Highlights in the Management of Breast Cancer From the 2012 San Antonio Breast Cancer Symposium (SABCS)

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1 February 2013 Volume 11, Issue 2, Supplement 2 A SPECIAL MEETING REVIEW EDITION Highlights in the Management of Breast Cancer From the 2012 San Antonio Breast Cancer Symposium (SABCS) A Review of Selected Presentations From the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) December 4 8, 2012 San Antonio, Texas Special Reporting on: Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in HER2-Positive, First-Line Metastatic Breast Cancer HERA TRIAL: 2 Years Versus 1 Year of Trastuzumab After Adjuvant Chemotherapy in Women With HER2-Positive Early Breast Cancer at 8 Years of Median Follow-Up Relative Effectiveness of Letrozole Compared to Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial Trastuzumab Plus Adjuvant Chemotherapy for HER2-Positive Breast Cancer: Final Planned Joint Analysis of Overall Survival (OS) From NSABP B-31 and NCCTG N9831 Confirmatory Overall Survival Analysis of CLEOPATRA: A Randomized, Double-Blind, Placebo-Controlled Phase III Study With Pertuzumab, Trastuzumab, and Docetaxel in Patients With HER2-Positive First-Line Metastatic Breast Cancer Final Analysis of Overall Survival for the Phase III CONFIRM Trial: Fulvestrant 500 mg Versus 250 mg PLUS Meeting Abstract Summaries With Expert Commentary by: Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trial Education University of California San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco, California ON THE WEB: Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE

2 Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting Monitor patients who become pregnant during PERJETA therapy for oligohydramnios Additional Important Safety Information Left Ventricular Dysfunction Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution s normal limits Withhold PERJETA and Herceptin and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group ( 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

3 FOR THE FIRST-LINE TREATMENT OF HER2+* METASTATIC BREAST CANCER STRENGTHEN HER DEFENSE Indication: PERJETA (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-her2 therapy or chemotherapy for metastatic disease. Extend progression-free survival (PFS) with an FDA-approved HER2 dimerization inhibitor 1,2 Consistent PFS results were observed across a broad range of patient subgroups 1 At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively 1 The most common adverse reactions (ARs) (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 1 * HER2+ = human epidermal growth factor receptor 2 positive. IRF = independent review facility. Stratified by prior treatment status and geographic region. PFS (%) AD P+H+D Pl+H+D 6.1-Month Improvement in Median IRF -Assessed PFS 1 HR = % CI [ ] P< MONTHS MONTHS Placebo + Herceptin + docetaxel MONTHS Patients at risk PERJETA + Herceptin + docetaxel In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. For more information, scan the QR code or visit References: 1. PERJETA Prescribing Information. Genentech, Inc. June Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366: Genentech USA, Inc. All rights reserved. PER Printed in USA. (09/12)

4 PERJETA (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6) 1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti- HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETAtreated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m 2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions ( 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group ( 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETA-treated group and 2.5% in the placebo-treated group according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest or FISH amplification ratio 2.0 by Dako HER2 FISH PharmDx test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience 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 clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other antineoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETAtreated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial Body System/ Adverse Reactions PERJETA + trastuzumab + docetaxel Placebo + trastuzumab + docetaxel n=407 n=397 Frequency rate % Frequency rate % All Grades % Grades 3-4 % All Grades % Grades 3-4 % General disorders and administration site conditions Fatigue Asthenia Edema peripheral Mucosal inflammation Pyrexia Skin and subcutaneous tissue disorders Alopecia Rash Nail disorder Pruritus Dry skin Gastrointestinal disorders Diarrhea Nausea Vomiting Constipation Stomatitis Blood and lymphatic system disorders Neutropenia Anemia Leukopenia Febrile neutropenia* Nervous system disorders Neuropathy peripheral Headache Dysgeusia Dizziness Musculoskeletal and connective tissue disorders Myalgia Arthralgia Infections and infestations Upper respiratory tract infection Nasopharyngitis Respiratory, thoracic and mediastinal disorders Dyspnea Metabolism and nutrition disorders Decreased appetite Eye disorders Lacrimation increased Psychiatric disorders Insomnia * In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple timepoints for antibodies to PERJETA. Approximately 2.8% (11/386)

