Nov 2014 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • November 2014 • Vol. 9, No. 11

SOLID TUMORS Reports From ESMO TAS-102 shows OS benefit in refractory mCRC ................ Pertuzumab established as part of standard regimen for HER2+ metastatic breast cancer .........................

HEMATOLOGIC DISEASE Clinical Conundrums ..........................

Jane N. Winter, MD: How I manage advanced HL in adults, Part 2 .............

Crizotinib Is Effective As First-Line Therapy For ALK+ Lung Cancer Madrid—The targeted oral tyrosine kinase inhibitor (TKI) crizotinib was found to be more effective than chemotherapy for first-line treatment of anaplastic lymphoma kinase (ALK)positive non-small cell lung cancer (NSCLC) in a Phase III trial, defining a potential new treatment standard for this NSCLC molecular subtype. In this study, which was limited to patients positive for rearrangements of the ALK K gene, crizotinib (Xalkori, Pfizer) provided a nearly four-month see CRIZOTINIB, B page 9

by the

numbers

November Is Lung Cancer Awareness Month Lung cancer is the leading cause of cancer death, resulting in 28% and 26% of cancer-related deaths in men and women, respectively.

27%

73%

Estimated Cancer-Related Deaths Lung and bronchus All other cancer sites

Source: 2014 American Cancer Society, Inc. Surveillance Research

IMAGES in ONCOLOGY

Report From ESMO

INSIDE

Vogl, NY on Preventing Fractures

Finally, There’s Some Direction on How To Use Zoledronic Acid

t the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), Gabriel Hortobagyi, MD, from The University of Texas MD Anderson Cancer Center, in Houston, presented data from the OPTIMIZE-2 trial on Steven Vogl, MD reducing the frequency of 4-mg IV zoledronic acid administration from every 4 weeks to every 12 weeks in the second year of therapy for breast cancer that has metastasized to bone.1 At a median follow-up of 11.9 months after entry, skeletal-related see VOGL, NY, Y page 26

Colon cancer cells; new guidelines released for managing older patients with colorectal cancer; story on page 8.

Be Prepared for EHR Breaches, Experts Warn I

f you have not yet endured an electronic patient data theft, you most likely will experience one before too long, experts warn. They say the transition to electronic health records (EHRs) has not been accompanied by adequate safeguards, and they are calling on physicians to do more to protect patient data. “Health care systems will be seeing large-scale hacks of the type we’ve seen with retailers like Target,” said Katherine Downing, MA, the director of Health Information Management Practice Excellence at the American Health Information Management Association, in Chicago. Ms. Downing noted that the FBI recently warned health care providers about the likelihood of such cyberattacks (http://reut.rs/1w9sZSL). Health data are much more valuable than data from other industries because EHRs typically contain far more information, said Ms. Downing. Indeed, a single complete EHR profile can include information on health insurance, prescription drugs, financial details and Social Security numbers. That wellspring of information means a record can sell for $50 on the black market, while a Social Security number fetches only $1 (http://bit.ly/1pS2nzz). Thieves use that information to do everything from accessing medical care, obtaining prescription drugs and, according to a recent report, filing false income tax returns that, in one case, resulted in more than $175,000 in tax refunds being issued see EHR BREACHES, S page 24

RE VIE WS & COMMENTAR IES

Expert Insights From The Mount Sinai Tisch Cancer Institute ADT Does Not Improve OS in Patients With Localized Prostate Cancer ......................... 20 William K. Oh, MD

Statin Use for Colorectal Cancer Improves Survival ....................... 21 Randall Holcombe, MD

AV NO AI W LA BL E

NEW—A LIQUID FORMULATION—TREANDA® (bendamustine HCl) Injection

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

What else is new about TREANDA? NEW CONCENTRATION

mg/mL

NEW DOSAGE STRENGTHS

NEW NDCs

180 mg/2 mL 63459-396-02 45 mg/0.5 mL 63459-395-02 J Code 9033

It may be necessary to update your pharmacy and/or patient medication management systems. FOR MORE INFORMATION, CALL 1-800-896-5855 OR VISIT TREANDAHCP.COM

Supplied in single-use, 2-mL vials.

Indications TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. 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 CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common nonhematologic 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 for both indications (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. Please see accompanying brief summary of Full Prescribing Information on the following pages.

™

Brief Summary of Prescribing Information 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 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 2.1 Dosing Instructions for CLL Recommended Dosage: g The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, y , Dose Modifications and Reinitiation of Therapy py for CLL: TREANDA administration should be delayed in the event of 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 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 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 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 4). 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.

TREANDA® (bendamustine hydrochloride) Injection

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 (2.1) and (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 allergictype 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. 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 of the label [See Warnings and Precautions]: 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 329 patients who participated in an activelycontrolled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) 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. 6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in * 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients

System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

TREANDA (N=153) All Grade Grades 3/4

Chlorambucil (N=143) All Grade Grades 3/4

121 (79) 52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

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

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

5 (3)

11 (7)

3 (2)

2 (1)

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These ﬁndings conﬁrm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150 Laboratory Abnormality

Chlorambucil N=141

All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

In the CLL trial, 34% of patients had bilirubin elevations, some without associated signiﬁcant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 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 3. 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.

TREANDA® (bendamustine hydrochloride) Injection

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders 0 Tachycardia 13 (7) Gastrointestinal disorders 7 (4) Nausea 132 (75) 5 (3) Vomiting 71 (40) 6 (3) Diarrhea 65 (37) 1 (<1) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 2 (1) Abdominal pain 22 (13) 0 Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 1 (<1) Dry mouth 15 (9) 0 Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) General disorders and administration site conditions 19 (11) Fatigue 101 (57) 3 (2) Pyrexia 59 (34) 0 Chills 24 (14) 1 (<1) Edema peripheral 23 (13) 4 (2) Asthenia 19 (11) 1 (<1) Chest pain 11 (6) 0 Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) Infections and infestations 5 (3) Herpes zoster 18 (10) 0 Upper respiratory tract infection 18 (10) 4 (2) Urinary tract infection 17 (10) 0 Sinusitis 15 (9) 9 (5) Pneumonia 14 (8) 11 (6) Febrile neutropenia 11 (6) 2 (1) Oral candidiasis 11 (6) 0 Nasopharyngitis 11 (6) Investigations 3 (2) Weight decreased 31 (18) Metabolism and nutrition disorders 3 (2) Anorexia 40 (23) 8 (5) Dehydration 24 (14) 1 (<1) Decreased appetite 22 (13) 9 (5) Hypokalemia 15 (9) Musculoskeletal and connective tissue disorders 5 (3) Back pain 25 (14) 0 Arthralgia 11 (6) 2 (1) Pain in extremity 8 (5) 0 Bone pain 8 (5) Nervous system disorders 0 Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) Psychiatric disorders 0 Insomnia 23 (13) 1 (<1) Anxiety 14 (8) 0 Depression 10 (6) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 38 (22) Dyspnea 3 (2) 28 (16) Pharyngolaryngeal pain 1 (<1) 14 (8) Wheezing 0 8 (5) Nasal congestion 0 8 (5) Skin and subcutaneous tissue disorders Rash 1 (<1) 28 (16) Pruritus 0 11 (6) Dry skin 0 9 (5) Night sweats 0 9 (5) Hyperhidrosis 0 8 (5) Vascular disorders Hypotension 2 (1) 10 (6) *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 4. 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%).

Percent of patients Hematology variable

All Grades

Grades 3/4

Lymphocytes Decreased

Leukocytes Decreased

Hemoglobin Decreased

Neutrophils Decreased

Platelets Decreased

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. 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. Iss. 09/2013 (Label Code: 00016287.06) TRE-40206 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • NOVEMBER 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

Oncology Nursing

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

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

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

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

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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

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

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

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

Bioethics

Steven Vogl, MD

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.

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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

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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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Substantial Benefits Confirmed

Combination Therapy Boosts Survival in Low-Grade Glioma Chicago—A combination of radiation and chemotherapy has been associated with a major survival benefit in patients with low-grade glioma. After an average follow-up of almost 12 years, patients who received both radiation and chemotherapy had a median survival that was 5.5 years longer than that of patients who received radiation alone. “This is the first prospective study ever to demonstrate a treatment-related increase in survival in grade 2 glioma,” said Jan Buckner, MD, a professor of oncology, at Mayo Clinic in Rochester, N.Y. The most recent data from this study, presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 2000), suggested that although adverse events (AEs) were greater with the combination therapy than with radiation alone, the regimen remained reasonably well tolerated considering the large survival benefit. Enrollment for this study, known as RTOG 9802, began in 1998 and was completed in 2002. Patients with grade 2 glioma considered to be at high risk for early progression due to subtotal resection or age greater than 40 years were randomized to radiation alone or radiation followed by six cycles of PCV (procarbazine, lomustine [CCNU] and vincristine). A highly significant progression-free survival (PFS) from this trial was reported earlier (J ( Clin Oncol 2012;30[25]:30653070, PMID: 22851558), after a median of 5.9 years of follow-up, but overall survival (OS) had not reached statistical significance at that point.

MRI scan of a low-grade glioma. In the most recent analysis of data from this study, which enrolled 251 patients, the follow-up had reached 11.9 years, with death from cancer or another cause recorded in 55%. When the two arms were compared, the hazard ratio (HR) for OS was 0.59 ((P=0.002 by log-rank analysis), with a median survival of 7.8 years for those who received radiation alone versus 13.3 years for those who received the combination. This relative advantage was achieved although the rates of every salvage therapy, including surgery (26% vs. 14%), chemotherapy (56% vs. 23%) and any form of radiotherapy (19% vs. 6%) were far more common in the radiation-only arm. When the study population was evaluated for independent prognostic variables, only the assigned therapy and histology were independent predictors of a survival advantage. By histology, survival was significantly greater in those with oligodendroglioma than in those with astrocytoma.

The median survival of those with mixed oligodendroglioma and astrocytoma histologies fell in between. There was a substantial list of AEs that occurred more commonly with the combination, including fatigue, nausea, weight loss, abnormal liver function tests and hematologic toxicities, but most AEs were of grade 3 severity or less. There have been no cases of myelodysplasia or leukemia reported in either group so far. Furthermore, neither group developed significant cognitive impairment at three or five years, as measured by the Mini-Mental State Examination evaluation. These data suggest that the risk for cognitive dysfunction from radiotherapy is not as high as once feared, encouraging use of radiotherapy with some form of chemotherapy early in the course of the disease. Further study, such as exploratory analyses of the relative impact of molecular subtypes, such as 1p/19q deletions,

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are planned, but mature results from this study suggest that low-grade glioma patients at risk for early progression achieve greater benefit from chemotherapy with radiation than from radiation alone. These data were called “practice changing” by an ASCO-invited expert, Martin J. Van Den Bent, MD, PhD, a professor of neuro-oncology at Erasmus Cancer Center, in Rotterdam, the Netherlands. Although many other questions about optimal practice are yet to be answered, these data “in 2014 establish the safety of chemotherapy with radiotherapy in the treatment of diffuse glioma.” Moreover, he noted that the relative benefit of the combination might be greater than reported because the curves were still separating at the time of the most recent analysis. RTOG 9802 is the third trial to demonstrate benefit with PCV in glioma, according to Dr. Van Den Bent, but he observed that many clinicians have switched to temozolomide because it is less toxic. PCV and temozolomide have not been compared yet in a randomized study, so Dr. Van Den Bent suggested that the relative efficacy is unknown. However, he said that this trial establishes that there is a benefit to adding chemotherapy to radiotherapy in low-grade glioma.

