherapy in the Pancreatic Cancer Setting),12 an ongoing, multicenter, Phase IIb study that compares immunotherapy with chemotherapy in metastatic pancreatic cancer.

Supported by

Two-Part Immunotherapy

expression on pancreatic cancer cells, coupled with minimal expression on normal tissues, makes mesothelin a good choice for tumor-selective immunotherapy.17 “The concept of CRS-207,” Dr. Saenger explained, “is that the mesothelin-expressing Listeria will trigger the immune system to pump out inflammatory mediators in response to a bacterium associated with the same protein that is present on cancer cells. In essence, the vaccine trains the immune system to attack when confronted with mesothelin.” The immune system is therefore more likely to attack pancreatic cancer cells, which express mesothelin. A Phase I study demonstrated both the safety and immune activation of CRS-207.17 The other component of this approach to immunotherapy is GVAX-irradiated pancreatic cell lines. GVAX relies on a classic vaccination model. The irradiated tumor cells enter the body and express granulocyte-monocyte colony-stimulating factor (GM-CSF) before they die.13 This elicits a broad immune response,13 triggering the immune system to target cells associated with GM-CSF. The immune system attacks not only the vaccine cells, but also the patient’s own GM-CSF–producing pancreatic cancer cells. GM-CSF is upregulated in pancreatic cancer, and may help to “mask” the tumor from the immune system.19 “In pancreatic cancer,” Dr. Saenger said, “the immune system has decided to accept the malignancy. We want to change that with GVAX, by creating strong signals to attack the cells associated with GM-CSF.”

Live attenuated Listeria monocytogenes vaccine is one component of the immunotherapy regimen.14 The use of bacteria to reduce solid tumors has a lengthy and fascinating history, dating back to at least the 1890s, when William Coley Phase II and IIb Studies injected bacterial mixtures called Coley’s toxins to In a Phase II study,13 patients with metastatic pan15 treat cancer. creatic cancer received either of 2 regimens: Listeria vaccines were evaluated GVAX/CRS-207—2 doses of GVAX (with “GVAX in a mouse model of pancreatic low-dose cyclophosphamide for plus mesothelinintraepithelial neoplasms in T-regulatory cell depletion) folexpressing Listeria is the most the Jaffee laboratory at Johns lowed by 4 doses of CRS-207 Hopkins. Dr. Saenger particievery 3 weeks; or GVAX alone—6 advanced treatment under study for pated in these earlier studies doses of GVAX/low-dose cyclopancreatic cancer right now.” before arriving at NewYorkphosphamide every 3 weeks.

—Yvonne Saenger, MD Presbyterian/Columbia. The bacFor the full cohort assessed after terium was genetically engineered a median follow-up of 7.8 months, to express Kras—hence the name of median overall survival (OS) was 6.1 the bacterium is LM-Kras. Study animals were months with GVAX/CRS-207 versus 3.9 months with bred for mutations KrasG12DD/Trp53R172HH/Pdx-1-Cre (KPC mice) GVAX alone (P=0.011). Among per-protocol patients, who or KrasG12D and Pdx-1-Cre.14 The mutant Kras was targeted received at least 3 doses of immunotherapy, median OS because it is a very common oncogene in human pancre- was 9.7 months with GVAX/CRS-207 versus 4.6 months with atic cancer.14,16 Mice received LM-Kras alone or LM-Kras in GVAX alone (P=0.0074). Adverse events included injection sequence with an anti-CD25 antibody and cyclophospha- site reactions after GVAX and transient fevers, rigors, and mide to deplete T-regulatory cells.14 lymphopenia after CRS-207.

Results were auspicious: Immunization of KPC mice with The Phase IIb ECLIPSE study20 compares the combination LM-Kras, when accompanied by depletion of T-regulatory of GVAX/CRS-207 to a physician’s choice of single-agent checells, reduced progression of early-stage pancreatic intraepi- motherapy or to CRS-207 alone in previously treated metathelial neoplasms.14 LM-Kras sequenced with cyclophospha- static pancreatic adenocarcinoma. The primary end point of mide increased infiltration of lesions by inflammatory cells.14 the study is OS in patients treated with GVAX/CRS-207 verThis study provided a proof of concept that Listeria-based sus OS in those treated with chemotherapy. The study is still immunotherapy might be useful in slowing progression of recruiting patients.12 If final results of ECLIPSE are favorable, pancreatic cancer.14 the next step may be submission to the FDA for approval.

In preparation for clinical studies, the Listeria bacterium “Immunotherapy offers great promise, giving us the potenwas manipulated to express the protein mesothelin, cre- tial for a durable response not seen with chemotherapy,” Dr. ating the vaccine now known as CRS-207.17 Mesothelin is Saenger said. “GVAX plus mesothelin-expressing Listeria is the highly expressed by pancreatic cancer cells, but not by nor- most advanced treatment under study for pancreatic cancer mal pancreatic cells or the cells of chronic pancreatitis.18 High right now.”

Leadership in Research NewYork-Presbyterian Hospital is a recognized leader in pancreatic cancer research, working to improve the dire outcome from this lethal disease. The comprehensive study and implementation of pCLE technology and Listeria-plus-GVAX immunotherapy together place this institution at the forefront of innovation in both diagnostic technology and clinical treatment. It is hoped that this culture of innovation will soon change the narrative for patients suffering from cancer of the pancreas.

References 1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Pancreatic Adenocarcinoma.

Version 2. 2014. www.nccn.org. Accessed November 9, 2014.

3. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-1966.

4. SEER Cancer Statistics Review 1975-2010. Age-adjusted SEER incidence and U.S. death rates and 5-year relative survival (percent) by primary cancer site, sex and time period. www. http://seer.cancer.gov/statfacts/ html/all.html. Accessed November 10, 2014.

5. Meining A, Chen YK, Pleskow D, et al. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc.

2011;74:961-968.

6. Kahaleh M, et al. Probe-based confocal laser endomicroscopy in the pancreatic duct provides direct visualization of ductal structures and aids in clinical management. Dig Liver Dis (in press).

7. Coté GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology. 2013;144:1262-1271.

8. Anderson CD, Pinson CW, Berlin J, et al. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004;9:43-47.

9. Meining A. Shah RJ, Slivka A, et al. Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures. Endoscopy. 2012;44:251-257.

10. Caillol F, Filoche B, Gaidhane M, Kahaleh M. Refined probe-based confocal laser endomicroscopy classification for biliary strictures: the Paris Classification. Dig Dis Sci. 2013;58:1784-1789.

11. Talreja JP, Sethi A, Jamidar PA, et al. Interpretation of probe-based confocal laser endomicroscopy of indeterminate biliary strictures: is there any interobserver agreement? Dig Dis Sci. 2012;57:3299-3302.

12. A phase 2B, randomized, controlled, multicenter, open-label study of the efficacy and immune response of GVAX pancreas vaccine (with cyclophosphamide) and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously-treated metastatic pancreatic adenocarcinoma. (NCT02004262). www.clinicaltrials.gov. Accessed November 10, 2014.

13. Dung TL, Wang-Gillam A, Picozzi V, et al. A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results.

J Clin Oncol. 2014;32 (suppl 3). Abstract 177.

14. Keenen BP, Saenger Y, Kafrouni MI, et al. A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology. 2014;146:1784-1794.

15. Shahabi V, Maciag PC, Rivera S, Wallecha A. Live, attenuated strains of Listeria and Salmonella as vaccine vectors in cancer treatment.

Bioengineered Bugs. 2010;1:235-239.

16. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 32:1801-1806.

17. Dung TL, Brockstedt DG, Nir-Paz R, et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res. 2012;18:858-868.

18. Hassan R, Laszik ZG, Lerner M, et al. Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 2005;124:838-845.

19. Greenhill C. Pancreatic cancer: the role of GM-CSF in pancreatic cancer unveiled. Nature Rev Gastroenterol Hepatol. 2012;9:426.

20. Dung TL, Wang-Gillam A, Picozzi V, et al. A phase 2b, randomized, controlled, multicenter, open-label study of the efficacy and immune response of GVAX pancreas vaccine and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). J Clin Oncol. 2014;32(suppl 5s). Abstract TPS4159.

BB1426

The immunotherapy studied is a novel combination vaccine: GVAX-irradiated pancreatic tumor cells plus live, attenuated Listeria monocytogenes (CRS-207). This study was initiated by Elizabeth Jaffee, MD, at Johns Hopkins Medical Center, Baltimore, Maryland, and is based on years of basic immunology research in several laboratories around the country.

According to Yvonne Saenger, MD, NewYork-Presbyterian/ Columbia researcher, findings to date in a Phase II trial of metastatic pancreatic cancer have already given “a positive signal that GVAX plus Listeria as immunotherapy is clinically superior to GVAX alone.”13 Dr. Saenger declared that this finding “brings hope to the setting of pancreatic cancer, where, as we know, chemotherapy is often not very effective.” If the Phase IIb ECLIPSE trial produces favorable outcomes for the GVAX-plus-Listeria vaccine in comparison to chemotherapy, researchers will be even more encouraged.

The term vaccine should not be confused in this case with precancer prevention; GVAX plus Listeria is an immunotherapeutic intervention for patients diagnosed with pancreatic cancer. “A fully preventive vaccine, along the lines of human papillomavirus vaccine, is not feasible in pancreatic cancer,” Dr. Saenger said, “given the complex etiology of the disease and the small population of high-risk patients who might be candidates for prevention.”

Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Challenges of Studying Targeted Therapies in Kids Small patient numbers and few drug development initiatives in pediatric population slow progress Chicago—In sharp testament to achievements in pediatric oncology over the past 15 years, oncologists and researchers now are challenged to find enough pediatric cancer patients suited for the study of new targeted agents.

“As we become better at treating our patients, there are fewer patients with relapsed or refractory disease and fewer patients available for studying of new agents,” said Lindsay Baker Kilburn, MD, a hematologist/oncologist at National Children’s Medical Center, in Washington, D.C., who presented a summary of research into therapeutic approaches for children during the 2014 annual meeting of the American Society of Clinical Oncology (ASCO).

In recent years, researchers have zeroed in on the biology of pediatric cancers as they hunt for better therapies, mirroring the trend in adult oncology. As they learn more about the distinct biology of pediatric cancers, children who were previously diagnosed as having a single disease are being grouped into smaller subsets, leaving fewer patients suited for studies of these agents, said Dr. Kilburn. “So getting the right patients to study many of these targeted therapies becomes more complicated.”

Pediatric oncology always has lacked sufficient patients to run Phase III clinical trials, said Johannes Wolff, MD, the chairman of pediatric hematology, oncology and blood and marrow transplantation at the Cleveland Clinic Foundation in Cleveland. But designing effective trials has become more difficult in the era of targeted

therapy, he said. As a result, Phase III trials are not the standard for assessing molecularly targeted therapies in pediatric oncology.

Oncologists have had to develop unique tools to study drug efficacy in children, he said. “We’ve learned to analyze outcomes with much smaller patient numbers, and it is a process in the scientific community to find acceptance for those novel biostatistical methods,” said Dr. Wolff, who has published extensively about new types of clinical studies that could assess targeted therapies for children. In a 2012 report that outlined new approaches, Dr. Wolff recommended that clinicians and researchers use genomics-based analysis along with morphoproteomic analysis to help select therapeutic targets and regimens for children ((Pediatr Blood Cancer 2012;59[1]:27-33).

In an interview, he stressed that clinicians need to perform detailed outcome evaluations for all of their pediatric patients, including comparisons of individual tumor response with targeted therapy to predicted responses. “If we have success with that, we would possibly be able to find new ways to approve drugs, and to make it possible

for the whole world to do things that are really impossible now.”

Insufficient numbers are just one part of the problem in studying targeted therapies in children, said Dr. Kilburn. Drug development initiatives in pediatric cancers are few, meaning that children generally are treated with drugs intended for adults. And children with recurrent or refractory cancers— the population most often used to evaluate new agents—sadly, have short survival, leaving limited information on long-term toxicities.

Randy Windreich, MD, an assistant professor of pediatrics at the University of Pittsburgh, said there is tremendous uncertainty about the long-term side effects of targeted therapies in children. Some have been shown to stunt the growth of pediatric patients, delay puberty or hasten the onset of conditions such as diabetes, Dr. Windreich told Clinical Oncology News. Other research is beginning to explore cognitive and neuropsychological effects.

“Some children will be taking these medications for a much longer time than their adult cancer counterparts, and the long-term effects on children may not be the same or may not

‘We’ve learned to analyze outcomes with much smaller patient numbers, and it is a process in the scientific community to find acceptance for those novel biostatistical methods.’

—Johannes Wolff, MD

be as well understood as those seen in adults,” he said. “When we’re talking about 50 or 60 years here, and possibly even longer, in contrast to maybe only 20 or 30 years in adult patients, there’s a lot more time for new, previously unknown adverse effects to arise.”

Even so, molecularly targeted therapies are opening up new alternatives for very sick children, said Dr. Windreich.

“It’s almost refreshing, for lack of a better word, to have options outside of standard chemotherapeutic agents to offer pediatric patients and, more importantly, to have encouraging data to back them up.” Dr. Windreich said “this is an area of pediatric oncology that will continue to be developed and will help further the movement toward individualized medicine where we no longer have to use a ‘one-size-fits-all’ approach and instead can tailor a patient’s treatment to his [or her] specific cancer.”

Field Still in Early Development Although no major studies of targeted therapies in pediatric oncology have been published or presented thus far in 2014, oncologists did release an “exciting” new model that will help get targeted therapies to kids in need, Dr. Wolff said. This spring, Vanderbilt-Ingram Cancer Center, in Nashville, Tenn., released an updated free mobile app, My Cancer Genome, which provides information about genetic alterations in various types of cancer and therapies available to treat those alterations. This Web-based approach will help clinicians select a therapy for patients based on their markers, he said.

He recommended that oncologists use the app and offered some suggestions for clinicians interested in starting pediatric patients on targeted therapies. “The key to remember is that ... we only use these therapies with our backs at the wall when we have nothing else to do,” Dr. Wolff said. He added that “as a scientist,” he feels “this should never be done unless you find a way to analyze the outcomes,” but “as a clinician,” he knows that “these patients need much more attention than regular patients who can follow a protocol.”

Underscoring the challenge of treating this patient population, he said, “many of these patients don’t make it despite the targeted therapy. It is the most difficult way in pediatric oncology because these patients are the sickest of all.”

—Christina Frangou None of the sources reported any relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Early Progress Seen in Pediatric Immunotherapy Chicago—Heralded as a game-changer in adult oncology, immunotherapy is reshaping pediatric oncology too, but in very different ways.

“Unlike our adult [oncology] colleagues who are looking at immunotherapy as possibly their only effective therapy, [in pediatrics] we’ve got an approach that we need to integrate into chemotherapy, radiation and surgery. That gives us a lot to be excited about,” said Paul M. Sondel, MD, PhD, the Walker Professor of Pediatrics and Human Oncology at the University of Wisconsin, Madison.

“This is really a paradigm shift for the field,” said Dr. Sondel’s colleague Christian Capitini, MD, an assistant professor of pediatric hematology, oncology and bone marrow transplantation.

“We’ve had the same three modalities for decades. There’s never really been a fourth option for kids once these modalities fail.”

Although the key studies presented at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) looking at immunotherapy in pediatric populations were preliminary Phase I studies, Drs. Sondel, Capitini and other experts said the research demonstrates that two types of immunotherapies—chimeric antigen receptor (CAR) therapy, also called adoptive T-cell therapy, and monoclonal antibodies—are revolutionizing treatments for children with cancer.

Explaining the potential advantage of immunotherapeutic techniques with respect to resistance, Dr. Capitini said, “Even if you have a new chemotherapy drug for kids who have relapsed, these new drugs tend to act in a similar pathway to some other drug they got before.

But when you talk about immunotherapy, resistance to chemotherapy does not mean resistance to immunotherapy. It’s a totally new tool in your armamentarium, so it gives a lot of people new hope.”

CAR Therapy Is a Breakthrough CAR therapy, in particular, is generating much excitement in pediatric cancer. In July, an experimental CAR therapy, CTL019, became the first cancer immunotherapy to receive the FDA’s “breakthrough therapy” designation, after preliminary data from a Phase I study showed that 89% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) had a complete response to therapy. The data, presented at the European Society for Blood and Marrow Transplantation’s annual meeting, reported on 22 children and five adults (abstract PH-O001).

Randy Windreich, MD, a pediatric oncologist at the Children’s Hospital of Philadelphia, where researchers have

been at the forefront of CAR therapy, said the short-term results in patients with ALL are very promising. “I think I share almost everybody’s excitement about the recent adoptive T-cell therapies for relapsed and refractory ALL. When ALL patients would relapse after bone marrow transplant, or when their leukemia would be so resistant to conventional chemotherapy that they could never even achieve remission, this would be an almost certain death sentence in the past. But now,” he said, “these new adoptive T-cell therapies offer some hope not only to patients and families, but also to pediatric oncologists, that there is another type of treatment that could offer potential cures to our patients with these very stubborn leukemias.”

Data presented at ASCO show that an innovative form of CAR therapy, known as dual or bispecific CAR therapy, offers enhanced therapeutic efficacy. Dual CARs carry two signaling domains, allowing simultaneous exposure to two antigens. In a study led by investigators at Baylor College of Medicine, in Houston, dual CAR therapy was shown to target HER2 and a mutated interleukin-13 molecule in high-grade glioma (HGG) cells (abstract 10027).

“Targeting the heterogeneity in HGG with such a multispecific T-cell approach could potentially achieve near-complete targeting of tumor subpopulations and reduce the risk of recurrence,” said the investigators, led

by Meenakshi Hegde, MD, an assistant professor in pediatrics at Baylor.

Dual CAR therapy can hit multiple different targets, resulting in an immune attack that should make it more difficult for a tumor to escape by losing its target, Dr. Sondel said. “It’s as though you are not only giving a drug that’s going to treat the cancer but you are, in essence, giving tiny biologic machines that are reproducing to be able to attack the cancer in a very large way,” he said. “This is an exciting approach that’s been used for patients with very refractory disease with some really terrific results.”

He noted that one potential obstacle with CAR therapy in pediatric leukemia is that the CAR T cells stay in children’s bodies for long periods, possibly damaging their healthy B cells.

Monoclonal Antibodies Show Promise Monoclonal antibody therapy has been established as another immunotherapy option in pediatric patients.

In 2010, Dr. Sondel and his colleagues published results from a Phase III study showing that a GD2 antibody known as ch14.18 significantly improved survival in children with high-risk neuroblastoma ((N Engl J Med d 363[14]:1324-1334,

‘It’s as though you are not only giving a drug that’s going to treat the cancer but you are, in essence, giving tiny biologic machines that are reproducing to be able to attack the cancer in a very large way.’

—Paul M. Sondel, MD, PhD PMID: 20879881). After two years, overall survival was 86% in the immunotherapy group and 75% in the standard-treatment group. The study was terminated early because of the benefit shown in the interim analyses. Experts said that long-term data are still needed to confirm that these therapies provide a sustained response.

But in the meantime, the experience with ch14.18 also shows the challenge of getting therapies out to kids who need them in a challenging fiscal environment, Dr. Capitini said. No pharmaceutical company wanted to make the antibody after the study because of small patient population. Until this year, the drug was available only on an experimental basis. In January, United Therapeutics took over production of ch14.18.

“If it were for lung cancer, I’m sure a company would have jumped on it

immediately with those kinds of results.

But with neuroblastoma, it’s only a handful of cases,” said Dr. Capitini, adding that he expects to see similar problems in the future with therapies for other rare cancers.

One of the next challenges will be to turn more attention to children with difficult-to-treat pediatric cancers, said Dr. Windreich. “We’ve made tremendous progress in developing immunotherapy for pediatric cancers, but there are still some major subgroups, such as those with metastatic sarcomas and brain tumors, who have not seen major improvements in survival despite intensifying treatments.”

—Christina Frangou Drs. Sondel, Capitini and Windreich did not report any relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Oral Chemotherapy Access Legislative Landscape

the ACCC’s Oncology Reimbursement Meeting, held in October. “It has just gotten so bad. The two sides will not work together.”

One bill that actually had bipartisan support was the Cancer Drug Coverage Parity Act (H.R. 1801/S. 1879), which would require private health insurers that offer IV chemotherapy benefits to patients with cancer to provide parity benefits for oral and self-injected anticancer drugs, increasing patient access to these medications.

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‘We must act now to address the growing crisis facing community-based care.’