5 of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti- PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of antipertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on C max. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on C max. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on C max ). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were 65 years of age and 5 patients (1%) were 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 ml/min) or moderate (CLcr 30 to 60 ml/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 ml/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date. PERJETA (pertuzumab) Manufactured by: Genentech, Inc. PERJETA is a trademark A Member of the Roche Group of Genentech, Inc. 1 DNA Way 6/12 PER South San Francisco, CA 2012 Genentech, Inc

6 S p e c i a l m e e t i n g r e v i e w e d i t i o n Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in HER2-Positive, First-Line Metastatic Breast Cancer Pertuzumab is an anti human epidermal growth factor receptor 2 (HER2) monoclonal antibody that prevents HER2 receptor heterodimerization, which has complementary mechanisms of action with trastuzumab. CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) is a pivotal international, randomized, double-blind, placebocontrolled, phase III trial. 1,2 A total of 808 patients with centrally-confirmed HER2-positive breast cancer were randomized to receive docetaxel plus placebo and trastuzumab or docetaxel plus pertuzumab and trastuzumab. The primary endpoint was progression-free survival (PFS). In addition, and pertinent to this presentation of the data, collection of tumor tissue and serum samples was mandatory. Tumor tissue from archival samples represented over 90% of the collections in this study. CLEOPATRA was presented at the 2011 San Antonio Breast Cancer Symposium (SABCS), 1 and the study results were published. 2 The primary endpoint was met, with an improvement of PFS from 12.4 months to 18.5 months. Importantly, a statistically significant improvement occurred in overall survival (OS). The objective of the current analysis was to explore whether, within the HER2-positive patient population, further subgroups based on biomarker profiles could be identified that derived differential benefit from HER2- targeted therapies. 3 Therefore, a panel of biomarkers that was predefined by the protocol was assessed in tumor tissue and serum samples to explore their potential predictive and overall prognostic value. Analyzing the samples required a significant effort with the collection of many samples. A number of markers were analyzed by several methods. Immunohistochemistry and a modified H-score assessed HER2, HER3, insulin-like growth factor (IGF)-1R, PTEN, and pakt. Quantitative reverse transcriptase polymerase chain reaction (PCR) by concentration ratio assessed HER1, HER2, HER3, AREG, and betacellulin tumor mrna levels. Fluorescence in situ hybridization (FISH) analyzed c-myc. Mutational analyses through PCR-based methods examined 8 hotspots within PIK3CA on tumor DNA and FcyR polymorphisms in DNA extracted from whole blood. A Single-Arm Phase IIIb Study of Pertuzumab and Trastuzumab With a Taxane as First-Line Therapy for Patients With HER2-Positive Advanced Breast Cancer (PERUSE) This single-arm phase IIIb trial will combine pertuzumab and trastuzumab plus a taxane (docetaxel, paclitaxel, or nab-paclitaxel) in patients with HER2-positive advanced breast cancer in the first-line treatment setting (Abstract OT1-1-02). The study plans to enroll 1,500 patients over 18 months, with a patient population that is reasonably representative of patients who present to oncology centers. The trial will obtain data on patient subgroups of special interest, including elderly patients, visceral versus nonvisceral disease, performance status, type of taxane, and prior exposure to trastuzumab in the neoadjuvant setting. Patients will receive pertuzumab and trastuzumab every 3 weeks, and a taxane according to local guidelines. The antibodies and chemotherapy will be administered until disease progression, unacceptable toxicity, or the predefined study end. After the taxane course is completed, patients with hormone receptor positive disease will have the option to receive endocrine therapy in conjunction with the antibodies. The primary endpoint of the trial is safety and tolerability. The secondary endpoints are PFS, OS, overall response rate, clinical benefit rate, duration of response, time to response, and health-related quality of life. The primary analysis will be of AEs that are grade 3 or above and related to pertuzumab. Disclaimer Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. 6 Clinical Advances in Hematology & Oncology Volume 11, Issue 2, Supplement 2 February 2013

