XII Michelangelo Foundation Seminar Paradigm shift? The Food and Drug Administration collaborative project P. Cortazar, Silver Spring, USA
FDA Perspective: Moving from Adjuvant to Neoadjuvant Trials in Breast Cancer Drug Development: Is this a Feasible Paradigm Shift? XII MICHELANGELO FOUNDATION SEMINAR Patricia Cortazar, MD U.S. Food and Drug Administration Clinical Team Leader Breast Oncology Group
Outline Current drug development program How can we improve breast cancer drug development? CTNeoBC Meta-analysis FDA Guidance for Neoadjuvant Trials Regulatory aspects on this paradigm shift
Drug Development Process PRE-CLINICAL TRIALS CLINICAL TRIALS FDA REVIEW FDA APPROVED PHASE 1 PHASE 2 tudy PHASE 3 Post marketing St 3-6 YEARS 6-10 6-7 YEARS 6-10 MONTHS 3-6 YEARS IND SUBMITTED TO FDA NDA SUBMITTED TO FDA
Historical Breast Cancer Drug Development Metastatic Adjuvant Prevention Agents first developed in MBC: Tamoxifen 1977 Docetaxel 1996 Trastuzumab 1998 Anastrozole 1995 Letrozole 1997 Subsequently developed : Tamoxifen 1985 Docetaxel 2004 Trastuzumab 2006 Anastrozole 2003 Letrozole 2004 Tamoxifen 1998
Current drug development paradigm needs improvement
How can we Improve Drug Development in Breast Cancer? - New scientific knowledge provides huge opportunity for improvement - Future drug development must include innovation - Should use innovative endpoints and trial designs to support drug approval
Why is FDA interested in Neoadjuvant Trials?
452 Breast Cancer Neoadjuvant Trials ClinicalTrials.gov October 2012 9
How Can Neoadjuvant Trials Expedite Drug Development? Potential for accelerated approval in high risk EBC Provide guidance for better targeted adjuvant and MBC trials: Select the patient population Decrease the trials sample size Increase the possibility of success Discard ineffective drugs Fast identification of unresponsive tumors creates a new treatment setting for post-neoadjuvant failures
What is FDA doing to expedite breast cancer drug development? Opening path forward to neoadjuvant trials to support Drug Approval CTNeoBC Meta-analysis to learn about neoadjuvant trials Writing a Guidance for neoadjuvant trials Looking at other alternatives to accelerate approval in breast cancer
Considerations for Future Neoadjuvant Breast Cancer Approvals Is pcr the appropriate primary endpoint? What is the pcr relationship with long term outcomes (EFS and OS)? For which molecular subtypes?
Issues with pcr - Lack of uniform pcr definition Absence of invasive cancer: In the breast In the breast and axillary lymph nodes In the breast and axillary lymph nodes Absence of invasive and in situ cancer - Surgical management of axilla is evolving - Trials included heterogeneous tumor subtypes pcr rates varies by molecular subtypes Heterogeneous population can attenuate pcr rate
Before FDA opens a regulatory path for neoadjuvant trials it is essential to have better knowledge of neoadjuvant endpoints needed to support regulatory approval for neoadjuvant breast cancer
Collaborative Trials in Neoadjuvant Breast Cancer CTNeoBC
CTNeoBC Collaborators FDA Italian Breast Group German Breast Study Group (GBG, AGO-B) German Breast Study Group (GBG, AGO-B) NSABP EORTC NCI/CTEP
CTNeoBC Key Objectives To determine the relationship of pcr to EFS and OS To determine the definition of pcr that correlates best with long-term outcome To identify the breast cancer subtypes in whom pcr is best correlated with long-term outcome To determine the magnitude of pcr effect needed to improve EFS and OS
Selected Trials 12 neoadjuvant randomized controlled trials pcr clearly defined with all necessary data collected Long-term follow-up EFS and OS data collected GBG: 7 trials 6377 NSABP: 2 trials 3171 EORTC: 1 trial 1856 ITA: 2 trials 1589 Total # patients 12993
CTNeoBC Meta-analysis results will be presented in a few months
Draft Guidance for Industry: Use of pcr in Neoadjuvant Treatment of High-Risk EBC to Support Accelerated Approval 20
Accelerated Approval In 1992 FDA regulations allowed accelerated approval of products for diseases that are serious or lifethreatening where the product appears to provide benefit over available therapy. Accelerated approval is based on a surrogate endpoint (pcr) that is reasonably likely to predict clinical benefit. After accelerated approval, post marketing clinical trials are required to confirm that the product does provide clinical benefit (disease-free or overall survival). 21