—Brad Tallamy Oral and self-injected cancer medications can provide clinical advantages over more traditional cancer agents, and in some cases are “the only or the best treatment option” for a particular patient, Clifford Hudis, MD, FACP, who was the president of the American Society of Clinical Oncology (ASCO) at the time, explained in a 2013 letter to U.S. Rep. Brian Higgins (D-NY), one of the sponsors of the House bill.

Professional cancer associations, such as the ACCC and ASCO, as well as many patient cancer support and advocacy groups, have supported these bills, which also had “decent support” among legislators, according to Mr. Farber, who provided a legislative update at the ACCC meeting.

Although federal efforts to approve oral chemo parity legislation have failed, local efforts have been very successful. “On the state level, there has been a lot more success in getting these laws passed,” he said.

“There have been 30 states plus the District of Columbia that have passed oral [drug] parity legislation.”

Sequestering Sequester Cuts Another cancer drug bill, the Cancer Patient Protection Act (H.R. 1416), also was not passed this year. This bill would have exempted physicianadministered cancer drugs, mostly at clinics, from sequester cuts, according to Mr. Farber. Sequestration is automatic, broad spending cuts that Congress imposed in 2011 after the Debt “Super Committee” failed to find enough spending cuts to reduce the national deficit by $1.2 trillion.

One of the results of the sequester was that the Centers for Medicare & Medicaid Services reduced reimbursements by 2% starting April 1, 2013.

These are across-the-board payment

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reductions that affect medications, including cancer drugs.

“We have been working on a bill that was introduced this year, H.R. 1416, which would exempt cancer drugs from the sequester cuts,” Mr. Farber explained. “We think pulling the drugs out is especially important because we have no say as providers in how much they cost, and it is really unfair to have a penalty on providers for something they have no control over.”

He said the Cancer Patient Protection Act garnered a lot of backers, with more than 100 members of Congress supporting it from both sides of the aisle, which is rare in Congress these days. However, there was no Senate companion bill, so it did not move ahead.

Grassroots Activity A new group, the Patient Access to Community Treatment (PACT) Coalition, formed this year to re-engage and re-energize Congress to roll back the sequester cuts. PACT met on Capitol Hill in September to bring the importance of preserving patient access to community care to the attention of legislators (map). Stakeholders discussed the financial and quality-of-life benefits of community care, as well as federal policies that have contributed to recent closures and consolidation of many community oncology practices.

Sequester cuts were on the agenda.

“We must act now to address the

growing crisis facing community-based care,” said Brad Tallamy, the director of PACT, citing data showing that since 2008, more than 1,300 community cancer centers have closed, consolidated with hospitals, merged or reported financial problems. Beyond that, 63% of small practices report they are likely to merge, sell or close operations in the next year. In addition to advocating for the Cancer Patient Protection Act, PACT is supporting potential legislative corrections, such as H.R. 800 and S. 806, which would exclude customary prompt-pay discounts from Medicare Part B reimbursement formulas.

According to the group, these legislative efforts are important steps toward stabilizing reimbursement to providers, which could enable them to stay in business.

SGR Cuts in the Crosshairs Another sore point for oncologists— and all other physicians—is the sustainable growth rate (SGR); Medicare uses this complex formula to set provider reimbursements, which are tied to the gross domestic product (GDP).

“Over the last six or seven years, the formula would call for significant reductions in Medicare payments to physicians,” Mr. Farber said.

Every year, Congress has stopped these reductions with short-term legislative fixes. These annual fixes have cost well over $138 billion, according

to Mr. Farber.

This year was the best shot that physicians had to permanently overturn the SGR. A new plan to replace the formula would have stabilized payments and tied reimbursement to quality measures that supported innovation, and it would have cost far less than all the short-term fixes taken together. “This year, we had a cheap price tag [and] bipartisanship— both houses and people from both parties supported the bill—but at the end of the day, they still had a short-term patch,” Mr. Farber explained.

Congress could not come up with a method to fund the new bill, so it died despite its widespread support, and, because it is the end of the year, Mr. Farber does not anticipate passage of any of the health care bills. “Nothing health care–related is going to pass [this year],” he said. In fact, “it is very unlikely that any health care issues will come up” during the lame duck session.

Next year, however, with a new Congress convening, it is possible that many of these issues and related legislation will resurface. If any health care bills are in fact reintroduced, Mr. Farber noted, it will be important for health care providers to contact their legislators and offer their views on the key provisions.

If lawmakers don’t hear about the consequences of these regulations, Mr. Farber warned, they won’t change them.

—Marie Rosenthal

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Inclusion of three top chemotherapy drugs draws ire

Genentech Doubles Down on Specialty Pharm Model G

enentech has moved all of its cancer infusion medications to the specialty distribution chain to ensure patient safety and better inventory control.

However, some hospitals are unhappy with this decision, citing several potential adverse consequences, including significantly higher drug purchasing costs, treatment delays, increased administrative burdens and a resultant strain on the manufacturer–oncology team relationship.

Charlotte Arnold, a spokesperson for Genentech in South San Francisco, Calif., said safety issues and other patient-focused concerns motivated the decision. “We are committed to patient safety and protecting the integrity of our medicines as they move through the supply chain, and we believe the specialty distribution model best serves patients’ safety and access to our infused cancer medicines,” Ms. Arnold said.

High Usage Equals High Concern Two of the three products moved to specialty distribution—bevacizumab (Avastin, Genentech) and rituximab (Rituxan)—are essential cancer therapies because they are indicated for multiple cancer types, according to Niesha Griffith, RPh, MS, an administrator of Oncology Pharmacy and Infusion Services at the Arthur G. James Cancer Hospital at The Ohio State University in Columbus. Combined with the third product, trastuzumab (Herceptin), which is used primarily for breast cancer, the medications are among the top five cancer treatments used globally.

As a result, there will be a significant financial impact from this change in distribution, according to Matt Farber, MA, the director of Provider Economics and Public Policy at the Association of Community Cancer Centers (ACCC), in Rockville, Md. With the move of these drugs to the specialty distribution chain, Mr. Farber noted, hospitals will spend considerably more for them than if they purchased the products through their normal wholesaler.

Ernest R. Anderson Jr., RPh, MS, a pharmacy consultant in Brockton, Mass., explained why a move to specialty pharmacy distribution can increase costs.

When hospitals order drugs through the normal distribution chain, he noted, they are privy to various discounts and rebates that specialty distributors are not. Hospitals also tend to purchase as many products as possible from the same distributor to receive a volume discount.

Hospitals estimate that they will spend an additional $200,000 to $4 million, depending on their size, to purchase

‘Even if [physicians] cannot [stop using Genentech products], the sheer fact that they are thinking about it ... should make Genentech stop and think about this.’

—Matt Farber these three products because they are so widely used for cancer treatment. These added expenditures could increase the cost for treating cancer by more than $300 million annually, several hospital pharmacists estimated.

However, these estimates are nearly impossible to confirm because they involve confidential contracting terms among manufacturer, distributor, hospital and payor, according to Jason Rucker, the director of Copay Offset Monitor at Zitter Health Insights, a health care research firm that assists companies with issues related to product access, reimbursement and managed markets.

Mr. Farber said ACCC members are also indicating that the loss in rebates and other discounts will be in the six figures or higher for individual hospitals and cancer centers, depending on the facility, so the financial piece is “definitely an issue.”

Using a separate specialty distributor for these cancer drugs also means additional ordering, invoicing, mailing costs and staff time, as well as waste disposal costs, pharmacy stakeholders point out. According to a letter sent to Genentech by the Hematology/Oncology Pharmacy Associ-

that the drug that they need and want will be available,” Mr. Farber stressed, adding that there has never been a supply problem with these three products when they went through the wholesalers.

Ms. Arnold agreed that access is an important issue. “Patients are our primary concern, and we believe patients are getting their medicines when they need them,” she stressed.

In fact, ensuring prompt access to these medications is another reason why Genentech decided to switch to specialty pharmacy. The products “require tighter inventory management than our other medicines,” she explained. “While we are not reducing the numbers of distributors, using the specialty pharmacy chain does reduce the number of distribution centers from 80 to five, and this helps us better manage and track our supply, particularly if the supply was to become constrained.”

As an example, Ms. Arnold said when pertuzumab (Perjeta) was launched in 2012, the FDA only approved a limited supply due to manufacturing challenges. “We were able to launch with a limited supply because the specialty distribution enabled us to better manage our inventory,

‘The majority of hospitals already have accounts set up and purchase our other three medicines [via the specialty pharmacy] … model with minimal concern from customers.’

—Charlotte Arnold ation (HOPA), which was signed by several groups, including ACCC, the packaging issue is a real burden. When products are shipped by courier services—the preferred method used for most specialty pharmaceuticals—the packaging is more extensive than that used by conventional distributors, and is not returned.

Ms. Arnold said that “while we don’t believe there has been an appreciable increase in shipping materials, we are working closely with our authorized distributors to ensure any potential additional packaging is kept to a minimum.”

Because of the sheer volume of these products being used in the United States today, providers say they are concerned about supply delays and patient access to the medications. “We want to make sure

and we were able to do that with no customer outages or patient impact,” she said.

Absorbing the Costs With most hospitals still facing financial constraints, there is a question as to whether they can absorb the added costs that may result from specialty distribution. Whether providers, patients or third-party payors will ultimately pay these costs “is too soon to tell,” Mr. Farber said. “Hospitals are looking at all the data now to see the best way they can move forward on this.”

Asked to comment on the potential for cost shifting, Ms. Arnold said, “There is no change to the list price or wholesale acquisition cost that Genentech charges for these medicines, so we don’t anticipate

any change in patients’ insurance or outof-pocket ability to pay.” As for the other players in this scenario, “we are not privy to and do not influence the terms between hospitals and distributors.”

One of those other players is the government. As the largest third-party payor through the Centers for Medicare & Medicaid Services, the Department of Veterans Affairs, and federal and state worker insurance plans, the government certainly has a stake in any drug distribution changes that might affect cost. However, there does not seem to be a legal means for government involvement in the dispute.

Other than a large facility getting its local representative to draft a letter to Genentech, “I don’t see any official action on the part of the government,” Mr. Farber said. “They might not be very happy, but I’m not sure [they have] recourse [unless patient] access is impinged.”

Ms. Arnold reminded pharmacists that they use the specialty channel for many cancer drugs and that this was “not a new model.” Many medications, including several other cancer therapies that Genentech manufactures (pertuzumab, ado-trastuzumab emtansine [Kadcyla] and obinutuzumab [Gazyva]), are distributed through the specialty supply chain, she pointed out.

“The majority of hospitals already have accounts set up and purchase our other three medicines this way. Starting with Perjeta in 2012, we launched cancer medicines into this model with minimal concern from customers.”

Still, “we recognize that some hospitals may need to make some adjustments to working with this slightly different delivery system for these medications,” Ms. Arnold said.

“This is in fact a very different situation,” Ms. Griffith countered. “The other drugs that are [purchased] through the specialty channel are not nearly as widely used as these three medications.” Those other agents, she noted, “are niche products that are used for a specific type of cancer. We see SPECIALTY MODEL, page 19

15

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy

Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” mCRC = metastatic colorectal cancer; OS = overall survival.

WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae.

Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41).

Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix ® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS/RAS mCRC • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted

from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis.

Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1

Visit www.vectibix.com

Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic g Toxicity: y Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRASS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)].

• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)].

Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRASS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RASS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)].

RASS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRASS or NRASS and hereon is referred to as “RAS.” DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRASS mutational status in colorectal tumors and confirm the absence of a KRASS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRASS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes.

Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].

Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Dose Modifications for Dermatologic g Toxicityy [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®.

If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose.

• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibixx®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)].] Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].]

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RASS and KRAS– S Mutant mCRC A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)].

Determination of KRASS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibixx®. Vectibixx® is indicated only for the treatment of patients with KRASS wild-type mCRC. Vectibixx® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)].] In Study 3, 221 patients with KRAS-mutant S mCRC tumors receiving Vectibixx® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41).

Perform the assessment for KRASS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®.

Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].

Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix ® versus the risk of pulmonary complications must be carefully considered.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis.

Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RASS and KRAS-Mutant S mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix ® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRASS mCRC. Vectibix® Monotherapy py In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).

Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1) Study 1

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inflammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Vectibix® Plus Best Supportive Care (N = 229) Any Grade Grade 3-4 n (%) n (%)

Best Supportive Care (N = 234) Any Grade n (%)

Grade 3-4 n (%)

13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66)

13 (6)

2 (< 1)

132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation.

The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix® in Combination with FOLFOX Chemotherapy py The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRASS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRASS mCRC were diarrhea and dehydration.

The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRASS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.

Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS S Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

116 (36) 96 (30) 68 (21) 26 (8)

46 (14)

14 (4) 21 (7) 32 (10) 8 (2)

30 (9)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1) 4 (1)

24 (7)

1 (< 1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1) 9 (3)

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibixx® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibixx® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibixx® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].]

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.

Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.

In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore ® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)]

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk.

Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.

Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibixx®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibixx® [see Clinical Pharmacology (12.3)].]

Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.

Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

22 (7)

85 (26) 26 (8) 42 (13) 10 (3)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10) 30 (9)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.

2 (< 1) 1 (< 1)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

SYSTEM ORGAN CLASS Preferred Term SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

6 (2) 1 (< 1) 15 (5) 5 (2)

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14.

Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved.

80748-R2-V1 – v22 10/14

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What Do You Do When a Patient Refuses Care?

F

aced with a young child with cancer who expressed a wish to cease treatment but had a strong potential of being cured with oncologic therapy, Florida oncologist Damon Reed, MD, said he would do everything in his power, including getting a court order, to deliver curative therapy to the patient.

A recent case in Canada highlights this dilemma that oncologists can face.

A 10-year-old aboriginal girl with acute lymphoblastic leukemia was told she would have a 75% chance of survival with treatment but that she would have a 100% chance of relapse and death if she ceased chemotherapy. Despite these odds, the girl said she wanted to use traditional aboriginal medicines, and her parents supported that decision.

But some oncologists, including Dr. Reed, the director of the Adolescent and Young Adult Program and medical director of the Sarcoma Department at Moffitt Cancer Center, in Tampa, Fla., would strongly disagree with that approach, given the high chance of success with chemotherapy. “I would have a huge problem with that decision,” Dr. Reed said, stressing that the process of cancer care should be “about determining the risks and benefits [of treatment].”

On the other hand, if the case was such that treatment offered a 5% cure rate, Dr. Reed said he would not as vigorously pursue treatment for the patient, given the prognosis was not very good.

Finding Common Ground The key to helping the families make good decisions is good, clear communication with the family and members of

SPECIALTY MODEL continued from page 15

are not talking about niche products [with the new distribution announcement]; we are talking about widely used, essential cancer treatments.”

Whether they verbalize a complaint to the manufacturer or not, Ms. Griffith added, “we are never happy when drugs go through the specialty channel.”

Genentech’s current move to specialty distribution carried an additional sting: The company did not give stakeholders a chance to express their concerns before the decision was made, and they had less than three weeks’ notice to prepare for the change, according to Mr. Farber.

Several stakeholders are trying to meet with Genentech to address some of these concerns and are considering various options for voicing their displeasure with the company. Sources said several facilities are talking about banning Genentech sales representatives from the hospital and denying them

the family’s religious community to ensure that the decision is a fully informed one, according to Theodore Moore, MD, the chief and clinical director of pediatric hematology/oncology and director of the Blood and Marrow Transplant Center at the University of California at Los Angeles Jonsson Comprehensive Cancer Center.

“We try to bring folks of similar faith [together] and see if there is common ground,” said Dr. Moore, noting that in the pediatric setting, the age of the patient is a factor that weighs into the decision making. “If the patient is at an age where [he or she] can arrive at an educated decision about treatment, and the decision is based on the patient’s faith, we would honor that decision. We can’t have such hubris that we think our way is the only way.” The availability of advanced treatments, such as targeted therapies, does not mean that they are right for all patients, he added.

Like Dr. Reed, Dr. Moore said clinicians are apt to be more forceful in advocating for treatment if there is a high probability of a patient being cured with therapy. “If you are talking about a 7-year-old child with Wilms’ tumor, where there is a 90% cure rate and few complications with treatment, you would want to bring in folks to help make the decision.”

Many hospitals and cancer centers have not developed policies to respond to these complex oncology cases, but typically

they have in place an ethics committee whose role may be to help resolve these dilemmas, said Paul Bunn, a past president of the American Society of Clinical Oncology and professor of medicine at the University of Colorado in Denver.

“It is certainly not frequent [to refer to a hospital ethics committee],” said Dr. Bunn in an interview.

“I have been in practice 30 years [in adult oncology], and the need for an ethics intervention has happened once. In that case, it was involving the [mental] competence of the patient and the power of attorney of the family.”

In the pediatric setting, being sensitive to the wishes of patients and families and their religious beliefs may require adding another voice to the dialogue, such as an ethicist, said William Meadow, MD, a professor of pediatrics and co-section chief of neonatology at the University of Chicago Medicine Comer Children’s Hospital.

“Oncology becomes complicated,” Dr. Meadow said. “There are issues, such as who is insisting against treatment and why and where the moral right should fall. If there is ambiguity, the family might go to the [hospital] ethics committee. The decision might be to err in favor of what the parents are saying.”

In particular, when a child has little chance of survival and 100% chance of morbidity, and has already endured multiple courses of chemotherapy and

the next therapeutic step is a risky intervention, such as a stem cell or bone marrow transplant, “more standing” might be given to parents questioning that next step, explained Dr. Meadow.

However, the decisions are much more divisive when treatment carries more potential benefit for the child.

“Physicians have an obligation to the child,” Dr. Meadow said. “It happens all the time that physicians can and will file for custody,” and courts have a longstanding history of decisions deemed in the child’s best interest.

The case of Chad Green illustrates this.

In the late 1970s, at the age of 2, Chad developed acute lymphocytic leukemia.

His parents did not want to resume chemotherapy and instead opted to try the unconventional treatment laetrile. A legal battle ensued, resulting in a court order outlining that Chad should be treated.

His parents chose to ignore the order, and the U.S. Supreme Court upheld the lower court order. The parents still refused chemotherapy, Chad died, and his parents were found guilty of criminal contempt.

Oncology treatment is typically more straightforward in the adult setting, where the expressed wishes of the patient are respected, said Amit Oza, MD, from Princess Margaret Cancer Center, in Toronto, Ontario, Canada. “Simply put,” Dr. Oza said, “adults of sound mind can refuse any treatment for any reason.

In such instances, with cancer patients, we continue to monitor disease progression and discuss other treatment options, including, as needed, palliative care.”

access to leading cancer doctors. Ascension Health, the largest nonprofit health system in the United States, is following through with such actions, according to an online report by the St. Louis Post-Dispatch (http://bit.ly/1oZIziz).

The facilities also are re-evaluating their participation in Genentech-sponsored clinical trials. A knee-jerk reaction would be to stop using Genentech products, but that option is less likely than the other two, Mr. Farber admitted. In some cases, there are other clinical treatment pathways that providers can take, but often these drugs are the clear choice for a given patient.

“The last one would be hard to [accomplish], given that doctors will always do what is clinically warranted and best for the patient,” Mr. Farber said. “Even if they cannot do that, the sheer fact that they are thinking about it, however, should make Genentech stop and think about this.”

Hospitals and cancer centers also are concerned that other companies will follow Genentech’s lead. “Unless you get a

loud enough and forceful enough pushback from the provider community, I do see this expanding,” Mr. Farber said.

“This is coming at a time when all of us are doing everything we can to control costs,” Ms. Griffith said. That makes it all the more worrisome, she said, to have to suddenly deal with the budget impact of increased costs associated with Genentech’s expanded specialty model.

Ms. Arnold stressed that the company values its partnership with the oncology community. “Our relationship to our customers is extremely important to us, and we will work with them on this change,” she said. “We believe doctors have the right to prescribe the medication that they think is best for their patient, and they will continue to do so.”

Based on a letter Genentech wrote in response to HOPA’s letter, which had little in it to indicate any compromise on the company’s part, Mr. Anderson predicted that the dispute “will be an extended battle.”

Mr. Farber concurred. Providers, he

noted, want to make sure that they have access to the therapies that they want to give, when they want to give them and where they want to give them. “My job is to try to stop anything that is going to get in the way of that,” he said. “If this new policy is going to [be such an obstacle], then we are going to try and push back as best we can against it.”