7 H i g h l i g h t s i n t h e M a n a g e m e n t o f B r e a s t C a n c e r F r o m t h e S A B C S Enzyme-linked immunosorbent assay analyzed serum levels of the HER2 extracellular domain, AREG, epidermal growth factor, and transforming growth factor-α. The different assays had different sample sizes because of both the performance of the assays as well as a predefined priority ranking. An exploratory subgroup analysis of PFS by biomarker level was conducted, with no adjustments made for multiple testing. Two types of correlations were investigated. One was predictive effects, which looked at qualitative associations of biomarkers with pertuzumab treatment benefit. The second was prognostic effects independent of the treatment arm, which looked for relationships of each biomarker to clinical outcome, with both arms pooled. Median values were used as cut-offs for high and low levels of biomarkers, except for c-myc, where the target was a centromere ratio of 2 or greater, and for PIK3CA, where wild-type was compared with mutant and where 8 mutations at 4 hotspots in exons 7, 9, and 20 were examined. The first part of the study explored potential predictive biomarkers. A consistent effect favoring pertuzumab was observed in the group of serum markers, independent of any biomarkers in the group. The same applies for HER ligands and for receptor tyrosine kinases in tumor tissues, where a consistent treatment effect was observed in all biomarkers. Even in the cases of low versus high HER2 protein or of low versus high IGF-1R, the observed differences were well within the boundaries of variation. Finally, the same consistent effects for predictive biomarkers were observed for intracellular pathway markers, where pertuzumab was favored. Biomarkers were also analyzed independent of the treatment arms to explore their prognostic effects. Among the serum markers pooled from both arms, low levels of soluble HER2 were a marker of better prognosis (hazard ratio [HR], 1.23; P=.0433; Figure 1). When HER ligands and receptor Serum AREG [pg/ml] Serum EGF [pg/ml] Serum TGFα [pg/ml] Serum sher2 [ng/ml] High biomarker levels with better prognosis treatment benefit with pertuzumab was conserved with both the wild-type and mutant PIK3CA tumors. To summarize the findings on PIK3CA kinase biomarkers, those patients who harbor PIK3CA mutations clearly have a worse prognosis. However, the treatment benefit is maintained. Patients with a mutation in PIK3CA have a median PFS of 8.6 months in the trastuzumab-alone arm and 12.5 months in the pertuzumab arm. The available data set does not allow the prognostic impact of PIK3CA mutations to be attributed to a specific mutation or to mutations in a specific exon. The patients with wild-type PIK3CA had a median PFS of 13.8 months in the trastuzumab-alone arm and 21.8 months in the pertuzumab arm. The risk was similar for patients with the PIK3CA mutation (HR, 0.64; 95% CI, ), for those with wild-type PIK3CA (HR, 0.67; 95% CI, ), and for the entire study population (HR, 0.62; 95% CI, ). A longitudinal study of serum markers explored whether serum marktyrosine kinases were examined in both arms, high HER2 mrna (HR, 0.77; P=.0080) or protein (HR, 0.83; P=.0502) and high HER3 mrna (HR, 0.81; P=.0348) were markers of better prognosis, although the effect was of borderline significance in this exploratory analysis. Among the intracellular pathway markers, tumors with wild-type PIK3CA had a better prognosis, while those harboring mutations to PIK3CA had a worse outcome (HR, 0.63; 95% confidence interval [CI], ; P=.0001). By far, this was the strongest prognostic marker. Among patients treated in the trastuzumab plus placebo arm, those with tumors harboring PIK3CA mutations had a worse prognosis, with a median PFS of 8.6 months versus 13.8 months in the wild-type arm. Among patients treated in the pertuzumab plus trastuzumab arm, the prognosis was again worse in the subset with a PIK3CA mutation (PFS of 12.5 months) than in the subset with wild-type PIK3CA (PFS of 21.8 months). Notably, the PFS n* HR 95% CI P Value Low biomarker levels with better prognosis Covariate Effect Figure 1. In a biomarker subgroup analysis of the CLEOPATRA trial, low levels of soluble HER2 were a marker of better prognosis. *HR, <1.00 in all cases; P<.0001). AREG=amphiregulin; CI=confidence interval; CLEOPATRA=Clinical Evaluation of Pertuzumab and Trastuzumab; EGF=epidermal growth factor; sher2=soluable human epidermal growth factor receptor 2; HR=hazard ratio; PFS=progression-free survival; TGFα=transforming growth factor-alpha. Adapted from Baselga J et al. Paper presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 5-8, 2012; San Antonio, TX. Abstract S5-1. Clinical Advances in Hematology & Oncology Volume 11, Issue 2, Supplement 2 February