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Report From ESMO

New Drug for mCRC Shows Efficacy When All Else Fails Madrid—The novel agent TAS-102— which received fast-track designation from the FDA in October—resulted in a significant overall survival (OS) benefit in patients with refractory metastatic colorectal cancer (mCRC) during the Phase III RECOURSE trial. The advantage for both OS and progression-free survival (PFS) was highly consistent across every predefined subgroup and stratification evaluated. “There was also a statistically significant, and I believe clinically relevant, prolongation of time to ECOG [Eastern Cooperative Oncology Group] performance status deterioration,” reported Eric Van Cutsem, MD, PhD, the head of the Division of Digestive Oncology at University Hospital Gasthuisberg, in Leuven, Belgium. Presenting the data at the 2014 Congress of the European

Society for Medical Oncology (ESMO; abstract LBA13), Dr. Van Cutsem noted that the benefit of TAS-102 (Taiho Oncology) was observed even among patients who were previously treated with regorafenib (Stivarga, Bayer), another agent that has recently demonstrated efficacy in late-stage mCRC. An earlier report on the main results of RECOURSE was presented at the 16th ESMO World Congress on Gastrointestinal Cancer. The data from the most recent updated analysis was “very robust,” particularly in the challenging population enrolled in RECOURSE, said the invited discussant, Christophe Tournigand, MD, PhD, the head of medical oncology at Hospital Henri Mondor, University Paris Est, in Creteil, France. “The patients recruited for this trial had received almost all the drugs you can give

in this situation,” said Dr. Tournigand. He indicated that under these circumstances, the hazard ratio (HR) of 0.68 for OS ( <0.0001) is impressive. (P In this study, 800 patients with mCRC who had failed most commonly used chemotherapy, bevacizumab, and epidermal growth factor receptor inhibitors (in those with wild-type KRAS), were randomized in a 2:1 ratio to oral TAS-102 or placebo, with OS as the primary end point. The HR of 0.68 for OS in favor of TAS102 was achieved by extending median survival approximately two months (7.1 vs. 5.3 months). The PFS also strongly favored TAS-102 (HR, 0.48; P<0.0001). The time to worsening of ECOG performance status to 2 or higher was extended in the TAS-102 group by nearly two months (5.7 vs. 4.0; HR 0.66). These

differences were achieved despite 40% of patients in both arms subsequently receiving additional treatments. The relative OS advantage was remarkably consistent across subgroups and stratifications. For example, the HR for OS favoring TAS-102 was 0.64 in Western populations participating in the study and 0.75 among Asians. The HR was 0.69 whether or not patients received prior regorafenib. This is noteworthy because regorafenib is a multikinase inhibitor that also recently demonstrated an OS benefit relative to best supportive care in treatment-experienced patients with advanced mCRC ((Lancet 2013;381[9863]:303-312, PMID: 23177514). The HR for OS was lower among those with wild-type KRAS relative to those with mutant KRAS status

New Guidelines Issued for Older Pts With Colorectal Cancer D

ue to the increasing complexity and diversity of treatment options for patients with colorectal cancer (CRC), the International Society of Geriatric Oncology (SIOG) released new recommendations, highlighting the need for individualized treatment for older patients and stressing that multidisciplinary teams are essential to providing that treatment. Because of issues such as frailty and comorbidity, many older patients require a personalized management approach (Int ( J Cancer 2013;132[9]:21572163, PMID: 23015513). The guidelines also suggest that clinicians should use a comprehensive geriatric assessment to inform clinical decision making and provide patients with detailed information in advance to support their involvement in the decision-making process (see box). These recommendations are necessary to improve and elaborate on solutions for a crucial health problem that affects a sizeable population, according to Al Benson, MD, a professor of medicine at Northwestern University School of Medicine, in Chicago, who was not involved in the creation of the guidelines. Dr. Benson noted that the guidelines authors stress the importance of several factors that can influence treatment for older patients, such as comorbidities and functional performance status. These factors were highlighted because they are associated with early postoperative mortality in patients

Recommendations For Treating Older Patients With CRC

he SIOG task force’s recommendations for the management of older patients with CRC are based on the following overall conclusions:

with gastrointestinal malignancies ((Ann Surg Oncol 2013;20[2]:371-380, PMID: 22987098). The SIOG decided to update the guidelines in part because of rising numbers of new cases of bowel cancer in older patients. For example, the number of new cases of bowel cancer diagnosed in patients older than age 75 years in the United Kingdom rose by 30% from 1993 to 2010 (from 13,400 to 17,300) (http://www.ncin.org.uk/ cancer_information_tools/ukcis). “It’s nice to see a comprehensive overview focusing on the older population because previous trials have been criticized for not including any geriatric-specific parameters,” said Cathy Eng, MD, a professor and the associate medical director of the Colorectal Center in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved in the development of the guidelines. “Geriatric oncology is a large emerging field, and is a legitimate concern to

• Embracing the notion of personalized treatment is essential for further improvements in the management of older patients. • Multidisciplinary teams are the key to individualized treatment of these patients. • A comprehensive geriatric assessment informs clinical decision making. • Patients need to be provided with information to support their immersion in the initial decisionmaking process with regard to treatment. • The possibility for morbidities and the options if serious complications occur or treatments fail should be discussed in advance. • Investigators should design trials using low-toxicity treatments that preserve most of the efficacy of full-dose treatments. • Investigators should design patient-centered assessments to expand the evidence base in the treatment of these patients. —P.B.

our oncology workforce,” she said. “I think this area is very different from standard oncology services because when you are dealing with patients who are on multiple medications and who have dementia, doctors have to weigh their decisions accordingly.” Dr. Eng noted, however, that she thought the task force should have included more than one geriatrician and the guidelines should have touched on quality of life as an issue. “I think this area is very important because a lot of our elderly patients have other issues and are wondering what the actual benefit is,” she said. “So if we are going to extend their life, quality has to be an issue and we have to take these things into account.” Another problematic area is that the little data that exists on older patients comes from clinical trials, and there is no detailed literature on how this data might apply to patients in a real clinical setting, according to Dr. Benson. “For the most part, clinical trials have relatively small subsets of the elderly population, and the patients who enter these trials probably reflect the most robust of the elderly patients with the very best performance status,” he said. “However, there have been reports that adherence to guidelines for colon cancer have resulted in improved survival. As a result, we generally feel that these guidelines will certainly optimize patient care and improve treatment of the disease.” —Paul Bufano

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(0.58 vs. 0.80), but the significance is not yet clear. TAS-102 was relatively well tolerated, an important consideration in patients with late-stage disease anticipating a limited survival benefit. Grade 3 or higher adverse events (AEs) were largely hematologic. Neutropenia, the most common of these grade 3 or higher AEs, occurred in 37.9%, but febrile neutropenia was uncommon. The other grade 3 or higher AEs included leukopenia (21.4%) and anemia (18.2%).

The evidence of activity in patients “who are clearly refractory” to other therapies led Dr. Tournigand to call the study “potentially important,” but he suggested that quality-of-life data would be helpful in clarifying the effect of this strategy on patient well-being. He also suggested that biomarkers might be helpful to identify patients with latestage disease who are likely to benefit from TAS-102 relative to regorafenib. Additionally, given the activity of TAS-102 in late-stage disease,

Dr. Tournigand expressed interest in determining where this agent may fit at earlier stages of CRC. Although it is not yet clear whether either TAS-102 or regorafenib “are team players or lone rangers” with regard to their compatibility in combination with other agents, Dr. Tournigand speculated that both agents are likely to be tested at earlier stages of treatment, including in front-line strategies. In highly experienced mCRC patients, however, TAS-102 appears to be a candidate as a new standard of

CRIZOTINIB continued from page 1

advantage for progression-free survival (PFS) relative to pemetrexed (Alimta, Lilly) plus either cisplatin or carboplatin, reported investigator Benjamin Solomon, MBBS, PhD, a consultant oncologist at the Peter McCallum Cancer Centre, in Melbourne, Australia, during the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract 1225O). The Phase III trial was one of several evaluating targeted therapies aimed at molecular subtypes of NSCLC that were presented at the ESMO meeting. Others included an open-label Phase II study with the TKI dabrafenib (Tafinlar, GlaxoSmithKline) in advanced BRAF V600E-mutant NSCLC (abstract LBA38_ PR) and a 27-patient study evaluating both the TKI neratinib and the mTOR inhibitor temsirolimus (Torisel, Pfizer) in HER2-positive NSCLC (abstract LBA39_ PR). Each of these studies suggested promising activity, supporting the growing importance of molecular subtyping in NSCLC, but the study with crizotinib is potentially practice changing. In the crizotinib trial, called PROFILE 1014, 343 patients with previously untreated ALK-positive NSCLC were randomized to receive 250 mg of crizotinib twice daily or up to six cycles of chemotherapy consisting of pemetrexed with either cisplatin or carboplatin. The median PFS was 10.9 months with crizotinib versus 7.0 months with chemotherapy (hazard ratio [HR], 0.45; P<0.0001). Relative to chemotherapy, crizotinib offered a higher objective response rate (74% vs. 45%; P<0.0001), faster time to response (6.1 vs. 12.1 weeks) and longer duration of response (49 vs. 22.9 weeks). A nonsignificant difference in the HR for overall survival (OS) favoring crizotinib (0.82; P=0.361) was observed, but Dr. Solomon acknowledged that a statistically significant OS advantage may be difficult to show even with longer follow-up. In this study, 70% of the patients in the chemotherapy arm crossed over, so any difference is likely to depend on the importance of early

These data ‘established the efficacy of crizotinib as first-line therapy in advanced ALK-positive lung cancer.’ —Alice T. Shaw, MD, PhD versus late TKI therapy. Visual disturbances were the most common adverse event associated with crizotinib, occurring in 71% of the patients in the TKI arm and 9% of the chemotherapy group. According to Dr. Solomon, these disturbances, such as blurred vision or light trails in the peripheral vision, generally are tolerable when patients receive prior counseling about this risk. Diarrhea (61% vs. 9%) and edema (49% vs. 12%) also were much more common among those treated with the TKI than with chemotherapy, but fatigue (28% vs. 29%), neutropenia (30% vs. 21%) and stomatitis (21% vs. 14%) were more common with chemotherapy. Most events in both arms were grade 2 or lower severity. The ESMO-invited discussant for PROFILE 1014, Alice T. Shaw, MD, PhD, an attending physician in the Thoracic Oncology Program at Massachusetts

General Hospital, in Boston, agreed that these data “established the efficacy of crizotinib as first-line therapy in advanced ALK-positive lung cancer.” Dr. Shaw, who authored a previous Phase III study that established crizotinib as a second-line option for ALK-positive NSCLC ((N Engl J Med d 2013;368[25]:2385-2394, PMID: 23724913), drew on the PROFILE 1014 data to conclude that ALK inhibitors should be considered for first-, second- and possibly third-line treatment in ALK-positive NSCLC. “Based on these data, crizotinib should now be used as first-line therapy in newly diagnosed ALK-positive NSCLC, but when patients relapse and a change is required, switching to a next-generation ALK inhibitor like alectinib or ceritinib (Zykadia, Novartis) is reasonably supported by multiple single-arm studies,” Dr. Shaw said.

treatment based on the highly significant OS advantage observed in this trial. Although the absolute median survival benefit of two months is modest, the therapy was relatively well tolerated in a population with essentially no remaining treatment options. —Ted Bosworth Dr. Van Cutsem reported that he has no financial relationships with pharmaceutical companies other than research funding paid to his institution.

Next-generation ALK inhibitors may be preferable in patients with brain metastasis, which is the most common type of distant recurrence. There is experimental and some clinical evidence that suggests that the newer agents are better able to cross the blood–brain barrier relative to the firstgeneration agent crizotinib. Overall, the data reinforce evidence that optimal therapy for NSCLC is increasingly dependent on molecular profiling. Although ALK-positive malignancies only represent about 4% of NSCLCs, the list of driver mutations that can be targeted with TKIs appears to be increasing. In addition to ALK, BRAF V600E and HER2, these include mutations in signaling pathways involving EGFR and KRAS. Although the order of first- and nextgeneration TKIs for ALK-positive NSCLC may evolve as more is learned about relative activity, resistance and tolerability, it is notable that many of these agents have effects on multiple pathways that may make them useful for treating more than one molecular subtype. For example, crizotinib inhibits the ROS1 and MET T pathways in addition to the ALK pathway. ROS1, which encodes a tyrosine kinase that is related to but distinct from ALK, is estimated to represent about 1% of NSCLC cases. At ESMO, Dr. Shaw presented results from a Phase I study evaluating crizotinib in the treatment of NSCLC with ROS1 chromosomal rearrangements. The objective response rate in a series of 50 patients with ROS1-positive NSCLC was 72%, and there were three complete responses. The median PFS was 19.2 months. The study, which was simultaneously published online ((N Engl J Med 2014 Sept 27. [Epub ahead of print]), provides additional and compelling evidence of the value of targeting NSCLC molecular subtypes. —Ted Bosworth Dr. Solomon reported financial relationships with Novartis and Pfizer. Dr. Shaw reported financial relationships with Ariad, Genentech, Ignyta, Novartis and Pfizer.

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Report From ESMO

Oncologists Slow To Adopt Hypofractionated Radiotherapy Madrid—Although large randomized trials in women undergoing lumpectomy for breast cancer have shown that hypofractionated radiotherapy is at least as favorable as conventional radiotherapy, some radiation oncologists have been reluctant to use this approach, fearing increased toxicity. Now a study presented at the 2014 European Society for Medical Oncology Congress (ESMO; abstract 294P) demonstrates that hypofractionated radiotherapy causes significantly less moist desquamation than conventional radiotherapy. The prospective study included 229 Belgian women with breast cancer, 150 from Ghent University Hospital (GUH) and 79 from Clinique et Maternite Sainte-Elisabeth Namur (CMSE). All the patients at GUH were treated with hypofractionation (40 Gy in 15 fractions). At CMSE, patients with a cup size of D or larger were treated with conventional radiotherapy (50 Gy in 25 fractions) and patients with a cup size of C or smaller were treated with conventional or hypofractionated radiotherapy, at the discretion of the radiation oncologist. The primary end point was acute moist desquamation. The investigators found that patients with a cup size no larger than C developed significantly more moist desquamation when treated with conventional radiotherapy than when treated with hypofractionation (39% vs. 9.5%; P<0.001). In patients with a cup size of D or larger, the rates of moist desquamation also were higher in those receiving conventional radiotherapy than in those receiving hypofractionated radiotherapy (68% vs. 20%; P=0.002). These results add to data from multiple randomized trials demonstrating that in women undergoing lumpectomy for breast cancer, lower total doses of radiotherapy delivered in fewer, larger doses over three weeks

(hypofractionation) are at least as safe and effective as standard radiation (50 Gy in 25 fractions of 2.0 Gy over five weeks). A large clinical trial from Canada supported the use of 42.5 Gy in 16 fractions over three weeks ((J Natl Cancer Inst 2002;94[15]:11431150, PMID: 12165639). Clinical trials from the United Kingdom support the use of 41.6 Gy in 13 fractions, or 40 Gy in 15 fractions, over three weeks ((Lancet 2008;371[9618]:1098-1107, PMID: 18355913; Lancet Oncol 2008;9[4]:331341, PMID: 18356109). Although these trials have demonstrated that hypofractionated radiotherapy is noninferior, more convenient and less costly than conventional radiotherapy, a study presented at the 2014 annual meeting of the American Society of Clinical Oncology revealed that the use of hypofractionated radiotherapy remains low (abstract 6522). In this study, researchers from the University of Michigan, Ann Arbor, and the University of North Carolina at Chapel Hill analyzed the Surveillance, Epidemiology, and End ResultsMedicare database between 2004 and 2010 to determine the uptake of hypofractionated radiation in older women with early-stage invasive breast cancer. Women were included if they had N0, M0 invasive breast cancer no larger than 5 cm; underwent a lumpectomy followed by radiation within two years after diagnosis; and received 13 or more radiation treatments. Patients who received accelerated partial breast radiation therapy were excluded from the analysis. According to lead investigator Reshma Jagsi, MD, DPhil, an associate professor of radiation oncology and a research investigator at the Center for Bioethics and Social Sciences in Medicine at the University of Michigan, Ann Arbor, the use of hypofractionated radiotherapy increased over time

Table. Use of Hypofractionated Radiotherapy 2004-2010

Year

Patients Receiving Hypofractionation Radiotherapy, %

2004

3.9

2005

3.8

2006

3.7

2007

5.6

2008

9.5

2009-2010

14.2

but was still low, 14.2%, in 2009-2010 (Table). The investigators pooled data from 2009 and 2010 because the dataset from 2010 was smaller than other years, said co-investigator Ronald Chen, MD, an assistant professor of radiation oncology at the University of North Carolina at Chapel Hill. Women were roughly twice as likely to receive hypofractionation if they were older than 80 years and had smaller tumors. Dr. Jagsi said that although cynics might believe that radiation oncologists are slow to pick up hypofractionation because it is not in their best interest (reimbursement depends on the number of treatment fractions), they might be hesitant to adopt new approaches because they go against traditionally

‘It is harder for us to get our heads around this approach [of hypofractionation], so it’s heartening that we do see some increase over time, and we hope that this continues.’ —Reshma Jagsi, MD, DPhil held beliefs. For many years, radiation oncologists have been taught that when small doses of radiation are used, normal tissues are given the chance to repair between fractions, and if too large a dose is given in one fraction, problematic late effects might occur. “It is harder for us to get our heads around this approach [of hypofractionation], so it is heartening that we do see some increase over time, and we hope that this continues,” Dr. Jagsi said. Studies are needed to understand barriers to dissemination/implementation of trial results to change clinical practice. Timothy Whelan, MD, the Canada Research Chair in Health Services Research in Cancer at Toronto’s McMaster University, thinks the slow uptake is predictable. “The results are not really surprising, as most oncologists were waiting until the publication of longterm follow-up, which really didn’t happen until 2010,” said Dr. Whelan. He pointed out that oncologists are gradually embracing hypofractionation, with use having increased from 3.9% in 2004 to 14.2% in 2010. He expects the uptake has risen since then and will continue to do so. —Kate O’Rourke Drs. Jagsi, Chen and Whelan reported no relevant financial relationships.

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HER2+ Metastatic Breast Cancer

Data Establish Pertuzumab as Part of Standard Regimen Madrid—In patients with HER2-positive metastatic breast cancer (HER2+ mBC), the new standard of care is chemotherapy and trastuzumab plus pertuzumab, according to a substantial overall survival (OS) benefit found in a multinational Phase III trial. After a median follow-up of 50 months, median survival increased by more than one year compared with chemotherapy and trastuzumab alone. When pertuzumab was added to treatment, “the median survival was 56.5 months, which is unprecedented and confirms this regimen as first-line therapy,” reported Sandra M. Swain, MD, the medical director of the Washington Cancer Institute at MedStar Washington Hospital Center, in Washington, D.C. Dr. Swain presented the final OS analysis of this trial, called CLEOPATRA, at the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract 350O PR). In this study, which included participants from 204 centers in 25 countries, 808 patients with HER2+ mBC were randomized to receive pertuzumab (Perjeta, Genentech) in an 840-mg loading dose followed by a 420-mg maintenance dose, or placebo. All patients received trastuzumab (Herceptin, Genentech), in an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose, plus at least six cycles of docetaxel (75 mg/m2 titrated to 100 mg/m2 if tolerated). The advantage of pertuzumab over placebo for progression-free survival (PFS) was reported previously ((N Engl J Med 2012;366[2]:109-119, PMID: 22149875). In the survival curves presented at ESMO, the benefit of pertuzumab emerged within the first year. After a median follow-up of 50 months, the median survival was 56.5 months in the arm that received pertuzumab versus 40.8 months in the placebo arm. The median 15.7-month increase in survival generated a hazard ratio of 0.68, or a 32% reduction in the risk for death ((P=0.0002). The extended safety analysis is consistent with safety data reported earlier. The rates of diarrhea (68% vs. 48%), rash (37.5% vs. 24%), mucositis (27% vs. 19%) and headache (25% vs. 19%) were higher with the addition of pertuzumab, but most adverse events were grade 2 or lower. There was no sign of increased cardiovascular risk with the two HER2 dimerization inhibitors combined. The trial was characterized as “an unquestionable therapeutic success” by Luca Gianni, MD, the director of medical oncology at the San Raffaele Scientific Institute, in Milan. Invited by ESMO to put these results in perspective, Dr. Gianni called the more than oneyear improvement in OS “dramatic,” and

suggested that this provides a new paradigm for treating HER2+ mBC. The trial data confirm that “dual HER2 blockade is feasible and safe,” Dr. Gianni said, noting that HER2-positive disease represents about 20% of breast cancers. He

said he believes that the next step in HER2+ mBC will be to individualize therapy by targeting mediators of resistance, such as mutations in the PIK3CA gene. However, he said he considers the CLEOPATRA data to be definitive. “The combination of pertuzumab, trastuzumab and docetaxel is not just an option for

the first-line treatment of HER2+ metastatic breast cancer,” Dr. Gianni said. “It is the new standard.” —Ted Bosworth Dr. Swain is an uncompensated consultant for Genentech/Roche. Dr. Gianni has financial relationships with AstraZeneca, BioScience, Boehringer Ingelheim, Celgene, Genentech, GlaxoSmithKline, Pfizer, Roche and Tahio.

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2014 • CLINICALONCOLOGY.COM

Clinical Conundrums Highlights from NEJM, JCO, Blood, and Lancet Oncology 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

composite measure of comorbidities and age as a new index for clinical decision making in the setting of allogeneic hematopoietic cell transplant (allo-HCT).

3. True or False? According to the

National LymphoCare database, 15% to 20% of patients with follicular lymphoma (FL) receive single-agent rituximab as their initial therapy.

1. True or False? Vitamin D defi- 4. True ciency is a risk factor for unfavorable outcomes in older adults with diffuse large B-cell lymphoma treated with R-CHOP (rituximab [Rituxan, Genentech], cyclophosphamide, doxorubicin, vincristine, and prednisone).

2. True or False? In a study pub-

lished in JCO, investigators proposed a

ANSWERS

1. True. In the study published in

JCO, patients treated in the RICOVER-60 (Rituximab with CHOP over age 60 years) trial with 25-hydroxyvitamin D3 levels ≤ or > 8 ng/mL treated with rituximab had 3-year event-free survival of 59% and 79%, and 3-year overall survival rates of 70% and 82%, respectively. These results must be confirmed in appropriately designed prospective trials. Bittenbring JT, Neumann F, Altmann B, et al. Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab. J Clin Oncol. 2014;32(29):32423248, PMID: 25135997.

2. True. Data from 3,033 consecutive

recipients of HLA-matched grafts from 5 institutions contributed to this analysis. The composite comorbidity–age index could be used by physicians to accurately account for the effects of age and comorbidities when making treatment decisions or estimating outcomes after alloHCT, with a variety of conditioning regimens. With this scoring index, patients with low scores (0 or 1-2) should be considered for randomized clinical trials or offered higher-intensity regimens. Likewise, patients with higher scores (≥3)

or False? Results from RESORT (Rituximab Extended Schedule or Re-Treatment Trial) indicated that if opting for single-agent rituximab as initial therapy for low tumor–burden FL, a strategy of retreatment with rituximab (RR) at disease progression should not be favored over a strategy of continuous maintenance therapy (MR) after 4 weekly sessions of rituximab.

would be more suitable candidates for lower-intensity preparative regimens. Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32(29): 3249-3256, PMID: 25154831.

True. Widely disparate therapeutic approaches are used for FL as reflected by the National LymphoCare Study. This study was designed to collect information on treatment regimens and outcomes for patients with newly diagnosed FL in the United States. There is no single standard of care for the treatment of de novo FL, although antibody use is ubiquitous when therapy is initiated. Importantly, these disparate approaches to the initial care of patients with FL render a heterogeneous group of patients at relapse. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the National LymphoCare Study. J Clin Oncol. 2009;27(8):1202-1208, PMID: 19204203.

4. False. RESORT indicates that if

opting for single-agent rituximab as initial therapy for low tumor–burden FL, a strategy of retreatment with RR at disease progression is recommended over a strategy of continuous MR. For the primary end point of time to failure, there was no difference between RR and MR (median, 3.9 vs 4.3 years, respectively;

5. True or False? An open-label ran-

domized Phase III trial published in Lancet Oncology showed that immediate rituximab monotherapy is effective at deferring disease progression and the need for chemotherapy or radiotherapy compared with the conventional watchand-wait (WW) approach in patients with advanced-stage, asymptomatic, low tumor–burden FL.

6. True or False? Brentuximab vedo-

tin (Adcetris, Seattle Genetics), administered sequentially with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or in combination with CHP (cyclophosphamide, doxorubicin, prednisone), has a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30positive peripheral T-cell lymphomas.

7. True or False? A study published in

NEJM M demonstrated that chimeric antigen receptor–modified T-cell therapy against CD19 antigen (CTL019 cells) was effective in treating relapsed and refractory acute lymphoblastic leukemia (ALL).

the following statements about CTL019 cellular therapy for treating relapsed and refractory ALL are correct except: a. CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow but not in cerebrospinal fluid (CSF) of patients who showed response. b. At 6 months, the probability that a patient would have persistence of CTL019 cells was 68%. c. At 6 months, probability that a patient would have relapse-free B-cell aplasia was 73%. d. All the patients treated with CTL019-based therapy had the cytokine-release syndrome (CRS).

9. True or False? European investiga-

tors reported in Blood d that in AL amyloidosis, progression to dialysis can be predicted based on the presence or absence of 2 easily identifiable risk factors—proteinuria greater than 5 g per 24 hours and estimated glomerular filtration rate (eGFR) less than 50 mL per minute.

8. A study published in NEJMM reports 10. True or False? Mismatch(es) at that chimeric antigen receptor–modified T-cell therapy against CD19 antigen results in sustained remission in patients with relapsed and refractory ALL. All of

nonpermissive HLA-DPB1 loci does not increase mortality after HLA (A, B, C, and DPB1) match myeloablative unrelated allo-HCT.

