Session 8: Accelerating the Development and Approval of New Drugs: FDA OHOP perspective Gideon Blumenthal, MD Office of Hematology Oncology Products Center for Drug Evaluation and Research, US FDA

Key Questions (from Dr Flaherty, session chair) Is there a need for centralized infrastructure for diagnostic testing, IRB, or umbrella protocols? Is cross validation of tumor-based testing or blood-based testing pre-competitive? What is the threshold of rarity that defines the need for national scale investigation (NCTN or private sector)?

FDA Expedited Programs Breakthrough Therapy Priority Review Accelerated Approval Fast Track Non-Clinical Early Clinical Registration Trial(s) NDA/BLA Submission APPROVAL IND Submission Dose Exploration / Prelim Activity SPA FDA Review Efficacy and Safety Data If considering accelerated approval, post-marketing clinical trials should be underway at the time of approval.

Breakthrough therapy designation Inception 2012 Since June 8, 2016: FDA approved 49 breakthrough-designated products, 25 in oncology ~40% of requests across center for drugs have been in oncology ~1/3 granted Source: http://www.focr.org/breakthrough-therapies

Examples of Breakthrough therapies granted and subsequently approved in NSCLC Ceritinib for crizotinib-refractory ALK+ NSCLC based on expansion cohort in Phase 1 First in human to Accelerated approval 3.25 years Expeditious resolution of “late” in cycle cGMP issue <5 month review Osimertinib in T790M mNSCLC First in human to accelerated approval ~2.8 years

Example of two accelerated approvals based on expansion cohorts in a “phase 1” trial: Keynote-01 Source: AAADV 2015

Original Lung-MAP Design PD-L1 mAb MEDI4736 Broad Biomarker Profiling: NGS,IHC Non-Match Docetaxel PIK3CA mut cdk4/6 CCND1 mut, del, amp FGFR mut, amp, fusi HGF Met amplific. By IHC PI3K TKI GDC-0032 Doce-taxel CDK4/6 TKI Palbo-ciclib Doce-taxel FGFR TKI AZD-4547 Doce-taxel HGF mAb Rilotumumab + erlotinib Erlotinib PFS/ PFS/ Interim Analysis (Phase 2 part): IRR PFS; futility/efficacy Final Analysis (Phase 3 part): Co-primary OS (powered) and PFS

Revised Lung MAP after nivolumab approval March 2015 2nd line NSCLC (docetaxel no longer SOC) Biomarker–Driven Sub-Studies Non-match Sub-Studies S1400B PI3K+ S1400C CCGA+* S1400D FGFR+ S1400G HRRD+* S1400I Checkpoint Naive S1400F Checkpoint Refractory Single Arm Phase II GDC-0032 Palbociclib AZD4547 PARP Nivolumab/Ipilimumab vs. Nivolumab PD-L1 / CTLA-4 Combination GDC-0032 vs. TBD Palbociclib vs. TBD AZD4547 vs. TBD PARP vs. TBD Two new sub-studies – S1400G and S1400F – added within 6 months; Additional Sub-studies expected within 6-9 month period *CCGA = Cell Cycle Gene Alternation, HRRD = Homologous Recombinant Repair Deficiency

Real World Evidence for rare indications? Example MSI-high rare tumor types: gallbladder, endometrial, etc. Collect ORR/ DoR data of PD1/PDL1 in real world settings? Leverage existing safety/efficacy data

Key Questions (from Dr Flaherty, session chair) