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New Approval Mechanism for Breast Cancer using pathologic Complete Response Sandra M. Swain, MD, FACP Medical Director, Washington Cancer Institute MedStar Washington Hospital Center Professor of Medicine Georgetown University March 7, 2014 Sandra Swain, MD Steering Committee (Uncompensated) - Roche / Genentech Contracted Research: Puma /( Pfizer), BMS, Sanofi-Aventis, Roche / Genentech How can we speed drug development in today’s climate? ASCO Strategies Trial Design • Clinically meaningful outcomes • FDA‐ASCO endpoint workshops • Streamlined eligibility criteria • Optimizing data collection Practice/Process Improvement • Community Research Forum • Workload assessment tool • Practice readiness Policy • Breakthrough therapy designation • Insurance coverage • Advocacy for cooperative groups and community based research Design: Clinically Meaningful Outcomes Goal: Trials with greater impact and meaning to patients • Molecular targets increasing expectations • No tolerance for incremental change • ASCO workgroup proposed new benchmarks led by Lee Ellis, MD – Benchmarks vetted by experts – Invited public comment – Complex, controversial topic – J Clin Oncol March 17, 2014 Innovative Ideas for Breast Cancer Drug Approval Milestones of HER2/anti‐HER2 therapies in BC 1978 1982 1983 1984 EGFR discovery Cohen neu oncogene discovery Weinberg Her2 cloned Ullrich and Coussens EGFR MoAb inhibited growth Mendelsohn MBC : metastatic breast cancer MoAb : monoclonal antibody 1985 1987 1998 2006 FDA approves single agent trastuzumab for 2nd line and in combination with paclitaxel for 1st line MBC Amplification of Her2/neu correlates with shorter survival Slamon Her2 amplification in breast cancer Aaronson 2007 2012 2013 FDA approves pertuzumab + trastuzumab + docetaxel for MBC FDA approves lapatinib + capecitabine for MBC FDA approves trastuzumab in adjuvant setting FDA approves TDM1 for MBC SM SWAIN FDA Expedited Programs Designations Fast Track: clinical or nonclinical evidence of unmet need Breakthrough: Preliminary clinical evidence suggests improvement over available therapies (more intensive FDA guidance) Priority Review: 6 mo review (vs 10 mo) Approval Pathways Accelerated Approval Guidance for Industry Expedited Programs for Serious Conditions–– Drugs and Biologics Draft Guidance June 2013 Breakthrough Therapies • Signed into law July 9, 2012 – As of Feb 24, 2014 • 41 designations granted • At least 14 for oncology (2 of 4 approvals: Ibrutinib and obinutuzumab) • Granted early in development process, ideally during or after phase I • Allows FDA to work closely with sponsor and provide commitment to expedite review • Potential to cut down time to approval Accelerated Approval Pathway • Positive benefit‐risk profile • Surrogate endpoint reasonably likely to produce clinical benefit • Postmarketing confirmatory trials required and usually underway at time of application • May be withdrawn if confirmatory trial fail to verify benefit Guidance for Industry: Pathologic Complete Response in Neoadjuvant Treatment of High‐ Risk Early‐Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval • Uniform definition of pCR for regulatory purposes • Summarize relationship known between pCR and prognosis • Describe trial designs and patient populations where pCR reasonably likely to predict clinical benefit • Trial designs permit confirmation of clinical benefit and support conversion to regular approval Draft: FDA issued May 2012 CTNeoBC Trials Trials AGO 1 ECTO EORTC 10994/BIG 1‐00 GeparDuo GeparQuattro GeparTrio GeparTrio‐Pilot NOAH NSABP B‐18 NSABP B‐27 PREPARE TECHNO Total Patients 668 1355 1856 907 1495 2072 285 334 1523 2411 733 217 13856 Cortazar, et al Lancet e pub 2014 Event-Free-Survival and Overall Survival with 3 pCR definitions CTNeoBC ypN0 important, no real difference ypT0/is or ypT0 Cortazar, et al Lancet epub 2014 pCR (ypT0/is ypN0) and Event-Free-Survival and Overall Survival CTNeoBC HR=0.48, (95% CI: 0.43, 0.54) HR=0.36, (95% CI: 0.31, 0.42) Cortazar, et al Lancet e pub 2014 pCR and Event-Free-Survival HR-pos/HER2 neg Breast Cancer CTNeoBC HR=0.49, (95% CI: 0.33, 0.71) HR=0.63, (95% CI: 0.38, 1.04) HR=0.27, (95% CI: 0.14, 0.50) Cortazar, et al Lancet e pub 2014 pCR and Event-Free-Survival HER2 pos Breast Cancer CTneoBC HR=0.39, (95% CI: 0.31, 0.50) HR=0.58, (95% CI: 0.42, 0.82) HR=0.25, (95% CI: 0.18, 0.34) Cortazar et al, Lancet epub 2014 pCR and Event-Free-Survival Triple Negative Breast Cancer HR=0.24, (95% CI: 0.18, 0.33) Cortazar et al Lancet epub 2014 Trial‐level correlation between treatment effect on pCR and event‐free survival or overall survival Cortazar, et al Lancet e pub 2014 Conclusions CTNeoBC • ypT0/is ypN0 had stronger association with outcome than ypT0/is • Strongest association of pCR with outcome – TNBC – HR+: high grade and HER2 neg – HER2+: HR neg • Increase in pCR did not predict improved EFS and OS at a trial level Cortazar, et al Lancet epub 2014 Why did Increase pCR not predict EFS and OS? • Heterogeneous tumor subtypes • Specific treatment (trastuzumab) only used in 3 trials so absolute overall differences in pCR were low (1‐11%) but high for NOAH (20%) with 13% difference in EFS • Factors unrelated to primary tumor response Neoadjuvant Pathway to Accelerated Approval Goal: to market highly effective drugs sooner – Not a lesser standard or “easy” route to market for marginal drugs – Target patients at high risk for recurrence and death – Utilize superiority designs – Design trials to detect a large improvement in pCR – Choose drugs with high likelihood of meaningfully improving long-term outcomes Tatiana M. Prowell, March 2013 Concerns about Neoadjuvant Pathway to Accelerated Approval • Delay between initial approval & confirmation of (or failure to confirm) clinical benefit • Limited data on cumulative toxicity (e.g., neuropathy) and rare/late toxicity (e.g., CHF, secondary malignancy) • Uncertainty about magnitude of improvement in pCR needed to improve EFS/OS – May vary by breast cancer subtype – Some patients with pCR will relapse and many with residual disease will not • Potential negative impacts on drug development – Assessing risks of drug studied first in early-stage breast cancer – Diminished drug development in advanced breast cancer Tatiana M. Prowell March 2013 Number of trials • Single Trial Model: – One large RCT to assess pCR & EFS/OS • Multi-Trial Model: – Accelerated approval based on smaller RCT(s) demonstrating large absolute improvement in pCR rate – Conversion to regular approval based on large RCT(s) with DFS/EFS/OS as primary endpoint Tatiana M. Prowell, March 2013 Panel Discussion Summary • Do we believe the advantages of granting accelerated approval (AA) based on a Neoadjuvant trial with pCR as endpoint outweighs the concerns? Does pCR predict clinical benefit? – Generally yes – Minimum improvement 20% – High risk only, 20-25% 5 year relative risk of recurrence Oncology Drugs Advisory Committee Meeting September 12, 2013 sBLA submission for Pertuzumab • “PERJETA is a HER2/neu receptor antagonist indicated for: Neoadjuvant treatment of breast cancer, in combination with trastuzumab and docetaxel for patients with HER2‐positive, locally advanced, inflammatory, or early stage breast cancer (>2 cm in diameter) as part of a complete early breast cancer regimen containing either fluorouracil, epirubicin and cyclophosphamide (FEC) or carboplatin NOAH Trial: 5 yr Outcomes EFS OS Gianni: Lancet Oncology (In Press) NeoSphere: Study design and objectives TH (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg) Patients with operable or locally advanced /inflammatory* HER2‐positive BC Chemo‐naïve & primary tumors >2cm (N=417) • Phase II design S THP (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg) pertuzumab (840420 mg) U HP (n=107) trastuzumab (86 mg/kg) pertuzumab (840420 mg) E TP (n=96) docetaxel (75100 mg/m2) pertuzumab (840420 mg) Study dosing: q3w x 4 R G R Y • Primary endpoint: Comparison of pCR rates TH vs THP TH vs HP THP vs TP • Secondary endpoints: Clinical response DFS Breast conservation rate Biomarker evaluation NeoSphere: Primary endpoint – pathologic complete response (breast only) (ITT population) p=0.0198 p=0.0141 50 p=0.003 pCR, % 95% CI 40 45.8 30 20 29.0 24.0 10 16.8 0 TH