Ms. Arnold said Genentech has no plans to reverse its decision. But in late October, some movement came in the form of a conference call between the company, the ACCC and other stakeholders. “We wanted to make Genentech aware of the operational and financial difficulties getting drugs to patients,” said Mr. Farber, adding that the meeting had positives and negatives. During the discussion, Genentech said it would look into packaging and delivery issues. As for financial losses that may result from the initiative, the company reminded callers that it had a robust patient financial assistance program.

—Louise Gagnon

—Marie Rosenthal

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PARADIGM SHIFT

EDITORIAL BOARD COMMENTARY

continued from page 1

Unfortunately, although measurable biological activity may have been noted in such trials, the percentage of patients achieving what was prospectively defined as “meaningful clinical benefit” was not sufficient to consider the trial to be “positive,” resulting in a halt in further clinical investigative efforts to search for the target.

But, as a result of the paradigm-changing ability to accurately, efficiently, and cost-effectively document the presence of a particular molecular target (or many individual targets) in a specific tumor, is it possible that today we can more easily define a unique cancer patient population that may benefit from the delivery of such specific (and currently “discarded”) therapeutic approaches?

Consider 2 examples from the arena of gynecologic cancer clinical investigation.

Early preclinical data suggested that overexpression of the HER2 receptor essentially was equally common in breast and ovarian cancer and was associated with a poor prognosis. As is well known, the anti-HER2 antibody trastuzumab (Herceptin, Genentech) has become a critical component of the standard of care in the management of breast cancer. However, in striking contrast, the single Phase II study that examined the potential clinical utility of this strategy in ovarian cancer revealed HER2 overexpression to be far less common in the pelvic malignancy (10% of patients tested vs approximately 30% in breast cancer), and the objective response rate in ovarian cancer patients whose “tumors overexpressed HER2” was less than 10%.1 Not surprisingly, based on this unimpressive experience, further exploration of a role for anti-HER2 antibody therapy in ovarian cancer did not occur, and there is no established role for this agent in the malignancy.

But consider for a moment the possibility that in the struggle to find even 1 in 10 ovarian cancer patients able to enter this trial, including those whose cancers

Maurie Markman, MD Cancer Treatment Centers of America Drexel University College of Medicine Philadelphia, Pennsylvania

even “moderately” overexpressed this receptor, the investigators missed an even smaller molecularly defined population of patients who might benefit from this strategy. So, the question to be addressed is as follows: What if the only patients treated with trastuzumab were among the very limited population (likely far less than 5% of ovarian cancer patients) whose tumors were revealed to have major levels of amplification of HER2? Is it possible that in such a highly selected population the objective response rate, and evidence of clinical benefit, would perhaps be quite high (eg, >50%)?

Similarly, the administration of single-agent gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), represents another strikingly “negative” study of targeted therapy in ovarian cancer.2 In this case, the justification for the study was preclinical evidence that a substantial percentage of ovarian cancers overexpress EGFR on their cell surfaces. Again, an objective response rate of far less than 10% was documented in this study.

Not surprisingly, and just as was

observed in studies of patients with non-small cell lung cancer, overexpression of EGFR was found to not be a clinically relevant “target.” However, the single patient in the ovarian cancer study whose tumor was shown to contain an “activating mutation in EGFR” (the necessary requirement in lung cancer) was the sole responding patient in the trial.2 Therefore, the question to be asked is: If an analysis was conducted of the activity of gefitinib (or another small-molecule inhibitor of EGFR) in ovarian cancer patients whose malignancy possessed an “activating EGFR mutation,” what would be the observed response rate?

Finally, it must be acknowledged that such a “formal trial” of anti-HER2 therapy in highly HER2-amplified ovarian cancer or of a small-molecule inhibitor of EGFR in the presence of a unique molecular alteration is almost certain to never be conducted, due to the demonstrated rarity of these specific clinical settings.

But does this perhaps sound like a wonderful example of where the concept of “N of 1” clinical research would be highly

relevant, where the tumors of a very large population of ovarian cancer patients could undergo testing for the presence of any number of possible molecular targets and where the presence of a unique finding would lead to treatment with a novel strategy? The nonidentified results could be made publicly available so that multiple interested parties (patients, insurers, governmental regulators, pharmaceutical companies, etc) would be able to evaluate the outcomes.

Are we ready to contemplate such a paradigm-changing approach to clinical cancer investigation?

References 1. Bookman MA, Darcy KM, Clarke-Pearson D, et al. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003;21(2):283-290, PMID: 12525520.

2. Schilder RJ, Sill MW, Chen X, et al. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group study. Clin Cancer Res. 2005;11(15):5539-5548, PMID: 16061871.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Sarah Tilyou at

smtilyou@mcmahonmed.com

Supportive Care Agents Effective in Phase III Trials New agents show benefit in management of anorexia/cachexia and nausea and vomiting Madrid—A series of Phase III trials presented at the European Society for Medical Oncology 2014 Congress have validated activity of novel agents in palliative and supportive cancer care.

In two related Phase III trials, anamorelin showed activity against cancerassociated anorexia and cachexia. In a third trial, rolapitant showed benefit against cisplatin-associated nausea and vomiting.

Anorexia/Cachexia Presenting data from the two trials that represent the largest set of Phase III data ever collected in the treatment of anorexia and cachexia, Jennifer S. Temel, MD, the clinical director of thoracic oncology at Massachusetts General Hospital, in Boston, said anamorelin (Helsinn), increased lean body mass by approximately 1 kg within 12 weeks, whereas lean body mass decreased over the same

period in the placebo arms ((P<0.0001; abstract 14830PR).

Although the findings from these two trials, called ROMANA 1 and 2, are encouraging in the context of very limited options for cancer-related anorexia and cachexia, they are not definitive.

Anamorelin, a ghrelin mimetic agent that stimulates the growth hormone secretagogue receptor, was associated with improvement in one of the two primary

end points, lean body mass, but there was no significant improvement in the other primary end point, hand grip strength.

More data, such as an ongoing analysis of the effect of anamorelin on overall survival, may provide a clearer picture of the role of this agent.

The design of the two studies was identical. Both randomized patients with unresectable stage III/IV non-small cell lung cancer with an Eastern Cooperative

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Oncology Group performance status of ≤2 to 100 mg of anamorelin or placebo.

ROMANA 1 included 484 patients and ROMANA 2 included 495 patients. The primary end points were evaluated at the end of 12 weeks.

In ROMANA 1, the median increase in lean body mass was 1.1 kg, and in ROMANA 2, the increase was 0.75 kg.

Lean body mass declined by 0.44 and 0.96 kg over the same period, respectively, in the placebo arms of the two studies. The modest improvement in muscle strength, measured with an analysis of hand grip, did not achieve statistical significance in either study, although Dr. Temel noted that proper employment of this measuring tool proved challenging for study participants.

Quality of life (QoL), assessed with the Functional Assessment of Anorexia/Cachexia Therapy questionnaire, improved significantly in both studies.

Overall, anamorelin was well tolerated.

The most commonly reported adverse events were nausea and hyperglycemia, but both were reported in 5% or fewer patients, and grade 3 or higher events of any kind were uncommon.

In his evaluation of these data, the ESMO-invited discussant, Florian Scotté, MD, the head of the Supportive Care Unit in the Department of Medical Oncology at Georges Pompidou European Hospital, in Paris, emphasized the challenges of controlling anorexia and cachexia. Effective treatments have been elusive because the problem is likely to be multifactorial, involving issues of psychology as well as metabolism.

Although ROMANA 1 and 2 were “wellperformed studies” that generated “good results” for the end point of lean body mass, Dr. Scotté questioned whether this is meaningful to patient well-being in the absence of evidence of a change in outcome. He suggested anamorelin might be a step forward, but other interventions are likely to be needed for a cancer complication that generally requires a comprehensive approach.

Nausea/Vomiting In the other Phase III study, the focus was rolapitant, an NK-1 receptor antagonist under development by Tesaro (abstract LBA47). In the multinational trial, 532 patients were randomized to rolapitant or placebo. All the patients also received granisetron and dexamethasone. The primary end point was complete remission (CR) in the delayed phase, defined as no emesis or rescue medications 24 to 120 hours after administration of the chemotherapy.

The CR rate increased from 58.4% with background therapy to 70.1% with rolapitant (P ( =0.001), according to Bernardo Rapoport, MD, from the Medical Oncology Centre in Johannesburg, South Africa. He said he considered this outcome

important, because controlling emesis during the delayed phase has been challenging. Several agents, including rolapitant, are effective in the first 24 hours, but nausea and vomiting often remain clinically significant beyond this point.

“Rolapitant is an exceptionally longterm NK-1 receptor blocker that remains in place for up to 120 hours,” Dr. Rapoport explained. In this Phase III trial, rolapitant controlled emesis during the first 24 hours (87.7% vs. 73.7%; P=0.005), but Dr. Rapoport suggested that it is the long-term efficacy that deserves attention. Control of emesis in

the delayed phase would be expected to not only improve QoL but also to provide cost savings if the need for intravascular hydration could be reduced.

The ESMO-invited discussant, Jorn Herrstedt, MD, DMSci, from the Institute of Clinical Research at the University of Southern Denmark, in Odense, was more circumspect. He suggested that although the study met its primary end point, the relative reduction in CR in the delayed phase might be due to a carry-over effect from rolapitant’s effects in the first 24 hours. He called for more evidence confirming a QoL advantage

to validate the findings. However, he acknowledged that the next updated antiemesis guidelines are likely to be influenced by the results because the study used a high-quality design.

—Ted Bosworth Dr. Temel reported no relevant financial relationships. Dr. Scotté reported financial relationships with Johnson & Johnson, LeoPharma, Merck, Roche, Sandoz, Sanofi and Vifor. Dr. Herrstedt reported a financial relationship with Helsinn.

Dr. Rapoport reported financial relationships with Merck and Tesaro.

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

How I Manage ...

Relapsed and Refractory Multiple Myeloma T

Florent Malard, MD, PhD

Mohamad Mohty, MD, PhD

Department of Haematology, Saint Antoine Hospital INSERM UMR 938 Université Pierre et Marie Curie Paris, France

How do we define a) relapsed and b) refractory MM, and do all patients with serologic relapse require immediate therapy?