P=0.54). For the secondary end point of time to first cytotoxic therapy, a statistically significant difference favoring MR was observed (cytotoxic therapy-free at 3 years: RR, 84% vs MR, 95%; P=0.03). The improvement in time to cytotoxic therapy came at a financial cost. It is important to note that only patients responding to induction rituximab were randomly assigned (71%), and that MR was a single dose of rituximab every 3 months (not 2 months) until treatment failure.

monotherapy should be regarded as a standard approach in the management of patients with low tumor–burden FL versus a WW strategy.

Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for lowtumor burden follicular lymphoma: eastern cooperative oncology group protocol E4402. J Clin Oncol. 2014;32(28):3096-3102, PMID: 25154829.

5. True. In

this U.K. study, 379 patients were randomly assigned to WW or rituximab induction plus MR for 2 years. The primary end points were time to initiation of new therapy and health-related quality of life (HRQoL), measured 6 months after the completion of rituximab induction. Rituximab-treated patients were far less likely to require new therapy at 3 years (88% vs 46%), and had a significant improvement in HRQoL, with more patients feeling in control of their situation and experiencing less anxiety about their diagnosis. The authors concluded that rituximab

Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424-435, PMID: 24602760.

6. True. Patients received sequen-

tial treatment (every 3 weeks) with brentuximab vedotin 1.8 mg/kg (2 cycles) followed by CHOP (6 cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) every 3 weeks for 6 cycles. Responders received single-agent brentuximab vedotin for 8 to 10 additional cycles (a total of 16 cycles). A double-blind randomized Phase III trial comparing BV+CHP with CHOP is underway. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a Phase I study. J Clin Oncol. 2014;32(28):3137-3143, PMID:25135998.

7. True. Thirty children and adults

received CTL019 therapy. Complete remission was achieved in 27 (90%), including 2 with blinatumomab-refractory disease and 15 who underwent HCT. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517, PMID: 25317870.

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2014 • CLINICALONCOLOGY.COM

8. a. CTL019 cells proliferated in

vivo and were detectable in the blood, bone marrow, and CSF of patients who had a response. Severe CRS, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab (Actemra, Genentech). Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517, PMID: 25317870.

9. True. They were able to design a

simple staging system from large retrospectively analyzed cohort, based on universally available measurements, proteinuria and eGFR, sharply

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discriminating groups of patients with different probabilities of losing renal function. However, these data should be interpreted in the context of improved therapy over the past several years. The proportion of patients requiring dialysis 3 years after diagnosis was 7% in renal stage II (presence of 1 risk factor) and 60% in renal stage III (presence of both risk factors), whereas no patient with baseline proteinuria of no more than 5 g per 24 hours and eGFR of at least 50 mL/minute/1.73 m2 (renal stage I) became dialysis-dependent. There was no significant difference in

patients’ survival among the 3 renal stages. The key to prevent irreversible renal damage is to treat early and effectively. 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.

10. False.

The investigators reviewed series of approximately 8,000 pediatric and adult allo-HCT patients and demonstrated that nonpermissiveDPB1 allele mismatch is associated with increased graft-versus-host disease and

increased transplant-related mortality in the setting of myeloablative matched (8/8 high-resolution typing) unrelated allo-HCT. The investigators concluded that nonpermissive HLA-DPB1 mismatches in otherwise 8/8 HLAmatched pairs should be avoided. Pidala J, Lee SJ, Ahn KW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014;124(16):25962606, PMID: 25161269.

Shahid Raza, MD, assisted in preparing this article.

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How I Manage ...

How I Manage Advanced (Stage III/IV) Hodgkin Lymphoma in Adults, Part 2 W

ith cure rates for Hodgkin lymphoma (HL) now exceeding the 80% mark, much of the attention has shifted from the achievement of durable remissions to reductions in long-term complications of treatment, especially secondary malignancies and cardiovascular disease. The eradication of HL in all patients, however, must remain the primary goal as we work to reduce late effects. The median age of patients with HL is in the prime of life, so both improvements in disease control and reductions in treatment-related mortality over the long term will impact overall survival (OS). Today’s challenge is to maximize cure rates and minimize secondary effects while also preserving an excellent quality of life.

Jane N. Winter, MD Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

What is the role of consolidation radiation therapy in advanced-stage patients treated with ABVD? In the pre-fluorodeoxyglucose positron emission tomography (FDG-PET) era, the results of clinical trials supported consolidative radiotherapy for those achieving partial but not complete remissions (CRs) documented by computed tomography (CT) scan. Differences in outcomes for patients with bulky disease seen in 2 cooperative group trials likely were attributable to differences in treatment regimens, underscoring the importance of not generalizing results achieved with one regimen to others. The more effective a chemotherapy regimen, the less likely that consolidative radiotherapy will be of additional benefit. The use of FDG-PET to discriminate those with residual masses but no active disease from those with incomplete responses to chemotherapy

will hopefully better define the subgroup likely to benefit from consolidative radiotherapy. In the HD15 trial, the German Hodgkin Study Group (GHSG) performed FDG-PET scans only on patients who achieved partial remissions with escalated (esc) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and had residual masses of at least 2.5 cm. Only those who were FDG-PET positive by central review at the completion of chemotherapy received consolidative radiotherapy. Outcomes for this subgroup were excellent, and they were no different from those for patients who were judged to have achieved CRs by CT scans alone and were not eligible for FDG-PET scanning per protocol. Clearly, radiotherapy will be of benefit in a shrinking population of patients to be defined best with modern imaging including FDG-PET. Whether results achieved after treatment with escBEACOPP can be translated to patients

Table. Deauville Criteriaa Score

Finding

No PET uptake

PET uptake ≤ mediastinum

PET uptake > mediastinum but ≤ liver

PET uptake moderately higher than liver

PET uptake markedly higher than liver and/or new sites of disease

Implies PET uptake in new sites unrelated to lymphoma

CT, computed tomography; HL, Hodgkin lymphoma; iPET, interim PET; PET, positron emission tomography a

Careful collaboration with radiologist encouraged for interpretation of the PET-CT scans in HL. Baseline, iPET, and end-of-therapy PET scans are scored from 1 to 5 according to uptake in sites initially involved by HL.

Adapted fro from om reference 1.

treated with less-intensive regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), remains to be seen. Caution is advised. The integration of early FDG-PET into the treatment strategy complicates matters, as does the looming issue of secondary effects from radiotherapy. The acceptance of “involved site” radiotherapy and possibly “involved nodal” radiotherapy, rather than the more extensive fields required by involved field radiotherapy also may mitigate long-term toxicity while maintaining disease control. As evidenced by the NCIC/ECOG HD06 trial, long-term follow-up (ie, beyond 10 years) will be required to best compare strategies.

What is the role of interim FDG-PET scanning? Interim FDG-PET (iPET) performed after only 2 cycles of ABVD chemotherapy is a powerful predictor of outcome, with high sensitivity and specificity. Standardization of FDG-PET scoring using the Deauville criteria, which assigns scores (1-5) based on comparison of uptake with that of the mediastinum and liver, should facilitate comparison of clinical trial results and lead to the integration of iPET scanning in treatment paradigms (Table).1 A retrospective analysis of 260 patients has confirmed the superiority of iPET over the International Prognostic Score as a predictor of clinical outcome and the reproducibility of scoring using the Deauville criteria.2 For iPET-positive patients (Deauville 4-5), the 3-year progression-free survival (PFS) was 28%, compared with 95% for the negative group (Deauville 1-3). Similar

results have been reported in a prospective multicenter study of 304 patients treated with ABVD, with only 25% of patients with a positive iPET achieving continuous CR in contrast to 92% of PET-negative cases.3 The success of the earliest iPETadapted clinical trial conducted by Dann and colleagues in Israel4 has led to a series of trials both escalating and deescalating therapy, based on the results of an interim scan. At the present time, the optimal strategy remains unclear. PET scanning is now performed with an integrated CT, enhancing its diagnostic precision. The US Intergroup led by the Southwestern Oncology Group has completed a Phase II trial that adapted therapy based on iPET with an integrated CT performed after 2 cycles of ABVD.5 Patients with negative scans (Deauville 1-3) completed an additional 4 cycles of ABVD, whereas those with positive scans proceeded to 6 cycles of escBEACOPP. The 2-year PFS and overall survival (OS) for the HIV-negative group were 76% and 95%, respectively. Among the 18% with a positive iPET treated with escBEACOPP, the 2-year PFS was 61%, compared with an expected PFS of 15% to 30%. The apparent benefit associated with this iPET-adapted strategy will need to be confirmed. Other groups are investigating a variety of strategies in randomized trials. Preliminary results from the RATHL (Responseadjusted Therapy for Hodgkin Lymphoma) study have been reported, with a high percentage of patients treated with ABVD converting from PET-positive to PET-negative after a change to escBEACOPP therapy.6 In this study, PET-negative patients were randomized to continue with conventional ABVD or with AVD, omitting bleomycin, for 4 cycles. Alternative investigational approaches for early PET-positive cases following ABVD induction include ifosfamidebased salvage therapy and autologous hematopoietic cell transplantation, or randomization to escBEACOPP or baseline BEACOPP with or without rituximab. European groups are comparing iPET-adapted strategies with nonadapted approaches, with the early PET occurring after the first cycle of ABVD in one study. In contrast to the many studies in progress that escalate therapy after an

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References

Complete assigned therapy ×4

Stage III, IV HL

Complete assigned therapy or physician choice

This ongoing, open-label, randomized, multicenter study (NCT01712490) will compare A+AVD versus ABVD in 1,040 patients with stage III/IV classical HL. Primary end point: modified (m) PFS (death, progression, or receipt of chemotherapy or radiotherapy by patients not in CR after completing AVD + BrVe or ABVD will count as progression event). Key secondary end point: OS. Key inclusion criteria: histologically confirmed previously untreated stage III/IV classical HL. Patients will be stratified by region and International Prognostic Score, and will be randomized 1:1 to receive AVD + BrVe (1.2 mg/kg with each dose of AVD) or ABVD administered IV on days 1 and 15 of 28-day cycles for 6 cycles.

Figure. A randomized, open-label Phase III trial of AVD + BrVe vs ABVD as front-line therapy in patients with advanced-stage classical HL (C25003). A, doxorubicin; AVD, doxorubicin, vinblastine, dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BrVe, brentuximab vedotin; CR, complete remission; CT, computed tomography; HL, Hodgkin lymphoma; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival Based on references 9 and 10.

early positive iPET and continue with standard therapy if iPET is negative, the GHSG begins with their standard, escBEACOPP, and reduces the number of cycles of escBEACOPP to a total of 4 for iPET-negative patients, and adds rituximab to an additional 6 cycles of escBEACOPP for iPET-positive cases. Results for these trials will be available shortly. We do not yet have conclusive evidence that an iPET-adapted strategy is better than one that does not adjust therapy based on early iPET results, at least when escBEACOPP is the initial therapy. If ABVD is the initial therapy, there is accumulating evidence that outcomes can be improved by changing to a more intensive strategy. The best way to adapt treatment after a positive iPET is still unknown. Again, long-term

follow-up will be key in assessing the relative benefits of the many possible approaches.

Can treatment be personalized based on age and prognostic factors? Although preliminary studies suggest that iPET-directed escalation of therapy improves outcomes for those initially treated with ABVD, the improvement in outcomes appears only partial, with as many as 40% of iPET-positive cases still failing initial therapy. In the absence of a clinical trial, it is tempting to select young patients with good performance status and high-risk disease (International Prognostic Scale scores ≥4) for up-front treatment with escBEACOPP, yet to date we don’t have

AT A GLANCE • National Comprehensive Cancer Network guidelines recommend no more than 6 cycles of ABVD for any patient with advanced HL. • Interim FDG-PET performed after only 2 cycles of ABVD is a powerful predictor of outcome, with high sensitivity and specificity. • Standardization of FDG-PET scoring using the Deauville criteria is encouraged. • Treatment of advanced-stage HL is evolving and remains extremely challenging.

1. Meignan M, Gallamini A, Meignan M, et al. Report on the First International Workshop on Interim-PET Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257-1260, PMID: 19544140. 2. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica. 2014;99(6):1107-1113, PMID: 24658820. 3. Zinzani PL, Rigacci L, Stefoni V, et al. Early interim 18F-FDG PET in Hodgkin’s lymphoma: evaluation on 304 patients. Eur J Nucl Med Mol Imaging. g 2012;39(1):4-12, PMID: 21894546. 4. Dann EJ, Bar-Shalom R, Tamir A, et al. Riskadapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood. 2007;109(3):905-909, PMID: 17018856. 5. Press OW, Li H, Schoder H et al. Responseadapted therapy of Stage III-IV Hodgkin lymphoma based on interim FDG-PET imaging: early results of US Intergroup S0816. Haematologica. 2013;98(suppl 2):36. Abstract T108. 6. Johnson P, Frederico M, Fossa A, et al. Response rates and toxicity of responseadapted therapy in advanced Hodgkin lymphoma: initial results from the international RATHL study. Hamatologica. 2013;98(suppl 2):02. Abstract T003.

evidence of the superiority of this strategy over standard ABVD, or ABVD followed by escBEACOPP for those with positive early PET scans.