8 S p e c i a l m e e t i n g r e v i e w e d i t i o n A Phase III, Open-Label, Randomized, Multicenter Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes No statistically significant superiority of eribulin mesylate versus capecitabine regarding OS or PFS was demonstrated by this phase III trial in patients with locally advanced or metastatic breast cancer who had previously been treated with anthracyclines and taxanes (Abstract S6-6). The median OS was 15.9 months with eribulin and 14.5 months with capecitabine (HR, 0.879; 95% CI, ; P=.056). Independent review found a median PFS of 4.1 months with eribulin (n=554) and 4.2 months with capecitabine (n=548; HR, 1.079; 95% CI, ; P=.305). Prespecified subgroup analysis found that particular patient subgroups may achieve greater therapeutic benefit from eribulin, including patients whose breast cancer is triple-negative (HR, 0.702), estrogen-receptor negative (HR, 0.779), and HER2-negative (HR, 0.838). Both eribulin and capecitabine had AE profiles consistent with their previously known side effects. Notable hematologic AEs included neutropenia (54% of patients in the eribulin arm vs 16% in the capecitabine arm) and febrile neutropenia (2% vs <1%). Nonhematologic AEs of note included hand-foot syndrome (<1% in the eribulin arm vs 45% in the capecitabine arm), alopecia (35% vs 4%), diarrhea (14% vs 29%), vomiting (12% vs 17%), and peripheral sensory neuropathy (13% vs <1%). The lack of a HER2-treatment naïve control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA. Mutations in PIK3CA were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PIK3CA mutational status. However, the PIK3CA mutational status may identify patients with poorer prognosis and particular unmet medical needs. Prior studies have shown that mutant PIK3CA is associated with lapatinib resistance 6 and with poorer prognosis after trastuzumab therapy. 7 Other studies have shown good prognosis with mutant PIK3CA, particularly in hormone receptor positive tumors Based on the data presented, these findings may justify clinical trials of HER2-targeted molers could be early detectors of disease progression. Samples were collected at multiple time points, including baseline, week 9, and then at the time of disease progression. No correlation was observed between serum marker levels and disease progression, and no difference was observed between the treatment arms. In summary, this analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy, despite a comprehensive exploration of a broad panel of candidate biomarkers. This finding is consistent with the TRYPHAENA (Trastuzumab Plus Pertuzumab in Neoadjuvant HER2- Positive Breast Cancer) 4 and NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) 5 studies that were presented at previous SABCS meetings. ecules in combination with PIK3CApathway targeted agents. References 1. Baselga J, Kim S-B, Im S-A, et al. A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in patients with previously untreated HER2- positive metastatic breast cancer (CLEOPATRA). Paper presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 7-10, 2011; San Antonio, TX. Abstract S Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366: Baselga J, Cortés J, Im S-A, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC). Paper presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 5-8, 2012; San Antonio, TX. Abstract S Schneeweiss A, Chia S, Hegg R, et al. Biomarker analyses of a phase II study of neoadjuvant pertuzumab and trastuzumab with and without anthracycline-containing chemotherapy for treatment of HER2-positive early breast cancer (TRYPHAENA). Paper presented at: the 37th ESMO Congress; September 28-October 2, 2012; Vienna, Austria. Abstract 202P. 5. Gianni L, Bianchini G, Kiermaier A, et al. Neoadjuvant pertuzumab and trastuzumab: biomarker analyses of a 4-arm randomized phase II study (NeoSphere) in patients with HER2-positive breast cancer. Paper presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract S Eichhorn PJ, Gili M, Scaltriti M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mtor/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68: Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12: Cizkova M, Susini A, Vacher S, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14:R Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mtorc1 signaling and better outcomes in estrogen receptorpositive breast cancer. Proc Natl Acad Sci U S A. 2010;107: Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15: Clinical Advances in Hematology & Oncology Volume 11, Issue 2, Supplement 2 February 2013