Relapsed and refractory MM have been defined by the International Myeloma Workshop Consensus.2 Two subtypes of refractory disease can be distinguished: 1) relapsed and refractory myeloma is defined as disease that is not responsive to salvage therapy or progresses within 60 days of last therapy in patients who achieve minimal response or better and then progress in their disease course; 2) primary refractory myeloma is a disease that is not responsive in patients who have never achieved a minimal response or better with any therapy. Relapsed myeloma is defined as previously treated myeloma that progresses and requires the initiation of salvage therapy but does not meet criteria for either primary refractory myeloma or relapsed and refractory myeloma categories.

Clinical relapse is defined as the presence of at least 1 direct indicator of increasing disease or end-organ damage related to the underlying MM: development of new soft tissue plasmocytoma or bone lesions, hypercalcemia, anemia, an increase in serum creatinine, or hyperviscosity.3 In patients with clinical relapse, the decision to begin a new treatment is relatively easy. In asymptomatic patients with a serologic relapse, it is more difficult. Indeed, on one hand, early treatment resumption could expose patients to side effects and increased risk for selecting MM-resistant clones.

On the other hand, delaying treatment could expose patients with MM to lifethreatening clinical complications, such as bone fracture, acute renal

he treatment of multiple myeloma (MM) has evolved substantially over the past decade, most notably with the introduction of highly effective novel agents, the use of which has resulted in considerable improvements in outcome, mostly in younger patients.1 Initially introduced in the relapsed setting, these novel agents, namely thalidomide, bortezomib, and lenalidomide, are now being increasingly incorporated into up-front treatment strategies, raising new questions about the feasibility of retreatment with such agents as well as what the best sequence of treatment is for each individual patient. In the front-line setting, the first remission is likely to be the period during which patients will enjoy the best quality of life (QoL). Thus, the goal should be to achieve a first remission that is the longest possible by using the most effective treatment up front. At relapse, the challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. The decision will depend on both disease- and patient-related factors.

failure, hypercalcemia, and so on. The best strategy is to monitor patients and watch the monoclonal component very closely to allow initiation of treatment at the appearance of clinical signs or a rapid doubling time (<3 months) of the monoclonal component.

How is relapse best prevented after conventional single autologous hematopoietic cell transplant (auto-HCT)?

For patients up to age 70 years who do not have prohibitive comorbidities, initial treatment for MM typically incorporates intensification with high-dose therapy and auto-HCT. The addition of several new novel agents—immunomodulatory drugs (thalidomide [Thalomid, Celgene] and lenalidomide [Revlimid, Celgene]) and proteasome inhibitors (bortezomib [Velcade, Millennium])— as part of induction regimens before auto-HCT have improved the complete response (CR) rates before and after transplant, leading to tangible improvements in outcome, as evidenced by improvements in progression-free survival (PFS) and overall survival (OS).

Thus, studies that have analyzed outcomes according to the quality of a socalled “good remission” (ie, CR, near CR, and very good partial response) have shown that survival was significantly worse in patients who do not achieve CR compared with those who do.4 In this respect, the achievement of a negative minimal residual disease status by multiparameter flow cytometry5 or by molecular studies6 appears to be the prerequisite for long-term remission and prolonged survival.

Recently, a number of randomized studies have demonstrated the superiority of 3-drug induction regimens

containing corticosteroids and 2 novel agents.7-9 There is no evidence that 4-drug regimens are superior, and they may be more toxic.10 Thus, patients with MM who have a good performance status and who can tolerate aggressive treatments should receive a 3-drug induction therapy combining novel agents and corticosteroids as well as auto-HCT to achieve the deepest possible response to improve survival and prevent relapse.

Given the availability of such well-tolerated and highly active novel agents, their use has been evaluated in the posttransplant setting as consolidation or maintenance therapy. Consolidation therapy is defined as a distinct course of therapy aimed at increasing the depth of response. It can consist of a limited number of cycles of single-agent or combination therapy, or of a second transplant.

Then, maintenance therapy is applied for a prolonged period (12 months or until progression), with the overall aim of maintaining the depth of response achieved in transplant using novel treatments, usually at a lower dose than used during either induction or consolidation. A number of studies have been conducted or are ongoing to investigate the use of novel agents as consolidation and maintenance therapies, and the emerging data strongly suggest a benefit for consolidation as well as maintenance therapy after auto-HCT. However, the available evidence does not allow for definitive recommendations to be made.

To prevent relapse after auto-HCT, the main goal must be to achieve the best response at the time of transplant.

How is therapy best selected in relapsed and refractory MM? In relapsed and refractory MM, the challenge is to select the optimal

treatment for each patient while balancing efficacy and toxicity. The decision will depend on both disease- and patient-related factors (Table).11,12 On one hand, disease-related factors are influenced by the quality and the duration of response to previous therapies and the aggressiveness of the disease, such as the presence of extensive bone disease, plasma cell leukemia, extramedullary MM, increased beta2-microglobulin, decreased albumin, or cytogenetic abnormalities.13 On the other hand, patient-related factors include preexisting toxicity, such as peripheral neuropathy (PN) or thromboembolic events from up-front therapy and other patient-related conditions, such as age, performance status, bone marrow reserve, and renal function.

Novel agents, such as thalidomide, bortezomib, and lenalidomide, have been extensively studied in relapsed and refractory disease. However, few studies, if any, have specifically addressed the “retreatment” and sequencing issues.

The duration of first remission and the timing of relapse are key determinants of the treatment strategy at relapse.

If relapse occurs after a long remission and a long treatment-free period, then it is possible to consider use of an alternative treatment or the treatment employed up front (retreatment approach) because the disease is likely to have remained sensitive to this treatment. If relapse occurs within a short time (<6-12 months) or while the patient is still undergoing treatment, this likely indicates an aggressive disease (relapsed and refractory) that has acquired resistance, warranting the use of an alternative regimen. Additionally, the presence of poor-risk clinical features, such as see MYELOMA, page 24

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MODEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result?

Improving the survival curve and changing the course of cancer itself.

C L I N I C A L E X PE R T I SE

T R A N SPL A N TAT I O N

C L I N I C A L T R I A L S A N D R E SE A RC H

More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology.

In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

t Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem cells for peripheral blood transplants t Four ICU beds integrated with Carolinas HealthCare System’s virtual ICU, which provides 24/7 oversight of all patients t Patient support, including familyfriendly patient rooms, an exercise room, a laundry room and lounge t Patient navigation

t First-in-man clinical trials testing novel therapies and treatment options t Access to high-quality care, and expertise from physicians who subspecialize in treating specific diseases t The ability to enroll patients in the newest, most promising trials, whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

24

HEMATOLOGIC DISEASE

MYELOMA

CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Table. Factors To Consider When Choosing Relapse Therapy

continued from page 22

cytogenetic abnormalities, may indicate high-risk disease requiring an approach different from that employed in a “slowly” relapsing disease. In this case, a more aggressive approach to treatment may be warranted, incorporating sophisticated novel agent combinations, allogeneic transplantation (allo-HCT) or enrollment in trials of investigational agents.13 For transplant-eligible patients, it is feasible to consider retransplantation at the time of relapse if adequate hematopoietic progenitor cells are available. Patients who are candidates for a second salvage auto-HCT at the time of relapse need to have enjoyed a reasonable response duration following the first transplant. In cases when relapse occurs within 12 to 18 months of the first auto-HCT, alternative treatments should be sought, preferably incorporating novel approaches, because such a relapse is associated with a poor outcome.14 In subsequent relapses, retreatment incorporating previously used agents is feasible, as long as a good and sustained response to these agents had been achieved, which would indicate that the disease has remained sensitive to these agents. The choice of treatment at relapse also will depend on the presence of a limiting toxicity. In patients with renal impairment, bortezomib-based regimens have shown the best safety profile.15 Nevertheless, several recent publications have demonstrated that a lenalidomidebased salvage therapy is feasible in cases of renal impairment, provided that dose modifications are implemented per guidelines.15 In the presence of PN, both thalidomide and bortezomib should be avoided, although subcutaneous administration has significantly reduced the incidence of PN. For patients at risk for thromboembolic or cardiovascular events, consensus recommendations regarding prophylaxis have been published.16 In patients whose disease has relapsed and is refractory to a particular drug, a change in the class of drug is indicated because the disease is likely to have become resistant to that particular class.

Patient-Related Factors

Treatment/Disease-Related Factors

• Age, performance status

• Cytogenetics

• Bone marrow reserve

• Components of initial therapy

• Renal function

• Duration of initial therapy

• Preexisting toxicity (eg, peripheral neuropathy, thromboembolic events)

• Efficacy of initial therapy

• Quality-of-life considerations

In case of disease that is relapsed and refractory to all available novel agents (immunomodulatory drugs and proteasome inhibitors), enrollment in clinical trials of experimental agents is highly desirable for patients who qualify. If patients do not qualify for inclusion in a trial, treatment will be aimed at alleviating symptoms and maintaining QoL, while stabilizing the disease as much as possible. For those patients, palliative treatment is warranted, using alkylating agents in combination with corticosteroids (oral cyclophosphamide and prednisone) or cisplatin-containing regimens, such as continuous infusion of dexamethasone, cyclophosphamide, etoposide, and cisplatin.

What is the role of allo-HCT in MM? The role of allo-HCT in MM is controversial because of its high morbidity and mortality and conflicting results.

Thus, in the setting of the standard myeloablative conditioning (MAC) regimen, nonrelapse mortality (NRM) ranges from 30% in the most recent studies to 49% in older studies, and evidence of survival benefit are lacking, precluding its use.

Reduced-intensity conditioning (RIC) regimens were developed to decrease NRM in patients who are older, heavily pretreated, or have medical comorbidities and who cannot tolerate the standard MAC regimen. Several prospective randomized studies compared auto-HCT with tandem autologous RIC allo-HCT in MM. Although some studies demonstrated an advantage in OS, PFS, and relapse

AT A GLANCE • Recently, a number of randomized studies have demonstrated the superiority of 3-drug induction regimens, containing corticosteroids and 2 novel agents.

• A number of studies have been conducted or are ongoing to investigate the use of novel agents as consolidation and maintenance therapies, and emerging data strongly suggest a benefit for consolidation as well as maintenance therapy after auto-HCT. • The goal should be to achieve a first remission that is as long as possible by using the most effective treatment up front.

• Duration of first remission • Relapse under treatment

in favor of tandem autologous RIC alloHCT,17 others studies failed to demonstrate such advantage.18 Furthermore, none of the patients in these studies received the more effective new standard therapies. Consequently it is impossible to draw final conclusions based on those results regarding the use of tandem autologous RIC allo-HCT in front-line treatment. Although allo-HCT in first line should still be considered investigational, it may be considered for young patients with high-risk disease (ie, ISS III and 17p cytogenetic aberration) who are willing to accept a high risk for NRM for a chance of better long-term survival.