Summary

8. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821, PMID: 21047225.

Treatment of advanced-stage HL is one of the most rapidly changing of the hematologic malignancies, and perhaps the most challenging. We continue to try to balance disease control with long-term risks, using our modern tools to best identify patients destined to do poorly with conventional therapies. In the absence of a clinical trial, my personal approach is to begin with ABVD. I perform an iPET/CT after 2 cycles and transition to escBEACOPP if the early PET is positive (Deauville 4 or 5), with consideration for consolidative radiotherapy for the sites that were PETpositive on the iPET scan. PET-negative patients complete 6 cycles of ABVD. Although PET promises to improve overall clinical outcomes by identifying those in need of aggressive therapy early in their clinical course, molecular strategies are likely to further improve our capacity to predict outcomes with specific regimens.7 Accrual to clinical trials is the key to advancing the field. New agents, such as brentuximab vedotin (Adcetris, SeattleGenetics), which have proven powerful in the setting of advanced relapsed disease,8 are likely to have significant impact on clinical outcomes when incorporated into up-front strategies (Figure).9,10

Scott DW, Chan FC, Hong F, et al. Gene expression-based model using formalinfixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;20;31(6):692-700, PMID: 23182984.

9. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, openlabel, dose-escalation study. Lancet Oncol. 2013;14(13):1348-1356, PMID: 24239220. 10. Radford J, Younes A, Ansell SM, et al. Phase III study of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as front-line treatment for advanced classical Hodgkin lymphoma (HL): the ECHELON-1 study. Haematologica. 2013;98(suppl 2):6. Abstract P017.

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 Multiple Myeloma by Mohamad Mothy, MD, PhD Saint-Antoine Hospital and University Pierre and Marie Curie Paris, France

NOW

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 Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed 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®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. 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. • 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 overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). 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% 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. • 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.

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 mCRC

• In an interim analysis of an open-label, multicenter, randomized clinical

• Because many drugs are excreted into human milk and because of the

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.

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.

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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 in Full Prescribing Information]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRASS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information]. 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 Vectibix®. 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 W 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 skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. 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 KRAS-Mutant S mCRC 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 Full Prescribing Information].] In Study 3, 221 patients with KRAS-mutant S mCRC tumors receiving Vectibixx® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). 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 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 available 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. py Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most frequently reported (> 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) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 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. py Vectibix® in Combination with FOLFOX Chemotherapy 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)

22 (7)

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

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

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

46 (14)

30 (9)

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

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

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%) 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 Vectibix® 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 Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® 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 highaffinity 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: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [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)] 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)

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 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, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [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)]

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14. 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. v20 05/14

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 2014 â&#x20AC;˘ CLINICALONCOLOGY.COM

reviews & commentaries from The Mount Sinai Tisch Cancer Institute Each month, Clinical Oncology Newss summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care.

This month we introduce The Mount Sinai Tisch Cancer Institute. We hope you find this Reviews & Commentaries section, both here and with additional commentaries on our website (ClinicalOncology.com), to be a valuable tool.

The Tisch Cancer Institute T

he Tisch Cancer Institute at Mount Sinai, in New York City, was established in 2008, with a vision to become an interdisciplinary cancer center. Steven J. Burakoff, MD, an accomplished leader in cancer immunology, was recruited to be its inaugural director. Previously the director of the NYU Cancer Institute, Dr. Burakoff built on Mount Sinaiâ&#x20AC;&#x2122;s long history of achievements in cancer research and treatment. Mount Sinai has been at the forefront of cancer research since 1964, when Irving Selikoff, MD, discovered the link between asbestos exposure and neoplasms in the lung, and confirmed multiple factors causing human cancer, as evidenced by the increased incidence of cancer among asbestos workers who smoked cigarettes. Under the direction of James Holland, MD, a founder of the Cancer and Leukemia Group B and a Lasker Award recipient for his contributions to chemotherapy treatment, the hospital also created the first Department of Neoplastic Diseases. Since its establishment, the Tisch Cancer Institute has assembled an accomplished senior leadership team that has created infrastructure and reporting mechanisms, and has provided the resources necessary to promote a collaborative and translational approach to cancer research. Through its more than 45 recruited physicians and researchers specializing in basic research, clinical research and population science, the hospital has enhanced its focus on advancing the study of cancer immunology and cancer cell signaling. The institute also has enhanced its existing programs in hematologic malignancies and solid tumors, expanded its research in cancer epidemiology and furthered the study of cancer immunology and vaccine therapy. In 2012, Mount Sinai opened the 116,000-square-foot Leon and Norma Hess Center for Science and Medicine, where cancer research and treatment play a prominent role. Two floors of dedicated cancer laboratory research space, as well as two floors of the expanded ambulatory Ruttenberg Treatment Center, are located in the Hess Center on adjacent floors. Radiation oncology and cancer imaging also are located in this space with state of the art treatment and imaging equipment. Patients are seen by medical, surgical and radiation oncologists in a multidisciplinary setting. The Hess Center places scientists and physicians in close proximity to foster the sharing of ideas, stimulate progress, and encourage creativity and entrepreneurship. Passion for pushing the boundaries of knowledge and intensive collaboration across academic departments and multidisciplinary institutes facilitate discoveries and their translation from the laboratory to patient care at the Tisch Cancer Institute and Mount Sinai. A key area that the Tisch Cancer Institute aims to focus on in the future is the continued growth of immunotherapeutic approaches to cancer, including head and neck, lung, prostate and breast malignancies. The institute also plans to expand the use of multiscale genomic

approaches to personalized cancer therapy, continue outreach of novel clinical and translational trials to patients, and create novel stem cell therapies for cancer in collaboration with the Black Family Stem Cell Institute at Mount Sinai.

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REVIEW

ADT Does Not Improve OS in Patients With Localized Prostate Cancer From JAMA Internal Medicine

ndrogen-deprivation therapy (ADT) for older patients with localized prostate cancer does not provide long-term overall survival (OS) or disease-specific benefits over conservative management ((JAMA Intern Med 2014;174[9]:1460-1467, PMID: 25023796). In earlier research reported in 2008, investigators from Rutgers University in New Brunswick, N.J., found that between 1992 and 2002, an increasing number of patients were receiving ADT as an alternative to surgery, radiation or conservative monitoring. Lead

researcher Grace Lu-Yao, PhD, studied 19,000 Medicare participants, and reported no increase in OS or prostate cancer–specific survival with the addition of ADT. Dr. Lu-Yao then expanded her study and confirmed the earlier results. She and her colleagues collected from Medicare claims and the population-based Surveillance, Epidemiology, and End Results databases, identifying 66,717 patients over the age of 66 diagnosed with T1-T2 prostate cancer between 1992 and 2009. None of the patients received definitive local therapy (radiation or surgery) within 180 days of diagnosis. The study excluded patients who

died within 180 days of the diagnosis and those who had regional or metastatic cancer. Median follow-up for OS was 110 months. The investigators grouped patient data into geographic health service areas to build an instrumental variable analysis, permitting the study of patient groups based on local treatment standards. This algorithm produced 122 distinct areas composed of high and low ADT use. Using the algorithm, the investigators evaluated patient characteristics such as prostatespecific antigen (PSA), age, diet, weight and race. During the course of this multiyear study, standards of care

changed and were integrated into the analysis. Accounting for known and allowing for unknown confounders made no difference. The investigators found no survival benefit among patients in high- or low-use ADT areas compared with patients who had conservative management of localized prostate cancer. The 15-year OS of patients treated with ADT was 20% in areas with high-use ADT, and 20.8% in areas with low use (95% confidence interval [CI], –2.2% to 0.4%). Fifteen-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, –1.1% to 1.2%).

COMMENTARY William K. Oh, MD Chief, Division of Hematology and Medical Oncology Professor of Medicine and Urology Ezra M. Greenspan, MD, Professor of Clinical Cancer Therapeutics Icahn School of Medicine at Mount Sinai Associate Director of Clinical Research The Tisch Cancer Institute New York, New York

rostate cancer continues to be a major cause of morbidity and mortality in American men. However, it is critical to use the suitable therapy for the appropriate risk group and not expose men to ineffective or harmful treatments. There are several factors that contribute to the confusion about optimal therapy for men with localized prostate

cancer includes options that are usually described as “watchful waiting” or “active surveillance,” with the usual distinction made that the former would not likely have any therapy and the latter, delayed local therapy. Primary androgen-deprivation therapy (PADT), however, represents a surprisingly common choice for treatment in the Medicare pop-

‘There is no difference in outcomes in either moderately or poorly differentiated cancers treated with PADT.’ cancer, including the lack of well-designed randomized clinical trials, the availability of multiple therapeutic approaches that range from surgery to radiation to conservative management, and the long natural history of the disease, which limits the quality of data available to help clinicians guide patient care. Conservative management of prostate

ulation who do not undergo local treatment with surgery or radiation, representing 38% of the total managed “conservatively” in the study by Lu-Yao et al. In an initial paper by these same investigators in 2008, there was a borderline significant improvement in survival in patients with poorly differentiated cancers. Now with further follow-up, they

report that there is no difference in outcomes in either moderately or poorly differentiated cancers treated with PADT. They conclude that PADT should not be considered an option for management of localized prostate cancer. Why would a doctor choose PADT to manage a patient with localized prostate cancer? Many of these patients are older men, with significant comorbidities. They will often have elevated PSA blood tests, which cause significant anxiety. They also may have symptoms such as urinary obstruction. We know that PADT will almost always decrease PSA and also may improve some urinary symptoms. However, ADT also is associated with significant toxicities, including hot flashes, fatigue, weight gain, loss of libido and osteoporosis. In the absence of randomized clinical trials to support its use, some clinicians have considered the possibility that it could be a “gentler” way to manage localized prostate cancer without surgery or radiation, particularly for older patients. This study should really confirm that PADT has no such role, and that if a patient is not a candidate for surgery or radiation, then conservative management without PADT should be the standard of care. This would save the patient the side effects of treatment and would also decrease the cost of care significantly.

Dr. Oh reported no relevant financial relationships.

SEND US YOUR NEWS Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.

Write to managing editor Sarah Tilyou at smtilyou@mcmahonmed.com.

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REVIEW

Statin Use for Colorectal Cancer Improves Survival From Journal of Clinical Oncology

tatin use in patients with colorectal cancer (CRC) was associated with a significant reduction in cancerrelated mortality and longer rates of survival in a recent study. In the largest population-based study undertaken to date, investigators from the United Kingdom sought to determine the effect of statin use after a cancer diagnosis ((J Clin Oncoll 2014;32[28]:31773183, PMID: 25092779). Well known for their effect on cholesterol and coronary heart disease, statins may possess anticancer properties by inhibiting

cell proliferation, inducing apoptosis or inhibiting angiogenesis, according to published reports (J ( Cell Biochem 2009;106[6]:975-983, PMID: 19224538). Using data from the U.K. Clinical Practice Datalink, which includes detailed demographic information and prescribing records, a national cancer registry and the Office of National Statistics, which provides death information, researchers at Queen’s University, Belfast, U.K., identified 7,657 patients diagnosed with stage I to III CRC between 1998 and 2009. They developed Cox regression models to calculate cancerspecific mortality. Patients with stage IV

cancer, as well as those who died within one year of their diagnosis, were excluded. Follow-up averaged five years. Statin users had a 28% reduction in the rate of CRC-specific mortality compared with nonusers (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.64-0.81). Patients who used statins for less than one year had a 21% reduction in their rate of CRC-specific mortality (HR, 0.79; 95% CI, 0.680.93) and those who used statins for more than a year showed a 35% reduction in cancer-related mortality (HR, 0.65; 95% CI, 0.56-0.77). The authors accounted for potential

confounders and analyzed the data by patient sex, age, primary cancer site, body mass index (BMI), smoking status, treatment, use of angiotensin-converting enzyme (ACE) inhibitors or aspirin, and previous statin use. Associations were found in men but not in women, and those with a higher BMI; however, these were not significant. Reviewing the effect of prior statin use, the results mirrored previous studies that showed a weak protective effect of prediagnostic statins on cancer-specific mortality (fully adjusted HR, 0.86; 95% CI, 0.79-0.93).