9 H i g h l i g h t s i n t h e M a n a g e m e n t o f B r e a s t C a n c e r F r o m t h e S A B C S HERA TRIAL: 2 Years Versus 1 Year of Trastuzumab After Adjuvant Chemotherapy in Women With HER2-Positive Early Breast Cancer at 8 Years of Median Follow-Up In 2005, the results of large randomized trials, including HERA (Herceptin Adjuvant), demonstrated statistically significant disease-free survival (DFS) benefit for 1 year of trastuzumab compared with no trastuzumab for patients with HER2-positive early breast cancer. 1,2 A secondary objective of HERA was to assess whether trastuzumab given for 2 years was superior to treatment for 1 year. 3 The protocol was revised to focus on this comparison after HERA is the only trial testing trastuzumab duration longer than 1 year. The HERA trial was a large international trial that involved all regions of the world except the United States. It was conducted as a partnership between the Breast International Group (BIG) and Russia, and it recruited 5,102 women in a little over 3 years. The HERA design was pragmatic, as it allowed oncologists around the world to select their preferred neoadjuvant or adjuvant chemotherapy regimen. After completion of surgery, chemotherapy, and radiation, the patients were randomized into observation, 1 year of trastuzumab, or 2 years of trastuzumab. The HER2 status had to be centrally confirmed prior to randomization, and the patients had to have very good heart function, with a left ventricular ejection fraction (LVEF) of 55% or greater. Of note, after the release of the strikingly positive results of HERA and 2 other US adjuvant trastuzumab trials at the 2005 American Society of Clinical Oncology (ASCO) meeting, 1,2 52% of the 1,698 women in the observation arm selectively crossed over to receive trastuzumab. This may be the highest crossover rate observed in all the adjuvant trastuzumab trials. The comparison of 2 years versus 1 year of trastuzumab was based on a 12-month landmark analysis following randomization into 1 of 2 trastuzumab duration arms. The trial planned for 2 interim analyses and 1 final analysis, with the final analysis being planned for 725 DFS events to obtain 80% power to detect a true HR of The current analysis was reported with 734 DFS events at a median of 8 years follow-up. The patient characteristics in the 1-year and 2-year trastuzumab cohorts were well-balanced with respect to demographics and baseline disease characteristics. About half of the patients had hormone receptor positive tumors. A total of 52% of the patients were younger than 50 years. About one-third of the patients had node-negative disease. A total of 94% of the patients were exposed to an anthracycline and 25% to a taxane. Importantly, trastuzumab compliance in both duration arms was good. In the trastuzumab 1-year arm, 9.5% of the patients discontinued treatment prior to completion of 1 year for reasons other than a DFS event. In the 2-year arm, 17.8% interrupted treatment prematurely, with 10.5% discontinuing before the end of the first year and 7.3% before the end of the second year. The Kaplan-Meier DFS survival curves for the 2-year and 1-year trastuzumab arms showed no difference (HR, 0.99; P=.86; Figure 2). When a predefined exploratory analysis based on locally determined hormone receptor status was performed, 2-year trastuzumab was not found to improve DFS in either subgroup. Pertuzumab in Combination With Trastuzumab and Docetaxel in Elderly Patients With HER2-Positive Metastatic Breast Cancer in the CLEOPATRA Study Analysis of the CLEOPATRA trial showed that patients younger than 65 years and those ages 65 years and older had superior PFS by independent review from treatment with pertuzumab plus trastuzumab plus docetaxel as compared with placebo plus trastuzumab plus docetaxel (Abstract P ). Among patients younger than 65 years, the independently assessed median PFS in the ITT population was 12.5 months in the placebo arm and 17.2 months in the pertuzumab arm (HR, 0.65; 95% CI, ; P<.0001). Among patients ages 65 and older, the independently assessed median PFS in the ITT population was 10.4 months in the placebo arm and 21.6 months in the pertuzumab arm (HR, 0.52; 95% CI, ; P=.0098). Both age groups had higher incidences of diarrhea, neutropenia, dysgeusia, and febrile neutropenia in the pertuzumab arm than in the placebo arm. Among patients ages 65 and older, diarrhea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were more frequent than in the younger age group, whereas neutropenia and febrile neutropenia were less frequent. The older subgroup had more docetaxel dose reductions and a lower median number of docetaxel cycles. These reductions, along with less frequent use of granulocyte colony stimulating factors, likely explain the lower incidence of neutropenia and febrile neutropenia in patients ages 65 and older compared with those younger than 65. Clinical Advances in Hematology & Oncology Volume 11, Issue 2, Supplement 2 February