At relapse, the feasibility of allo-HCT with RIC has been demonstrated in several studies.19-21 However, despite the use of RIC, NRM is still high, approximately 20% to 25% at 1 year,19-21 and relapse incidence remains also high, leading to a PFS of approximately 26% to 38% at 2 years.19-21 Furthermore, the high incidence of graft-versus-host disease significantly contributes to NRM and could impair QoL in surviving patients. Overall, allo-HCT cannot be routinely recommended outside of a clinical trial, given high NRM and morbidity; as mentioned above, it may be an option in a very few selected young patients, particularly those with high-risk disease.

Is there evidence of graftversus-myeloma effect?

Despite the controversial role of alloHCT in MM, the existence of a graft-versus-myeloma (GvM) effect is well established. The best illustration of GvM effect is probably the achievement of remission after donor lymphocyte infusion (DLI) in patients with persistent disease or relapse after allo-HCT.22 Furthermore, van Bergen et al showed that a patient with MM who received an alloHCT and DLI with minor histocompatibility antigens mismatch achieved CR accompanied by the emergence of cytotoxic T cells directed against some minor histocompatibility antigens expressed on MM cells.23

Future Prospects The introduction of novel agents that target both the tumor cell and its microenvironment to the treatment of MM has considerably improved outcomes,

Agents Being Tested In This Setting • Novel drugs such as pomalidomide (Pomalyst, Celgene) • Second-generation proteasome inhibitors such as carfilzomib (Kyprolis, Onyx), ixazomib, and oprozomib • Monoclonal antibodies targeting the CD38 molecule (eg, daratumumab) or CS1 (eg, elotuzumab) • Novel classes of agents, such as histone deacetylase inhibitors (eg, panobinostat) or filanesib (ARRY-520), a kinesin spindle protein inhibitor

and it is now possible to aim for deeper responses in a greater number of patients in an attempt to prolong remission duration and OS. Despite substantial progress, numerous questions surrounding the optimal treatment remain, especially as myeloma remains an incurable malignancy in most cases. In a disease that is characterized by multiple relapses, the sequencing of the different effective options is an important question. The first remission is likely to be the period during which patients will enjoy the best QoL. Thus, the goal should be to achieve a first remission that is as long as possible by using the most effective treatment up front. For almost all patients, whether or not they are eligible for transplant, this will consist of a novel agent–based regimen.

The results from the various studies published are encouraging because they suggest that the novel agents can be reused in subsequent lines of therapy.

Ongoing trials will help to answer some of these questions and better define the optimal sequence of treatments for an individual patient to balance efficacy and toxicity.

References 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood.

2008;111(5):2516-2520, PMID: 17975015.

2. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18): 4691-4695, PMID: 21292775.

3. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia.

2006;20(9):1467-1473, PMID: 16855634.

4. Gay F, Larocca A, Wijermans P, et al.

Complete response correlates with longterm progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood.

2011;117(11):3025-3031, PMID: 21228328.

5. Paiva B, Vidriales MB, Cervero J, et al.

Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood.

2008;112(10):4017-4023, PMID: 18669875.

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

6. Ladetto M, Pagliano G, Ferrero S, et al.

Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28(12):20772084, PMID: 20308672.

7. Cavo M, Tacchetti P, Patriarca F, et al.

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):20752085, PMID: 21146205.

8. Moreau P, Avet-Loiseau H, Facon T, et al.

Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118(22):5752-5758, PMID: 21849487.

9. Rosinol L, Oriol A, Teruel AI, et al.

Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120(8):15891596, PMID: 22791289.

10. Kumar S, Flinn I, Richardson PG, et al.

Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood.

2012;119(19):4375-4382, PMID: 22422823.

11. Lonial S. Relapsed multiple myeloma.

Hematology Am Soc Hematol Educ Program.

2010;2010:303-309, PMID: 21239810.

12. San Miguel JF. Relapse/refractory myeloma patient: potential treatment guidelines. J Clin Oncol. 2009;27(34):5676-5677, PMID: 19786652.

13. Avet-Loiseau H. Ultra high-risk myeloma.

Hematology Am Soc Hematol Educ Program.

2010;2010:489-493, PMID: 21239841.

14. Kumar S, Mahmood ST, Lacy MQ, et al.

Impact of early relapse after auto-SCT for multiple myeloma. Bone Marrow Transplant. 2008;42(6):413-420, PMID: 18587435.

15. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol.

2010;28(33):4976-4984, PMID: 20956629.

16. Dimopoulos MA, Palumbo A, Attal M,

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Coming Soon How I Manage Relapsed and Refractory Hodgkin Lymphoma Eva Domingo-Domenech, MD, and Anna Sureda, MD Institut Català d’Oncologia – Hospital Duran I Reynals Barcelona, Spain

et al. Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement. Leukemia.

2011;25(5):749-760, PMID: 21293488.

17. Bjorkstrand B, Iacobelli S, Hegenbart U, et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up.

J Clin Oncol. 2011;29(22):3016-3022, PMID: 21730266; Erratum in 2011;29(27):3721.

18. Krishnan A, Pasquini MC, Logan B, et al.

Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12(13):1195-1203,

PMID: 21962393.

19. Shimoni A, Hardan I, Ayuk F, et al. Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up. Cancer. 2010;116(15):36213630, PMID: 2056 4132.

20. Patriarca F, Einsele H, Spina F, et al. Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability. Biol Blood Marrow Transplant.

2012;18(4):617-626, PMID: 21820394.

21. Auner HW, Szydlo R, van Biezen A, et al.

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after

autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant.

2013;48(11):1395-1400.

22. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol. 2000;18(16):30313037, PMID: 10944138.

23. van Bergen CA, Kester MG, Jedema I, et al. Multiple myeloma-reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene. Blood. 2007;109(9):40894096, PMID: 17234742.

Visit the newly designed user friendly

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CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

Clinical Conundrums

Cephalon], fludarabine, and rituximab) regimen for patients with CLL and lymphomas was safe and effective before allogeneic hematopoietic cell transplantation (allo-HCT).

Highlights from JCO, Blood, Lancet Oncologyy and Biology of Blood and Marrow Transplantation

True or False? A study carried out by the Japan Adult Leukemia Study Group showed no difference between all-trans-retinoic acid (ATRA) and tamibarotene for maintenance therapy in patients with non–high-risk acute promyelocytic leukemia (APL).

Primum non nocere. (First, do no harm.)

Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

QUESTIONS

1.

True or False? It is important to review pre-cryopreservation CD34-positive cell dose and cord blood (CB) banking practices before selecting CB units.

2. True or False? According to a

study published in Blood, patients with

ANSWERS

1. True. CB units not from Netcord

Foundation for the Accreditation of Cellular Therapy (FACT)–accredited banks were more likely to have low postthaw recovery ((P<0.001). Furthermore, although median post-thaw CD34-positive cell viability was 92%, 8% of units had less than 75% viable CD34-positive cells.

Units not from Netcord FACT–accredited banks and units with cryovolumes outside the range of 24.5 to 26 mL were more likely to have poor post-thaw viability.

Purtill D, Smith K, Devlin S, et al. Dominant unit CD34+ cell dose predicts engraftment after doubleunit cord blood transplantation and is influenced by bank practice. Blood. 2014;124(19):2905-2912, PMID: 25185264.

2.

False. Investigators examined the survival and treatment outcome of 300 patients enrolled in a Phase II study of front-line FCR. After a median followup of approximately 11 years, 156 patients developed progressive CLL, with a median survival of 4.25 years after disease progression. The duration of first remission was a key determinant of survival after disease progression and first salvage. Patients with a short duration of first remission (<3 years) had a short survival period, regardless of salvage therapy received; these patients had high unmet medical needs and were good candidates for investigation of novel therapies.

In patients with a long duration of first remission (≥3 years), salvage treatment with either repeat FCR or lenalidomidebased therapy resulted in subsequent

chronic lymphocytic leukemia (CLL) who were treated with front-line FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan, Genentech]) can be rechallenged with the same regimen with good results if duration of first remission was longer than 2 years.

3.

True or False? In myelodysplastic syndromes (MDS), a higher abundance of TET2 mutations is associated with increased response to hypomethylating agents.

4. True or False? In a Phase I/II

study published in Blood, a non-myeloablative BFR (bendamustine [Treanda,

median survival exceeding 5 years; for these patients, FCR rechallenge represented a reasonable standard of care.

Tam CS, O’Brien S, Plunkett W, et al. Longterm results of first salvage treatment in CLL patients treated initially with FCR. Blood.

2014;124(20):3059-3064, PMID: 25281606.

3. False. The investigators sequenced

40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 patients with MDS. The mutations were collected before treatment with azacitidine or decitabine and were examined for association with response and overall survival (OS). Both agents demonstrated an overall response rate of 47%. Clonal TET2 mutations predicted response (odds ratio [OR], 1.99; P=0.036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild type. Response rates were highest in the subset of TET2mutant patients without clonal ASXL1 mutations (OR, 3.65; P=0.009). Of further interest, TP53 mutations (hazard ratio [HR], 2.01; P=0.002) and PTPN11 (HR, 3.26; P=0.006) were associated with shorter OS but not drug response.

Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood.

2014;124(17):2705-2712, PMID: 25224413.

4. True. The proportions of trans-

plants from matched siblings or unrelated donors were 54% and 46%. Remarkably, 55% of patients did not experience severe neutropenia. Forty-nine patients (88%) did not require platelet transfusion. The incidence of acute grade II/IV

5.

6. True or False? QT interval pro-

longation is common with arsenic trioxide (ATO; Trisenox, Cephalon) treatment and based on a study published in JCO, use of the Bazett QT correction formula is preferred over other formulas for assessment of corrected QT intervals.

7. True or False? A multi-institu-

tional study published in JCO demonstrated that post-transplant cyclophosphamide (without additional prophylactic immunosuppression) is safe and effective when combined with IV busulfan (Busulfex, Otsuka) and fludarabine

myeloablative conditioning in HLAmatched marrow allo-HCTs.

8. True or False? A study published

in Biology of Blood and Marrow Transplantation suggests that haplotypematched transplants can be performed safely for patients with acute myeloid leukemia (AML) or MDS in the absence of an HLA-matched donor.