COMMENTARY Randall Holcombe, MD Chief Medical Officer–Cancer, Mount Sinai Health System Professor, Division of Hematology/Oncology Deputy Director, The Tisch Cancer Institute Medical Director, Ruttenberg Treatment Center Director, GI Medical Oncology New York, New York

everal epidemiologic studies have suggested that statin use may lead to reductions in cancer recurrence and cancer-specific mortality. For CRC, at least two studies suggested benefit from statin use, but a third did not. These studies were small

the rate of CRC cancer-specific mortality compared with non-users. Patients using statins for less than one year had a 21% reduction and those using them for more than a year had a 35% reduction. The reduction in cancer-specific mortality

‘If the findings of Cardwell et al. are confirmed in subsequent prospective studies, statins may become an element of routine care for patients with curable stage CRC.’ and investigated specific CRC subgroups. The current population-based cohort study by Cardwell et al is the largest to date, with records for more than 7,600 patients with stage I to III CRC evaluated. Overall, statin users had a 28% reduction in

held for patients who had not used statins before a diagnosis of CRC as well as the group that was using statins before a diagnosis. There also was a 12% reduction in all-cause mortality in patients using statins.

This is the largest study to date investigating the effect of statins on CRC-specific mortality. There was very long follow-up after diagnosis of up to 14 years, as well as robust verification of cancer diagnosis, death and medication use. Because of its large size and completeness of the data, this is a seminal study suggesting benefit for CRC patients with statin use. The benefit remained even after adjusting for use of other medications that have been postulated to reduce CRC-specific mortality following diagnosis, such as ACE inhibitors, metformin and aspirin. The mechanism through which statins operate is unclear and not specifically investigated in this study. Statins have been shown to induce apoptosis in CRC cells in vitro and inhibit colon carcinogenesis in animal models. In other studies, statin use has been associated with a lower incidence of advanced neoplasm in patients undergoing colonoscopy and in a reduction in the frequency of metastases in newly diagnosed CRC patients. If the findings of Cardwell et al are confirmed in subsequent prospective studies, statins may become an element of routine care for patients with curable stage CRC. Dr. Holcombe reported no relevant financial conflicts of interest.

More REVIEWS & COMMENTARIES from THE MOUNT SINAI TISCH CANCER INSTITUTE Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com Experts from The Mount Sinai Tisch Cancer Institute provide clinical perspectives on important recently published studies in solid tumor and hematologic malignancies.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Clinical Relevance of Intrinsic Subtypes in Early-Stage Breast Cancer Matthew J.C. Ellis, MB, BChir, PhD

uniform, global standard for intrinsic subtyping applicable to both research and clinical practice and advance a more personalized approach to treating early-stage breast cancer.

Director, Lester and Sue Smith Breast Center Baylor College of Medicine Houston, Texas

Identification of Intrinsic Subtypes

Faculty

Introduction Breast cancer is a heterogeneous malignancy that varies clinically and molecularly from patient to patient, with implications for prognosis.1,2 Over the past decade, the advent of complementary DNA (cDNA) microarray and genomic sequencing allowed the molecular classification of breast cancers into 4 intrinsic subtypes2-4: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal-like subtypes. Each intrinsic subtype, identified by its gene expression patterns, has a distinct profile for risk and clinical features. Oncologists can benefit from the prognostic power of intrinsic subtypes. However, unlocking the full potential of subtyping depends on the availability of a robust diagnostic method, which can be run from routine pathologic samples and can support a

Researchers identified the intrinsic subtypes in the early 2000s.3 Working from the hypothesis that phenotypic diversity in breast tumors might correlate with molecular diversity, Perou and colleagues conducted cDNA microarrays to identify variations in gene expression in the breast tumor specimens of 42 patients, encompassing 8,102 genes.3 Using hierarchical cluster analysis (HCA)—a statistical approach that allows subtype grouping by similarity of expression patterns—the researchers were able to determine a unique molecular portrait for each subtype.3 Subsequent research, including work by The Cancer Genome Atlas, made use of ever-improving genomic tools and continued to employ HCA to refine the subtypes.4 By locating gene expression patterns using HCA, these studies ensured rigorous subtype identification. Hierarchical clustering does not start from a preconceived notion of subtypes, but rather generates subtype groupings solely on the basis of patterns that emerge from the data. There

is a distinct methodologic advantage to this process. It begins with tumor biology, and then builds up profiles of intrinsic subtypes with distinct clinical features. This is a more accurate and valid method than the conventional approach of finding a clinical feature based on clinical trial observations followed by a biological explanation.

Defining Intrinsic Subtypes It is useful to think about intrinsic breast cancer subtypes as distinct clinical entities. An analogy to another cancer, lymphoma, is instructive. Some lymphomas, such as follicular lymphoma (FL), are considered indolent diseases; others, such as diffuse large B-cell lymphoma (DLBCL), are considered aggressive diseases. FL, DLBCL, and other lymphomas are considered separate diseases with their own prognoses and modes of treatment. Similarly, different breast cancer subtypes can be considered separate diseases.

Luminal A Luminal A is the most common intrinsic breast cancer subtype.5,6 In a 2010 study, luminal A accounted for 44% of breast cancers in a cohort of approximately 4,000 newly diagnosed patients.7 In 2012, a study reported the incidence of luminal A tumors to be 66% among 934 newly diagnosed patients.5 The luminal A subtype is relatively indolent,

Luminal B Luminal B is a more aggressive, treatmentresistant tumor with a worse prognosis than luminal A.8,9 These tumors are typically HR positive—especially estrogen receptor (ER) positive—and often are HER2 negative.5,9 They generally display high Ki67 scores, indicative of rapidly proliferating tumors.9 Potential

HER2-E

100

OS probability

RFS probability

HER2-E

with a favorable prognosis and prolonged survival.5,7,8 In an analysis of 1,951 node-negative, early-stage breast cancer patients from trials of the International Breast Cancer Study Group, Metzger-Filho and colleagues reported a 10-year breast cancer-free interval (BCFI) of 86% and a 10-year overall survival (OS) of 89% for patients with hormone receptor (HR)-positive luminal A tumors.8 The BCFI and OS rates in luminal A tumors were higher than rates for other subtypes (P<0.001). Although luminal A tumors show a marked diversity of mutated genes—such as the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1—they have the lowest mutation burden of all 4 intrinsic subtypes.4 Luminal A subtype tumors often are HR positive and HER2 negative.4 TP53 mutations— associated with a loss of tumor suppression and poor prognosis—are uncommon in luminal A, with an incidence of 12%.4 Luminal A tumors also have a high level of tumor suppressor activity via the RB1 pathway.4

20 Overall log-rank: P=0.02

Overall log-rank: P=0.07

0 0 49 56

2 33 29

4 28 19

6 27 16

8 25 15

Time from randomization, y At risk (CEF) At risk (CMF) CEF CMF

10 14 6

12 0 0

0 49 56

2 42 46

4 32 28

6 30 21

8 27 19

10 14 8

Time from randomization, y At risk (CEF) At risk (CMF) CEF CMF

Figure. Univariate RFS and OS for HER2-enriched subtypes treated in the NCIC CTG trial MA.5. Kaplan–Meier plots compare treatment arms. CEF, cyclophosphamide-epirubicin-fluorouracil; CMF, cyclophosphamide-methotrexate-fluorouracil; HER2, human epidermal growth factor receptor 2; OS, overall survival; RFS, relapse-free survival Adapted from reference 12.

CLINICAL ONCOLOGY NEWS • NOVEMBER 2014

12 0 0

Supported by

HER2-Enriched Subtype HER2-enriched tumors constitute about 10% of breast tumors.5,7 This subtype cannot be viewed as coterminous with HER2 positivity because in a minority of cases tumors in the profile are HER2 negative; moreover, there are HER2-positive cancers that fall within other intrinsic subtypes.4 Nevertheless, about 80% of HER2-enriched subtype tumors have the HER2 amplification, and about 50% of all clinically determined HER2-positive tumors fall into this subtype. 4 An important aspect of the molecular portrait of the HER2-enriched subtype is the composite HER2/endothelial growth factor receptor (EGFR)/phosphorylated EGFR signature, which defines a key signaling pathway.4 The HER2-enriched subtype is more likely to be HR negative than luminal subtypes.4 HER2-enriched tumors also have a high frequency (72%) of TP53 mutations.4 The risk for regional and local metastases is relatively high,7 and there is a trend toward larger tumor sizes, ductal location, and poor tumor differentiation.10 Offsetting these risks, however, is the sensitivity of the HER2-enriched subtype to targeted therapy, such as trastuzumab. Carey and colleagues recently conducted a subtype analysis of samples from the Cancer and Leukemia Group B 40601 trial (N=305), which showed that patients with HER2-enriched subtype tumors attained a pathologic complete response (pCR) of 71% with paclitaxel plus trastuzumab and 80% with paclitaxel, trastuzumab, and lapatinib (another HER2-targeting agent).11 The positive result with the 2-drug regimen suggests that more aggressive therapy may not be necessary in this intrinsic subtype.11 Moreover, the HER2-enriched subtype strongly predicts sensitivity to anthracycline chemotherapy. This was observed by Cheang and colleagues in a subtype analysis via PAM50 assay of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.5, a clinical trial on nodepositive breast cancer patients randomized to adjuvant therapy with CMF (cyclophosphamide-methotrexate-fluorouracil) versus anthracycline-containing therapy with CEF (cyclophosphamide-epirubicin-fluorouracil).12 HER2-enriched subtypes demonstrated

a significantly better response to CEF than to CMF (62% vs 22%; P=0.0006). Although HER2-enriched subtype was associated with relatively poor clinical outcomes overall, treatment with CEF prolonged survival compared with CMF therapy. Among all 4 subtypes, HER2-enriched tumors showed the greatest benefit from CEF than from CMF, with improvements of 21% for 5-year relapsefree survival (RFS) and 20% for 5-year overall survival (OS; Figure). For both RFS and OS, interaction between HER2-enriched subtype and anthracycline sensitivity was significant (P=0.03). Although luminal B also showed a risk reduction with CEF rather than CMF, this difference did not reach the statistical significance for the HER2 subtype.12

Basal-Like Tumors Basal-like tumors represent about 10% to 20% of breast cancer cases.5,7 Many, but not all are triple-negative tumors: ER negative, progesterone negative, and HER2 negative.4,5 Basal-like tumors exhibit TP53 mutations frequently, with 80% of tumor samples positive for these risk-conferring mutations.4 The tumors tend to be highly proliferative.4 They are considered higher risk than luminal A tumors but lower risk than HER2-enriched and luminal B subtypes.2,5 Basal-like tumors are relatively sensitive to chemotherapy.12 Similarities have been reported between basal-like subtype tumors and tumors carrying BRCA1 mutations. Inactivation of BRCA1 and RB1 are among the many genomic features that basal-like tumors share with ovarian tumors.4 The basal-like subtype is especially prevalent in premenopausal, black women; analysis of a population-based study showed prevalence rates of 39%, 14%, and 16% for premenopausal black women, postmenopausal black women, and nonblack women of any age, respectively.1

The Emerging Role of Intrinsic Subtypes in Treatment To maximize the clinical utility of intrinsic breast cancer subtypes, research must answer a key question: How can we design a treatment paradigm based on intrinsic subtypes? Currently, it is possible to speculate on some general trends. Tumors of the luminal A subtype have a good prognosis, and are treatable with available standards of care, including endocrine therapies13 and conventional chemotherapies such as weekly paclitaxel.12 Luminal B is quite resistant to both endocrine therapy and chemotherapy9; thus, it is a prime candidate for development of novel, targeted therapies. The HER2-enriched subtype is sensitive to chemotherapy, with notable anthracycline sensitivity, as well as to HER2-targeted drugs.11,12,14 Available evidence suggests a therapeutic dilemma. On the one hand, because tumors of the HER2-enriched subtype respond well to anthracyclines12 and

trastuzumab plus a taxane,11 it is standard to offer patients a 4-drug combination (eg, anthracycline-cyclophosphamide then trastuzumab-taxane). On the other hand, since pCR to 2-drug therapy with trastuzumab plus a taxane is quite high, it may not be necessary to risk the significant amount of toxicity that would be incurred by adding an anthracycline or another HER2 targeted drug in all patients.11 Resolution of this dilemma requires the accrual of more data and experience. For example, dual HER2targeted therapy with lapatinib and trastuzumab may be optimal only in the subset of HER2-enriched tumors that also are HER2 positive. Basal-like subtypes also are relatively sensitive to chemotherapy, including anthracycline-based chemotherapy.12,14,15 It is unclear, however, whether the toxicity risks associated with anthracycline therapy are warranted in this subtype, given that the analysis of the NCIC CTG trial MA.5 showed only a trend and not a significant difference in risk reduction with CEF versus CMF.12 To move beyond speculation, more data linking subtype to treatment efficacy demonstrated in large clinical trials is needed. These data would optimally derive from a standard assay applied to pathologic samples from these trials. An important feature of this assay is the ability to use paraffinembedded tumor samples. This approach would allow investigators to run subtype analyses on trials with many years of outcomes data—going back to the banked samples from the initial patient workup to link subtype to survival data. This was done using the PAM50 assay for the NCIC CTG trial MA.512 and Austrian Breast and Colorectal Cancer Study Group 8 trials,13 generating useful information on the efficacy of specific treatments across subtypes. Using the same globalized assay in the clinical setting would support the translation of research from bench to bedside. As more analyses of this type become available, it also may be possible to describe relationships between intrinsic subtype and other prognostic indicators, such as receptor status, menopausal status, and staging at diagnosis, yielding more personalized treatment approaches. Additionally, ongoing work to elucidate the genomics of breast cancer continues to divulge novel treatment targets within subtypes. For example, there is a strong signature for PI3K activity in both basal-like and ER-positive luminal (A or B) breast tumors, but the frequencies of PIK3CA mutations and negative pathway regulators differ between basal-like and luminal subtypes.16 These differences have implications for how the PI3K pathway is targeted in the different subtypes.

clinical entities, each with its own clinical and molecular profile and, ultimately, its own treatment responsiveness. Harnessing the power of subtypes will require a robust subtype assay, to standardize subtyping in both research and clinical practice.