Guidance Goals: Recommend appropriate patient populations in whom pcr is expected to predict clinical benefit Recommend a standard pcr definition (CTNeoBC meta-analysis) Describe neoadjuvant trial designs for accelerated approval and conversion to regular approval
Patient populations that might benefit from Neoadjuvant Therapy - Patients at high-risk of recurrence and death despite best available systemic therapy High risk should be defined conventionally or by appropriate genomic measures Triple negative and HER2+ - Highest likelihood of pcr - Most compelling data to date that pcr predicts clinical outcome - Clear unmet need in the triple-negative subset, making benefit/risk more appropriate Hormone receptor positive both less likely to attain pcr and more likely to have long-term survival pcr not likely to predict clinical benefit
Neoadjuvant Drug Approval Pathway for New Drugs with no prior Approval High risk early breast cancer RCT powered for EFS and OS Accelerated approval based on pcr Regular approval based on EFS, DFS or OS If postop therapy is required (e.g. anti HER2), should be the same in both arms. Neoadjuvant Approval
Potential Neoadjuvant Drug Approval Pathways Drugs with prior approvals in Metastatic and or Adjuvant BC Breakthrough Therapies Drugs with prior approvals in other cancers Neoadjuvant Approval To be determined
Regulatory aspects on this paradigm shift 26
Differences in Neoadjuvant and Adjuvant trials NEOADJUVANT TRIALS ADJUVANT TRIALS Smaller sample size pcr fast assessment (months) In vivo assessment of tumor response Short drug exposure Needs prior safety information Rapidly identify unresponsive tumors Ideal scenario to study biomarkers Bigger sample size Best setting to assess long-term outcome (DFS, OS) Longer drug exposure Needs prior safety information Best scenario to study long term safety
Strengths and weakness of Neoadjuvant trials Strengths: - We hope that use of pcr as an endpoint to support accelerated approval in the neoadjuvant setting will encourage industry innovation and expedite the development of breakthrough therapies to treat high risk, early-stage breast cancer. Weakness: - The limited duration of neoadjuvant trials do not usually provide long-term outcomes (efficacy and safety) - Important clinical questions remain unanswered (e.g. optimal duration of therapy, consequences of long-term use) 28
Trastuzumab Trials NOAH Trial Adjuvant Studies NSABP B31/NCCTG 9831 AC TH vs AC T HERA Chemo H vs obs BCIRG 006 DFS HR p Value 0.48 <.001 0.54 <.001 TCH vs AC T AC TH vs AC T MBC Study 0.67 0.60 HR <.001 <.001 TTP p Value T+ Chemo vs Chemo 0.53 < 0.0001 HR OS p Value T+ Chemo vs Chemo 0.80.046 29
Dual Anti HER2 Trials Pertuzumab + Trastuzumab 100.0% Cleopatra Trial NeoSphere 90.0% 80.0% 70.0% Pertuzumab --- Placebo --- 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% HR: 0.62 P= < 0.0001 0.0% 0 100 200 300 400 500 600 700 800 900 1000 1100 Days PFS Pertuzumab + Trast/Tax Placebo +Trast/Tax Median mo 18.5 12.4 HR (95% CI) 0.62 (0.51-0.75) p-value < 0.0001 30
What is the magnitude of pcr improvement that would result in EFS or OS improvement? NEOADJUVANT ADJUVANT METASTATIC TRIALS pcr Re l pcr Abs TRIALS DFS HR TRIALS PFS Mo (HR) OS Mo (HR) NOAH Chemo + Tras 95% 19% 4 Registration Trials * 0.48-0.60 Slamon 2.7 (0.53) 4.8 (0.80) NeoSphere Pertuzumab + Tras 59% 17% AFFINITY Ongoing CLEOPATRA 6.1 (0.62) Not mature * NSABP B-31/ NCCTG 9831, BCIRG 006, HERA 31
Why do we still need adjuvant trials? Many breast cancer subgroups need extended post neoadjuvant therapy (hormonal therapy or anti HER2 therapy) Adjuvant trials will provide confirmation of long term efficacy Long term safety can only be assessed in well conducted adjuvant trials with long-term exposure and follow-up
How are neoadjuvant trials going to guide future adjuvant trials? - More targeted populations - Smaller sample size - Hopefully higher efficacy
By working together, we will overcome the drug development challenges and provide our patients with therapies that will provide clinically meaningful outcomes THANK YOU! 34