10 S p e c i a l m e e t i n g r e v i e w e d i t i o n P= Years From Randomization Disease-Free Survival (%) % 86.7% The 1-year and 2-year trastuzumab curves for OS are superimposable at 8 years of median follow-up (HR, 1.05; P=.63). At a much shorter follow-up of 4 years, the 1-year and 2-year trastuzumab arms also had similar DFS (HR, 0.89; P=.20). At 4 years of follow-up, a statistically insignificant separation of the curves for the 1-year and 2-year trastuzumab arms occurred in the hormone receptor negative cohort (HR, 0.82; 95% CI, ; P=.10). This trend points to the need for long follow-up in these adjuvant trials, even in an aggressive disease like HER2- positive breast cancer. Regarding safety, more patients in the 2-year trastuzumab arm experienced at least 1, and up to 3 or 4, adverse events (AEs). The patients in the 2-year trastuzumab arm had a 20.4% rate of grade 3 or 4 AEs, which was statistically significant. The 2-year trastuzumab arm also had more frequent asymptomatic or mild cardiac endpoints, which were known as secondary cardiac endpoints (7.2% vs 4.1% in the 1-year trastuzumab arm). In contrast, primary cardiac endpoints, which are severely symptomatic cardiac endpoints that involved New York Heart Association Class 3 or % 75.8% 81.0% 76.0% Trastuzumab 2 years Trastuzumab 1 year Figure 2. In the HERA trial, there was no significant difference in disease-free survival between 1 year of trastuzumab and 2 years of trastuzumab according to Kaplan-Meier analysis. CI=confidence interval; HERA=Herceptin Adjuvant; HR=hazard ratio. Adapted from Goldhirsch A et al. Paper presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 5-8, 2012; San Antonio, TX. Abstract S5-2. confirmed by a cardiologist, an LVEF below 50% with a drop of at least 10% below baseline, or cardiac death, were rare. No difference in primary cardiac endpoints occurred between the 1-year and 2-year trastuzumab arms. Fatal AEs occurred in approximately 1% of the patients. When the cumulative incidence of cardiac endpoints over 9 years from randomization was examined, the primary cardiac endpoints were found to be rare with no difference between the 2 arms. When both primary and secondary cardiac endpoints were examined, the constant event rate seen in the 2 arms during the first year of exposure was continued for a second year in the 2-year trastuzumab arm. However, the curves became horizontal, indicating that cardiac events were extremely rare after completion of trastuzumab. In summary, this analysis of 2-year versus 1-year trastuzumab found no evidence of long-term benefit from 2 years compared with 1 year when trastuzumab was given sequentially after chemotherapy. Secondary cardiac endpoints and other AEs increased in the 2-year trastuzumab arm. The majority of cardiac endpoints occurred during trastuzumab administration. An upcoming research publication will show that the majority of the cardiac endpoints are reversible. The transient DFS advantage for the 2-year arm in the hormone receptor negative cohort highlighted the need for long-term follow-up in trials investigating different durations of adjuvant trastuzumab. An updated analysis of 1-year trastuzumab versus observation at a median follow-up of 8 years was complicated by 2 important points. Of the 1,698 patients in the observation arm, 885 crossed over to receive trastuzumab after Previous intent-to-treat (ITT) results published at a median follow-up of 4 years suggested a decrease in the effects of trastuzumab. 4 A progressively smaller apparent DFS benefit of 1 year of trastuzumab in the ITT population occurred through 2008 (HR, 0.54 at 1 year median follow-up, 0.64 at 2 years median follow-up, 0.76 at 4 years median follow-up, and 0.76 at 8 years median follow-up). Although this finding generated some concern in 2008, the good news in 2012 was that no further attenuation of benefit occurred with a median follow-up of 8 years. Instead, a very robust reduction in the risk of DFS events occurred for patients receiving 1 year of trastuzumab. The hormone receptor positive and hormone receptor negative cohorts have the same pattern for DFS analysis. Analysis of OS of the ITT population for 1-year trastuzumab versus observation found, at 4 years median follow-up in 2008, that the OS benefit was 0.85, which was lower than that at 1-year median follow-up (HR, 0.76) and at 2 years median follow-up (HR, 0.66). 4 However, analysis of OS in the ITT population at 8 years of median follow-up in 2012 found no further attenuation of benefit (HR, 0.76). Instead, a very robust decrease in the risk of death (24%) occurred. This was also seen consistently in the 2 cohorts of hormone receptor positive and hormone receptor negative patients. In conclusion, when 1-year trastuzumab versus observation were 10 Clinical Advances in Hematology & Oncology Volume 11, Issue 2, Supplement 2 February 2013