9. True or False? The results of a

single-arm, multicenter trial published in Lancet Oncology suggested that in older adults, the addition of lenalidomide (Revlimid, Celgene) to standard R-CHOP-21 (“R2-CHOP”; rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) can overcome the inferior outcomes observed in previously untreated advanced-stage activated diffuse large B-cell lymphoma (DLBCL).

10. True or False? A large retro-

spective study demonstrated that the majority of DLBCL relapses are detected outside of planned follow-up visits.

graft-versus-host disease (GVHD) was 11%. The 2-year rate of extensive chronic GVHD was 26%. After a median followup duration of 26 months (range, 6-50 months), the 2-year overall and progression-free survival (PFS) rates were 90% and 75%, respectively.

monitoring. With the commonly used Bazett rate correction formula, 90% of patients had QTc greater than 470 ms, including 65% greater than 500 ms. By using alternative rate correction formulas, only 24% to 32% of patients had rate-corrected QT intervals greater than 500 ms.

Khouri IF, Wei W, Korbling M, et al. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/ lymphoma: reduced myelosuppression and GVHD. Blood. 2014;124(14):2306-2312, PMID: 25145344.

Roboz GJ, Ritchie EK, Carlin RF, et al. Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide. J Clin Oncol. 2014;32(33):37233728, PMID: 25245447.

True. Ninety-two patients (medi5. True. Patients with newly diag- 7. an age, 49 years; range, 21-65 years) with

nosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. When the analysis was restricted to 52 high-risk patients with an initial white blood cell count of at least 10×109/L, the intergroup difference was statistically significant, with 4-year relapse-free survival rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% confidence interval, 0.07-0.95).

Shinagawa K, Yanada M, Sakura T, et al. Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial. J Clin Oncol. 2014;32(33):3729-3735, PMID: 25245439.

6.

False. Use of the Bazett correction formula may result in unnecessary interruptions in ATO therapy. Alternative rate correction formulas (Fridericia, Hodges, Sagie-Framingham) should be considered for routine electrocardiographic

high-risk hematologic malignancies were enrolled at 3 centers (NCT00809276).

Forty-five patients received related allografts, and 47 received unrelated allografts. GVHD prophylaxis was solely with post-transplant cyclophosphamide at 50 mg/kg per day on post-transplantation days +3 and +4. The cumulative incidences of grades 3/4 acute and chronic GVHD were 15% and 14%, respectively. Nonrelapse mortality (NRM) rates at 100 days and 1 year were 9% and 16%, respectively. With a median follow-up period of 2.2 years, the 2-year diseasefree survival (DFS) and OS rates were 62% and 67%, respectively. Donor relatedness did not affect NRM, DFS, or OS. Moreover, the lack of a requirement for prolonged immunosuppression in a significant subset of patients can facilitate the early integration of adjunct therapies to prevent relapse.

Kanakry CG, O’Donnell PV, Furlong T, et al.

Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • DECEMBER 2014 • CLINICALONCOLOGY.COM

New Lymphoma Recommendations Reflect Advances I

n response to advances in the treatment of lymphoma, a task force of experts has released modernized recommendations for evaluating, staging and assessing treatment response in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).

“We wanted to find ways to improve patient evaluation, minimize ambiguity with universally applicable criteria, facilitate comparisons of patients and results among studies, and simplify the evaluation of therapies by regulatory agencies,” said Bruce D. Cheson, MD, the lead author of the new recommendations, dubbed the Lugano Classification ((J Clin Oncoll 2014;32[27]:30593068, PMID: 25113753).

Dr. Cheson, a professor of medicine and the head of hematology at Georgetown University Hospital’s Lombardi Comprehensive Cancer Center, in Washington, D.C., and his coauthors—leaders in the areas of hematology, oncology, radiation oncology, pathology, radiology and nuclear medicine—tackled a number of questions during the revision process: What was the relevance of the now roughly 40-year-old Ann Arbor staging system? Could a simpler scheme suffice? How could they incorporate positron emission tomography (PET) computed tomography (CT) into staging?

Are chest x-rays and bone marrow biopsies still necessary? And could PET-CT be used better for response assessment?

For example, “there is now a better way to interpret PET-CT—the fivepoint scale,” said Dr. Cheson, so the task force “wanted to incorporate that into the assessment.”

Highlights of the revised staging criteria include the discontinuation of the use of “X” as a designation for bulky disease and dropping the suffixes “A” and “B” in NHL (see sidebar). “We got rid of the suffixes because they’re nonprognostic, but we still need to record the information that patients have

symptoms,” Dr. Cheson said.

Based on several studies in HL and diffuse large B-cell lymphoma showing PET-CT to be more sensitive than bone marrow biopsy for identifying bone marrow involvement, the group also recommended limiting biopsy to large cell lymphoma if the PET-CT is negative and it is necessary to identify a discordant histology. “For other lymphomas, you still have to do a bone marrow biopsy if it affects clinical management,” Dr. Cheson said.

For end-of-treatment evaluation, the group recommended retaining PETCT for avid histologies using the fivepoint Deauville scale, and also refined definitions of response. “We stress that a complete remission can include persistent adenopathy as long as it is PETnegative, and that a single lesion could now be considered for progressive disease,” Dr. Cheson said. “We outlined how big it had to be and how much it had to grow, rather than what we used to use, which was the sum of the product of the diameters of six nodes, which was very cumbersome.”

Dr. Cheson said that he anticipated that some recommendations would be accepted more quickly than others.

“For instance,” he said, “getting rid of the bone marrow biopsy is very good for [community practitioners].” Routine surveillance scans, however, have long been discouraged, but doctors still order them. “Patients still get scans every three months for years. It’s a waste of money, and 90% of the time the doctor or patient picks up a relapse, scan or no scan.”

Some also may struggle to justify post-treatment PET-CT, Dr. Cheson noted. “You can ask, since there’s no evidence that acting on a positive PET scan makes a difference, why do it?” But, the clinical relevance of posttreatment PET is that it will guide follow-up. “If the patient has a negative PET, you may need to see them only

every four to six months,” Dr. Cheson said, although he acknowledged that PET is not always accessible. If this is the case, he said, the new recommendations “have better standardized” the use of CT to assess response.

“Pretty much everything here—discouraging surveillance scans, [dropping] bone marrow biopsy, how you assess response—has clinical relevance,” Dr. Cheson said. “We expect these recommendations to be widely adopted. There was input from all the major cancer centers and cooperative groups from around the world. Right now, these should be considered the standard for staging and restaging of lymphomas.”

Jane Winter, MD, a professor of medicine at Northwestern University’s Feinberg School of Medicine, in Chicago, said that a lot of the recommendations are consistent with what doctors already do—such as the emphasis on incisional or excisional biopsy—but she found some of the recommendations to be questionable or unnecessary.

“For example, eliminating the chest x-ray,” she said. “A chest x-ray is good to have as a baseline for comparison purposes and is much less expensive than a CT or PET-CT. It’s useful in so many situations. I worry that physicians will stop being reimbursed for simple inexpensive tests, like a chest x-ray, if they are no longer recommended despite their utility.”

The elimination of the designation X for bulky disease also gives her pause. “In HL, it’s very important to identify those with bulky disease, whether you call it ‘bulky disease’ or use the letter X. The presence of a mass greater than 10 cm leads us down a different treatment algorithm for those with early-stage disease,” she said.

The recommendation that Dr. Winter is most critical of is the discontinuation of bone marrow biopsy, especially in patients with large B-cell lymphoma. “I think we’re relying quite

bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32(31):3497-3505, PMID: 25267759.

transplantation outcomes for AML and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant.

2014 Sep 28. [Epub ahead of print], PMID: 25263628.

Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.

Blood. 2014;124(15):2325-2332, PMID: 25115890.

8. True. The study demonstrated com-

parable PFS for patients with AML and MDS patients treated with a haplotypematched versus HLA-matched donors.

No significant differences were found between haploidentical and matched unrelated donor (MUD) transplantation outcomes; however, there was a trend for improved outcomes in the minimal residual disease (MRD) group, with 3-year PFS for patients in remission of 57%, 45%, and 41%, for MRD, MUD, and haploidentical recipients, respectively ((P=0.417).

Di Stasi A, Milton DR, Poon LM, et al. Similar

True. According to investigators 9. True. REAL07 was an open-label, of10. this study, data do not support the use

multicenter trial that was conducted in 13 centers in Italy and one in Germany. Eligible patients were aged 60 to 80 years and had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II/IV DLBCL or grade 3b follicular lymphoma.

Patients received 15 mg oral lenalidomide on days 1 to 14 of six 21-day cycles, and standard doses of R-CHOP-21 chemotherapy. Of note, prednisone was administered at a dose of 40 mg/m2 on days 1 to 5.

of routine surveillance imaging for follow-up of DLBCL in complete remission. Approximately 680 individuals with DLBCL were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. Of these patients, 552 (81%) achieved complete remission, and 20% relapsed. The majority (64%) of

Highlights of Lugano Classification • Emphasis on excisional biopsy • Use of PET-CT for FDG-avid lymphomas and CT for non-avid histologies • Modifications of the Ann Arbor staging system for extent of disease • Standardization of splenomegaly at greater than 13 cm • Discontinuation of routine chest x-rays if a CT was performed • Treatment based on risk and prognostic factors in the context of limited or advanced disease • Discontinuation of the use of X as a designation for bulky disease • Discontinuation of the suffixes A and B in NHL

heavily on our nuclear medicine radiologists, and I worry that they may not be expert at identifying bone marrow disease. Most don’t see many scans from lymphoma patients, especially [HL],” she said. “Now, we’re asking them to score PET scans according to Deauville criteria and to identify bone marrow involvement. Even in our academic centers, we’re not always getting that information adequately; I think this is going to require a great deal of education.”

Dr. Winter found the simplification of the Ann Arbor system helpful, and said that most of the recommendations reemphasize and codify standard practice. “But we need to be very careful that there aren’t unintended consequences.”

—Monica J. Smith

relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in 9 of the 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in 4 of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients whose relapse was detected at scheduled follow-up compared with those whose disease was detected before that in the MER ( =0.56) and Lyon cohorts ((P=0.25).

(P Thompson CA, Ghesquieres H, Maurer MJ, et al. Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma. J Clin Oncol. 2014;32(31):3506-3512, PMID: 25267745.

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