Conclusion

Disclosure

The intrinsic subtypes are established predictors of risk in breast cancer. The subtypes delineate breast cancer into distinct

References 1.

Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-2502.

Parker JS, Mullins M, Cheang MCU, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-1167.

3. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature. 2000; 406(6797):747-752. 4. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. 5. Haque R, Ahmed SA, Inzhakova G, et al. Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1848-1855. 6.

Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):e1000279.

7. Voduc KD, Cheang MCU, Tyldesley S, et al. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010;28(10):1684-1691. 8.

Metzger-Filho O, Sun Z, Viale G, et al. Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol. 2013;31(25): 3083-3090.

9. Tran B, Bedard PL. Luminal-B breast cancer and novel therapeutic targets. Breast Cancer Res. 2011; 13(6):221. 10. Yang XR, Sherman ME, Rimm DL, et al. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev. 2007;16(3):439-443. 11. Carey LA, Barry T, Pitcher B, et al. Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa). J Clin Oncol. 2014; 32(suppl): Abstract 506. 12. Cheang MC, Voduc KD, Tu D, et al. Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 trial. Clin Cancer Res. 2012;18(8):2402-2412. 13. Gnant M, Filipits M, Greil R, et al. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 risk of recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345. 14. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678-5685 15. Carey LA, Dees EC, Sawyer L, et al. The triplenegative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-2334. 16. Ellis MJ, Perou CM. The genomic landscape of breast cancer as a therapeutic roadmap. Cancer Disc. 2013;3(1):27-34.

BB1422

drivers of proliferation in luminal B tumors may be TP53 mutations, which occur in 29% of cases, and transcriptional hyperactivation of MYC and FOXM1 pathways.4 Luminal B breast cancers also are associated with clinical risk factors, such as an earlier distant metastasis than luminal A and a propensity for relapse in bone and pleura.9 Luminal B breast cancer is a significant proportion of breast cancers and many breast cancer deaths are attributed to this subset5,7 because these cancers are relatively insensitive and poorly responsive to both endocrine therapy and chemotherapy.9

Dr. Ellis has reported that he is a consultant for Astra-Zeneca, Novartis, and Pfizer, Inc. He is also a patent holder for the PAM-50 assay.

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to the thief (http://bit.ly/1zeGD9E). The list of breaches is long and continues to grow: According to the Identity Theft Resource Center, there were 247 reported breaches of health care data as of September 2014, and more than 7 million patient records were compromised as a result (http://bit.ly/10xhSr4). The largest health care breach in 2014 resulted in 4.5 million patient EHRs being compromised. That breach occurred at the Community Health Systems, which is the second-largest for-profit hospital chain in the United States. Although large breaches like this make the news, the Identity Theft Resource Center’s website indicates that many breaches occur at smaller health care settings.

CLINICAL ONCOLOGY NEWS • NOVEMBER 2014 • CLINICALONCOLOGY.COM

Table. Notable Electronic Health Record Breaches Number of Patients Affected

Exposed Information

Facility

Date

Community Health Systems, Inc. (Locations throughout the U.S.)

April and June 2014

4.5 million

Social Security numbers, names, addresses, birthdays and, in some cases, telephone numbers

St. Joseph Health System (everal locations in Texas)

Dec. 16-18, 2013

405,000

Names, addresses, Social Security numbers, dates of birth

Aventura Hospital and Medical Center (Aventura, Fla.)

Sept. 13, 2012June 9, 2014

82,601; follows previous breach affecting 2,560 patients

Names, date of birth and Social Security numbers

L.A. Gay and Lesbian Center (Los Angeles, Calif.)

Nov.Dec. 2013

59,000

Names, contact information, medical or health care information, dates of birth, credit card information, Social Security numbers and health insurance account numbers

HealthITSecurity.com, December 11, 2013. “L.A. Gay and Lesbian Services suffers data breach” by Patrick Ouellette

NRAD Medical Associates of Garden City (18 locations in NY and NJ)

Around April 24, 2014

Approximately 97,000

Date of birth, addresses, Social Security number, health insurance information

newyork.cbslocal.com, June 25, 2014. “Long Island Radiology Practice Says 97,000 Patients May Be At Risk After Data Breach”

Despite Ongoing Breaches, Feds Tout Regulatory Measures As the incidence of EHR breaches continues relatively unabated (the number dropped slightly in 2014 compared with 2013), the Department of Health and Human Services (HHS) claims federal measures addressing the problem have had positive effects. In its most recent breach notification report, the HHS pointed to the effect of Section 13402 of the Health Information Technology for Economic and Clinical Health (HITECH) Act, which requires entities covered under the HIPAA to notify affected individuals, the HHS, and in some cases, the media, of health care data breaches. HITECH also requires business associates such as data analysis companies to report breaches of their systems to

covered entities. “The breach notification requirements are achieving their

Other Information

Source

Hackers based in China

Bloomberg, Aug. 20, 2014. “Heartbleed Flaw Said Used by Chinese in Hospital Hacking” by Chris Strohm databreachtoday.com, Feb. 6, 2014. “Hackers Hit Health System’s Server” by Marianne Kolbasuk McGee

Breach due to improper access by employee; tax return filed using a patient’s Social Security number; may have been part of tax refund scheme, where at least one thief received more than $175,000 under a false identity.

twin objectives of increasing public transparency in cases of breach

To Stay Safe, Stick With Established Vendors

espite the ongoing incidence of breaches of EHRs, KLAS Research has said there are several reliably secure oncology-specific EHR vendors to choose from. “If you stick with one of the well-established vendors, you should be safe,” said Monique Rasband, the senior director of research for Imaging & Oncology at Orem, Utah-based KLAS Research. “And if the price of a vendor seems too good to be true, it probably is.” Although security is not a criterion KLAS Research uses to evaluate oncology EHR vendors, the providers they have interviewed have not reported security concerns with the vendors KLAS rates, Ms. Rasband said. All of the oncology EHR vendors that the vendor rating firm measures are meaningful use–certified and have had abundant experience securely installing systems, she said. Those systems are: • Varian (ARIA) • Elekta, Inc. (MOSAIQ Oncology Information System) • Epic (Beacon) • Cerner (PowerChart Oncology)

• McKesson Specialty Health (iKnowMed) • IntrinsiQ, LLC (IntelliDose). Although this is not an EHR, it can be added to a traditional EHR to make it oncology-specific. In addition to some of the above, the American Society of Clinical Oncology recommends these meaningful use– certified oncology EHR vendors (http://www.asco.org/ policy-advocacy/ehr-vendor-lab): • Altos Solutions (OncoEMR) • GeniusDoc, Inc (GeniusDoc Hematology-Oncology EHR/PM) • MDLand International (iClinic Comprehensive EHR) • MEDITECH (Oncology Management) • MedSym Solutions (MedSymEHR, MedSym PM, MedSymLIS) One caveat to the established security of these vendors is the growing use of mobile devices to access EHRs, which Ms. Rasband said is opening up a “Pandora’s box” of security concerns. “Although the market has not yet fully adapted to the needs of providers who use these devices,” she said, “both sides are working to address related security concerns.” —D.W.

Ms. Rasband reported no relevant financial conflicts of interest.

Local10.com, Sept. 16, 2014. “Aventura Hospital and Medical Center reports data breach” by Christina Vasquez

and increasing accountability of covered entities and business associates,” the report concluded. “At the same time, more entities are taking remedial action to provide relief and mitigation to individuals and to secure their data and prevent breaches from occurring in the future.” In an email to Clinical Oncology News, a representative from the Office of Civil Rights (OCR) said no additional regulatory steps were currently being taken by the HHS to reduce the risk for health care breaches. Matthew Hollingsworth, the founder and president of Dayton, Ohio-based ChangeMed, a company that provides services, support and advice related to health care information technology (IT), said that an HHS requirement that HIPAA-covered entities conduct security risk assessments of their EHR systems provides a big incentive for providers to tighten EHR security. Failure to perform such an assessment proved costly for the NewYork-Presbyterian (NYP) Hospital and Columbia University, both of which paid the OCR $4.8 million after electronic patient health information (ePHI)

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‘The potential for fines when you do have a data breach is significantly lower when you can show you’ve done all you can to prevent a breach.’ —Matthew Hollingsworth

about 6,800 individuals, including data about patient status, vital signs, medications and lab results, was exposed in 2010 (http://1.usa.gov/1wDVMgf ). An OCR investigation concluded that neither organization had conducted “an accurate and thorough risk analysis that identified all systems that access NYP ePHI.” This case underscores the importance of taking steps to institute preventive measures. “The potential for fines when you do have a data breach is significantly lower when you can show you’ve done all you can to prevent a breach,” emphasized Mr. Hollingsworth.

Things You Can Do Right Now Smaller practices that do not have staff with specialized IT security knowledge might find it daunting to consider the challenge of securing data, given that large organizations like NYP and Columbia University have fallen victim to breaches. “However, there are steps even small practices can take to tighten the security of their EHRs,” Mr. Hollingsworth said. For example, the HHS has an online risk assessment tool that any office staff can use (http://bit.ly/1wDW6f5). Changing passwords often, ensuring there are sufficient firewall protections, using highly encrypted data and installing up-to-date antivirus software can help as well, Mr. Hollingsworth said. “Although a determined hacker can break into almost any system, these steps might encourage them to move on to a less secure system,” he said.

Many Still Emailing Patient Information Emailing unencrypted patient data also places that information at risk for falling into the wrong hands, said health IT expert Cary Presant, MD, a professor of clinical medicine at the University of Southern California Keck School of Medicine and a staff oncologist at City of Hope Hospital, both in Los Angeles. “HIPAA rules prohibiting the use of non-encrypted digital communications that contain patient health information are not being widely implemented,” Dr. Presant said. For patients, email is an easy mode of communication; physicians may succumb to patient pressure. However, Dr. Presant urged physicians

to educate patients about the associated risk for identity theft. Dr. Presant also urged both clinicians and office staff to take advantage of educational opportunities offered by organizations such as the American Society of Clinical Oncology. Ms. Downing echoed that recom-

mendation. “Make sure you and your staff are educated and trained as to how EHRs can be used in the most secure way,” she said. “Human error is one way for breaches to occur.” Ms. Downing also said that granting EHR access only to staff members who truly need such access is a preventive

measure practices can take. “And when you’re auditing access [to EHRs], make sure you document the process, and do the same with any other security-related policies,” Ms. Downing said. “That documentation will reduce your liability in case there is a breach.” For additional tips on how to protect your patients’ records, visit www.hhs. gov/ocr/privacy/hipaa/understanding/ training. —David Wild Ms. Downing and Dr. Presant reported no relevant conflicts of interest.

Visit the newly designed user friendly

CMEZone.com

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VOGL, NY continued from page 1

events (SRE)—fractures, radiation or surgery for bone pain, spinal cord compression—occurred in 23.3% of those on every-12-week therapy and 22% of those on every-4-week therapy. The median time to first SRE was 1 year in each arm. The skeletal morbidity rate (SMR)—the number SREs per patient per year—was 0.50 for every-12-week therapy and 0.46 for every-4-week therapy. The statistical analysis just manages to exclude with 95% confidence a 10% or more increase in SREs as a result of less frequent zoledronic acid therapy. In this double-blind, prospective randomized trial of 412 patients, serious adverse events were rare: Osteonecrosis of the jaw (ONJ) occurred in 1% of the every-4-week arm but not in any of the patients in the longer frequency group; renal adverse events occurred in 7.9% of the every-12-week arm and 9.6% of the every-4-week arm; neither group reported stress fractures of the femoral shaft. OPTIMIZE-2 originally was designed with a third arm of no treatment after the 9 initial IV bisphosphonate doses (initial pamidronate was also permitted). The “no further treatment” arm was dropped after initial accrual proved very low. Although some biochemical markers of zoledronic acid activity fade after the drug dose is attenuated or stopped, it still is not clear that any clinical benefit is lost when the drug is stopped.

