CALGB Breast Committee Neoadjuvant Trials (CALGB and 40603) Obstacles to Accrual. William M. Sikov, MD Study Chair, CALGB 40603

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1 CALGB Breast Committee Neoadjuvant Trials (CALGB and 40603) Identifying and Overcoming Obstacles to Accrual William M. Sikov, MD Study Chair, CALGB CALGB Summer Group Meeting Chicago, Illinois June 24, 2010 CALGB Breast Neoadjuvant Trials Brief review of study designs and objectives Patient t accrual logistics and challenges Recruiting physicians, especially surgeons Identifying eligible patients Barriers to accrual concerns and responses Neoadjuvant therapy Randomization Laptinib (40601); Bevacizumab (40603) Mandatory research biopsies Tactics of successful centers Page 1 1

2 CALGB Breast Neoadjuvant Trials: Background Neoadjuvant setting as setting to test promising approaches within CALGB/Intergroup Availability of tissue and ability to correlate potential biomarkers with clinical and pathologic response Funding support for clinical and basic research from NCI, BCRF, ARRA/ACTNOW (40603) - $ per patient (includes reimbursement for research biopsies) CALGB 40601/40603: Eligibility Invasive breast Ca with tissue for ER/PR, HER2 testing Stage II-III with intent to perform resection, except T4d 40601: ER/PR any, HER2(+):IHC 3+ or FISH >2 if IHC : ER and PR<10%, HER(-): IHC 0-1+, or FISH <2.0 if IHC2+ ANC >1000, platelets >100,000, creatinine <1.5 mg/dl or creat cl >30 ml/min, bilirubin <1.5 x ULN, ALT <2.5 x ULN Pretreatment breast MRI if contraindicated or not available, mammogram or US for tumor measurement Pre-treatment SLN if clinical N0 at MD discretion. Page 2 2

3 Breast Neoadjuvant Trials: Rationale HER2+ Dual HER2-targeting may be more effective than a single HER2-targeted agent Mechanisms of resistance to lapatinib (small molecule that targets both HER2 and EGFR TKs) and trastuzumab (anti-her2 monoclonal Ab) differ. CALGB 40601: Neoadjuvant HER2+ Trial N~400 HER2+ Stage II-III P + Herceptin x 16 wks P + Lapatinib x16 wks P + H and L x 16 wks S U R G E R Y Dose-dense AC x 4 then Herceptin for 1 yr (recommended) Tumor Biopsy Embedded Surgical and Rad Oncology Substudies pcr breast is 1⁰ endpoint pcr breast and axilla 2⁰ endpoint Correlative science embedded planned cross-validation with NeoALTTO Other considerations: Clean from correlative standpoint only taxane/her2 preop Discretionary adjuvant phase should appeal to docs Prepackaged kits Substantial funding (~ $7000 pp) Page 3 3

4 Breast Neoadjuvant Trials: Rationale Triple negative (TNBC) Preclinical and clinical data suggest some (if not all) TNBC have impaired DNA-repair mechanisms (similar to BRCA1-deficient cancers) may enhance sensitivity to platinums» May help define optimal regimen for studies of other agents (such as PARP inhibitors) that target DNA repair Subset analysis of bevacizumab b trials in advanced d disease suggest TNBC may have increased sensitivity to antiangiogenic agents CALGB 40603: Neoadjuvant Triple-Negative Trial Eligibility: Stage II-III (except T4d) ER/PR-poor, HER2- Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Registration Randomization Required Research Biopsies Optional Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Bevacizumab 10 mg/kg q2wks x 9 doses Paclitaxel 80mg/m 2 weekly x 12 Carboplatin AUC 6 q3weeks x 4 ddac x 4 Research Blood Tests and Tissue Banking Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Carboplatin AUC 6 q3weeks x 4 Bevacizumab 10 mg/kg q2wks x 9 doses Surgery XRT No Adjuvant Chemo planned N= Primary endpoint: path CR in breast Page 4 4

5 Breast Neoadjuvant Trials: Which Institutions Should Participate? Institutions with a history of accruing to neoadjuvant breast cancer trials Institutions where patients are often referred for neoadjuvant therapy Institutions who have accrued well to adjuvant breast cancer trials Institutions willing to obtain required pretreatment research biopsies Breast Neoadjuvant Trials: Accrual Changing the institutional culture when it comes to neoadjuvant therapy Open offer to have a surgeon or medical oncologist associated with the trials visit your site for an update on this treatment approach Explaining the rationale for neoadjuvant therapy especially in patients with aggressive (HER2+, TN) cancers (where pcr rate >30%) Increase BCS, improve cosmetic outcomes, assess response to treatment, allow time for genetic testing and allow patients to participate in clinical trials Page 5 5

6 Breast Neoadjuvant Trials: Accrual Identifying patients/logistics: Keep surgeons involved and aware of neoadjuvant studies Breast Tumor Board ideally, all newly diagnosed breast Ca patients are presented prior to definitive surgery so that neoadjuvant treatment can be considered Prompt evaluation by medical oncology and rest of multidisciplinary team Prompt scheduling of pretreatment study evaluations, including MUGA or echo and research biopsies Breast Neoadjuvant Trials: Barriers to Accrual Neoadjuvant therapy - helping patients and their families understand the concept Concern delay of curative surgery (doing something!) Randomized trials showing no difference in DFS/OS outcomes Minimal risk of disease progression while on treatment Improve surgical outcomes No way to measure impact of Rx in adjuvant setting Can allay this concern with prompt initiation of neoadjuvant therapy Page 6 6

7 Breast Neoadjuvant Trials: Barriers to Accrual Randomization Concern Uncertainty, If you think that the study treatment is better, why not give it to all of the patients? Effective treatment in all arms of the study; no placebos Best way to determine if study treatment better than standard; d; could not ethically administer study treatment e t off protocol Breast Neoadjuvant Trials: Barriers to Accrual Non-standard treatment Concern: 40601: Single agent lapatinib ib arm -?not receiving i standard of care Activity of lapatinib in Herceptin failures All patients receive 1 year of adjuvant Herceptin Concern: 40603: Carboplatin, bevacizumab - additional toxicities Potential synergy with standard treatment Risks of bevacizumab in young breast Ca pts much less than lengthy AE section in consent would suggest Page 7 7

8 Breast Neoadjuvant Trials: Barriers to Accrual Research Biopsies Concern - Additional procedure with discomfort and risks, no benefit to patient Importance of research biopsies and other correlative studies to better understand disease and response to treatment Scheduling of biopsies concurrent with other procedure (clip or port placement, FNA or SLN sampling) Ability to take biopsies at time of diagnosis (if cleared with institutional IRB) if collected in correct tubes Kit provided and funding for stand-alone biopsy procedure provided CALGB Breast Neoadjuvant Trials: Tactics of Successful Centers Page 8 8

9 CALGB Breast Committee Neoadjuvant Trials (CALGB and 40603) Identifying and Overcoming Obstacles to Accrual William M. Sikov, MD Study Chair, CALGB CALGB Summer Group Meeting Chicago, Illinois June 24, 2010 Page 9 9