THP H, trastuzumab; P, pertuzumab; T, docetaxel p values from Cochran‐Mantel‐Haenszel test and adjusted for multiplicity HP TP Gianni L, et al. Lancet Oncol 2011 DOI:10.1016/S1470‐2045(11)70336‐9 NEOSPHERE • pCR (ypT0/isypN0) – T + H: 21% – T + H + P 39% – Difference is 18% P=0.0063 – Difference is 24% in ER neg and 10% in ER pos TRYPHAENA • Cardiac safety primary endpoint • Supportive trial – Arm A: 73 pts P + H x 6 with FEC x 3 → T x 3 • pCR 56% – Arm B: 75 pts FEC x 3 → P + H x 3 with T x 3 • pCR 55% – Arm C: 77 pts P + H with T x 3 and carbo x 3 (all x 6) • pCR 64% – Herceptin completes 1 year TRYPHAENA: Cardiac Safety (%) ARM A 6.9 LVEF Decline LVSD 0 Grade > 3 Ongoing 0 LVEF < 50% ARM B 16 ARM C 10.5 2.7 1.3 1.3 0 LVEF decline > 10% and < 50% CLEOPATRA confirmatory overall survival analysis 1 year 94% 100 Overall survival (%) 90 2 years 89% 80 81% 3 years 70 66% 69% 60 HR=0.66 95% CI 0.52−0.84 p=0.0008 50 50% 40 30 20 Ptz + T + D: 113 events; median not reached Pla + T + D: 154 events; median 37.6 months 10 0 0 5 10 15 25 30 35 40 45 50 55 84 33 9 0 0 22 4 0 0 Time (months) n at risk Ptz + T + D 20 402 387 371 342 317 230 143 Pla + T + D 406 383 350 324 285 198 128 67 Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138 D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Swain SM et al. Lancet Oncology 2013 34 APHINITY: Study Schema N=3,806 S U R G E R Y Central confirmation of HER2 status Chemotherapy plus trastuzumab and pertuzumab R A N D O M I Z A T I O N Randomisation Accrual: 11/11 – 8/13 within 7 weeks HR: .75 of surgery F O L L O W U P 10 Chemotherapy plus trastuzumab and placebo Start treatment within 1 week Y E A R S Anti HER2 therapy for a total of 1 year (52 weeks) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy Pertuzumab HER2+ Breast Cancer Development Program Large safety experience Early Breast Cancer (EBC) Neoadjuvant (EBC) S U R G E R Y NEOSPHERE Adjuvant (EBC) Metastatic APHINITY 1L CLEOPATRA TRYPHAENA (MBC) 1L PERTAIN Perjeta treated patients • >500 in neoadjuvant studies • ~4500 in completed or ongoing studies Data included in this application Ongoing ODAC September 12, 2013 • “Has Perjeta® demonstrated a favorable benefit to risk evaluation for the neoadjuvant treatment of early breast cancer?” – Vote: 13 yes, 1 abstention – Reasons for yes • • • • • Totality of evidence CLEOPATRA survival benefit APHINITY already accrued Robust clinical development by company: N of 1 Safety reasonable Pertuzumab Neoadjuvant Approval • September 30, 2013 • Accelerated approval for pertuzumab used in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2‐positive, locally advanced, inflammatory or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. BERENICE Study Design Cohort A ddAC x 4 Weekly T x 12 P 840mg→420 mg 3-weekly Investigator choice H 8/kg→6mg/kg 3-weekly S U R G E R Y P 420 mg 3-weekly H 6mg/kg 3-weekly U P Cohort B FEC x 4 Dx4 P 840mg→420 mg 3-weekly H 8/kg→6mg/kg 3-weekly S Swain and C Dang, Co-PI F O L L O W S U R G E R Y P 420 mg 3-weekly F O L L O W H 6mg/kg 3-weekly U P NCCN Guidelines V1.2014 Neoadjuvant and Adjuvant Breast (T2 or N1) • • • • • • • AC→ paclitaxel + trastuzumab + pertuzumab TCH + pertuzumab AC→ docetaxel + trastuzumab + pertuzumab FEC→ docetaxel + trastuzumab + pertuzumab FEC→ paclitaxel + trastuzumab + pertuzumab Pertuzumab + trastuzumab + docetaxel→FEC Pertuzumab + trastuzumab + paclitaxel→FEC Milestones of HER2/anti‐HER2 therapies in BC 1978 1982 1983 1984 EGFR discovery Cohen neu oncogene discovery Weinberg Her2 cloned Ullrich and Coussens EGFR MoAb inhibited growth Mendelsohn MBC : metastatic breast cancer SM SWAIN antibody MoAb : monoclonal 1985 1987 1998 2006 FDA approves single agent trastuzumab for 2nd line and in combination with paclitaxel for 1st line MBC Amplification of Her2/neu correlates with shorter survival Slamon Her2 amplification in breast cancer Aaronson 2007 2012 2013 FDA approves pertuzumab + trastuzumab + docetaxel for MBC FDA approves lapatinib + capecitabine for MBC FDA approves trastuzumab in adjuvant setting FDA approves TDM1 for MBC FDA approves Pertuzumab + Trastuzumab neoadjuvant Springtime in Washington D.C.