Results Support Those From ZOOM Trial The results echo those of the ZOOM open-label trial, presented at the 2012 ASCO annual meeting and later published by Amadori et al.2 ZOOM accrued in Italy from 2006 to 2010, and, like OPTIMIZE-2, was supported by Novartis, the manufacturer of zoledronic acid. ZOOM randomized 425 women with breast cancer metastasis to bone to 4 mg zoledronic acid every 4 or 12 weeks after 12 to 15 months of prior zoledronic acid. Their mean time from diagnosis of bone metastases to entry was 18 months, mean age was 60, 99% had a performance status of 0 or 1, 57% had prior SREs, and 18% were taking opioids at entry; 10% were receiving their first anticancer therapy for metastatic disease, whereas 43% were receiving their third or more line of therapy. About 68% were getting chemotherapy and endocrine therapy at entry. During the study, 51% received endocrine therapy alone, and another 27% received endocrine therapy and chemotherapy. In ZOOM, the SMR went from 0.22 to 0.26 with lengthening of the zoledronic acid interval to 12 weeks, just excluding with 95% confidence an increase of 19% in the SMR, assuming that the SMR with every-4-week dosing could not be

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EDITORIAL BOARD COMMENTARY

Table. Bisphosphonates for Bone Metastases

Steven Vogl, MD

What Did We Know?

Medical Oncologist New York City

• Monthly pamidronate or zoledronic acid prevents fractures, bone pain, and spinal cord compression to a moderate extent; they probably prevent hypercalcemia very well. • Toxicity for the first 2 years is generally uncommon and mild.

What Did We Just Learn? • After about 1 year of therapy for bone metastases from breast cancer, little is lost by reducing the frequency of zoledronic acid administration from every-4-wk to every-12-wk.

What Do We Still Not Know? • Whether to start them —For a single irradiated metastasis —For purely blastic metastasis —For asymptomatic metastases —For bone metastases in a patient who already has a very good response to systemic anticancer therapy • How often to give them at initiation • How to modify the dose and schedule based on response and toxicity • Whether they can be stopped when the cancer is responding well, and what criteria to use to resume after a drug holiday • Whether they should be stopped for lack of efficacy or for toxicity such as ONJ or renal dysfunction • The real incidence of ONJ and renal dysfunction with prolonged use (>2 years) in prospectively studied populations ONJ, osteonecrosis of the jaw

higher than with every-12-week dosing. Toxicity in this trial was rare—ONJ in 4 patients on every-12-week therapy and 3 patients on every-4-week therapy, elevation of the serum creatinine at any point in less than 10% in each arm, with no grade 3 or 4 elevations in either arm.

Patient Characteristics Poorly Described in OPTIMIZE-2 Neither the OPTIMIZE-2 abstract nor presentation reported on patients’ concomitant anticancer therapy, the severity of their disease, or their rate of death from the disease. One suspects that very sick patients with a lot of bone pain and fractures were not entered, and that women with extensive metastases to lung, liver, brain, and peritoneum were not entered, so the results may not be applicable to such patients. The nature of systemic treatments given to the women studied in ZOOM suggests that few very ill women were entered into that trial. This means that we cannot use the results of OPTIMIZE-2 and ZOOM to justify de-escalating zoledronic acid dosing in women with dire visceral metastases who have made it out to the 12-month point of zoledronic acid therapy. Nonetheless, with these caveats, it seems safe to conclude that zoledronic acid can be reduced to every-12-week dosing after 9 monthly doses, with no significant loss of efficacy. Because ONJ and benign femoral stress fractures

probably relate to the cumulative zoledronic acid dose, these distressing side effects also will likely be reduced, especially in the small subset of women with breast cancers who live for a very long time on a succession of hormonal therapies and may be exposed to zoledronic acid for a decade or more.

Tailored-Dose Zoledronic Acid Trial Failed To Accrue Cancer Research UK attempted a study attenuating the frequency of zoledronic acid administration for those who achieved low levels of urinary N-telopeptide, a marker of bone resorption.3 The study, called BISMARK, was closed early for poor accrual, so no significant differences were demonstrated. The results that were available, however, suggested that the attenuated dosing after an initial 3 monthly doses did not increase the risk for first SREs but did increase the risk for second or more SREs.

Applicablity to Denosumab Unknown The subcutaneous monoclonal antibody denosumab (Xgeva, Amgen) inhibits nuclear factor-κB and prevents SREs in breast cancer about as well as (or perhaps slightly better than) zoledronic acid, with about the same rate of ONJ. Because these are completely different drugs with different mechanisms of action, however, extreme caution should be used in extending

information about zoledronic acid to denosumab. A study comparing denosumab every 12 weeks to every 4 weeks just began in Europe. The Swiss Oncology Group (SAKK) is conducting this Amgen-sponsored study in patients with bone metastases from breast or prostate cancer (NCT 02051218).

Results Probably Apply To Prostate, Lung Cancers Although both ZOOM and OPTIMIZE-2 were restricted to women with breast cancer, there is no reason to assume that results in other cancers would be different. A bone is a bone, and a fracture is a fracture. Because zoledronic acid is available as a generic drug and is relatively inexpensive, drug company funding is not likely to be made available to study the drug. Aside from one ongoing Alliance trial (CALGB 70604) of monthly versus every-3-month zoledronic acid from the start of therapy in breast cancer, myeloma and prostate cancer, the information we now have on dosing is likely all we will ever get. The issue of zoledronic acid frequency will be very relevant for metastatic prostate cancer, with a median survival from metastases of 4 to 5 years and a predominance of disease in bone. Unless Alliance data ultimately exclude a substantial decrement in events from every-12-week dosing at the outset, I suggest we extrapolate ZOOM and OPTIMIZE-2 to prostate patients and reduce their zoledronic acid frequency to every 12 weeks after 9 doses. Because of the virulence of lung cancer except when it is associated with EGFR and RoS-1 mutations, relatively few lung cancer patients with bone metastases will get into a second year of zoledronic acid therapy. Those who do also probably should have their zoledronic acid frequency attenuated.

Applicablity to Myeloma Uncertain The MRC Myeloma IX trial showed a median survival advantage of about 5 months for monthly zoledronic acid compared with clodronate, an oral amino-bisphosphonate.4 Zoledronic acid was administered in conjunction with systemic therapy based on melphalan, prednisone, thalidomide, and, for about half the patients, high-dose melphalan. This survival advantage lasted for many years; most of the survival advantage developed in the first 4 months of therapy, with the

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2014 • CLINICALONCOLOGY.COM

survival curves closely parallel thereafter. The data suggest that monthly intensive bisphosphonate therapy is quite important early in the course of these sick patients. Whether intensive bonedirected therapy needs to be continued beyond the initial period to maintain the survival advantage remains uncertain. I would guess not, but we really need data in myeloma patients to decide. The frequency and quality of responses for myeloma have increased markedly with the availability of lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Millennium), and they will probably improve further with pomalidomide (Pomalyst, Celgene), carfilzomib (Kyprolis, Onyx), and other new agents. With about 33% of myeloma patients entering complete remissions with negative immunofixations, the role of prolonged bone-directed therapy needs to be examined further. With median survival after diagnosis approaching 8 years, continued monthly zoledronic acid puts many at risk for ONJ during periods when the myeloma is producing no symptoms at all and is barely detectable, even with sophisticated techniques. Myeloma studies likely will not be supported by Amgen to study duration and intensity of denosumab until a trial demonstrates noninferiority to zoledronic acid. Denosumab was denied FDA approval for myeloma patients, probably because of an overall survival decrement in a small number of this patient population included in a much larger study of denosumab versus zoledronic acid.5 Amgen is supporting a trial comparing every-4-week dosing of denosumab with zoledronic acid in patients with myeloma, with an expected accrual of 1,520 (NCT 01345019). Government or charitable funding will be needed to study the intensity and duration of bone-directed therapy for myeloma using the end points of skeletal morbidity, ONJ, deterioration of renal function, and survival.

We Have Not Gotten Very Far! At the 1996 ASCO annual meeting, Dr. Hortobagyi presented the first randomized controlled prospective trial (called protocol 19) showing the benefits of 1 year of monthly pamidronate in

addition to chemotherapy for breast cancer with osteolytic bone metastases. The data were published later that year in The New England Journal of Medicine.6 The following year, protocol 18, which showed the benefits of pamidronate in women taking endocrine therapy for breast cancer, was presented at the 1997 ASCO annual meeting.7 Pamidronate reduced SREs and relieved pain but did not prolong survival. I recall complimenting Dr. Hortobagyi in 1996 on the quality of the study and the elegance of the presentation, then asking him if he had any data on how to administer the drug. I asked when we should start it, and when we should stop it, how we should modulate the dose, and how we should judge efficacy. He did not know the answers to these questions then, and I do not believe he knows them now (Table). It is not clear whether a woman with a single metastasis in a non–weightbearing bone without pain should get a bisphosphonate. It is not clear whether women with purely blastic bone metastases, painful or not, should get bisphosphonates before pain or lytic disease develops. The optimal dose and frequency of initial therapy with bisphosphonates has never been studied in prospective randomized trials, although the Alliance has one ongoing. We have no information on how to judge if bisphosphonates are working. We generally continue them even if the patient has worsening symptomatic cancer in bone, but no data exist to justify this practice beyond its prevalence in the published trials. In this situation, we change the chemotherapy or hormone therapy, but continue the bisphosphonate, changing neither the dose nor the schedule. Studies became available showing that a second year of pamidronate was safe, but no studies show that it adds benefit compared with just 1 year of therapy.8-10 In the belief that bones are important even for the very ill, until Dr. Hortobagyi presented OPTIMIZE-2, it was my practice to continue monthly bisphosphonates for breast cancer metastatic to bone until the patient became bedridden or moribund, or developed severe toxicity such as chronic renal failure or ONJ. I am no longer certain that this is correct, even at attenuated dosing, especially in

women with excellent responses to hormone therapy that can last several years who have no bone pain and are in excellent general condition.

Lament of an Aged Oncologist I have been administering IV bisphosphonates to prevent SREs for nearly 20 years. The first information on how to tailor drug administration for the patient appeared only in the past 2 years from OPTIMIZE-2 and ZOOM. Beyond the ongoing Alliance trial, oncologists are unlikely to get more information about bisphosphonates because they are generic and inexpensive, so no drug company is interested in studying them. Likewise, there are no economic incentives for Amgen to conduct studies to determine whether it would be clinically appropriate to delay the start of denosumab or stop it early in some circumstances. Both Novartis and Amgen deserve credit for sponsoring trials in which lessintense schedules of their drugs are evaluated for noninferiority. If we had a Congress with a long-term commitment to saving money and preserving quality, or an insurance industry (including Medicare and Medicaid) that looked beyond quarterly cost and profit analysis, then such studies might be funded by them in the hope of avoiding huge costs for therapies of little or no value in common circumstances. Without such funding, drug therapy is perforce based on drug company studies generally designed to maximize sales and profits.

References 1. Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE-2 trial. J Clin Oncol. 2014;32(5 suppl). Abstract LBA9500. 2. Amadori D, Aglietta M, Alessi B, et al. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol. 2013;14(7):663-670, PMID: 23684411. 3. Colman RE, Wright J, Houston S, et al. Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer. J Clin Oncol. 2012;30(suppl). Abstract 511.

4. Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376(9757):1989-1999, PMID: 21132037. 5. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125-1132, PMID: 21343556. 6. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996;335(24):17851791, PMID: 8965890. 7. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol. 1997; 17(3):846-854, PMID: 10071275. 8. Berenson JR, Lichtenstein Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol. 1998;16(2):593602, PMID: 9469347. 9. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98(8):1735-1744, PMID: 14534891. 10. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-1227, PMID: 21343561.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to smtilyou@mcmahonmed.com

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature coverage of the ESMO 2014 Congress, The Chemotherapy Foundation Symposium and ACCC’s Oncology Reimbursement meeting

—————————— New Column —————————— Upcoming issues of Clinical Oncology News will be featuring How I Manage Breast Cancer, a new column by Massimo Cristofanilli, MD, of Thomas Jefferson University’s Kimmel Cancer Center. Each installment will focus on the management of a particular subtype of breast cancer.

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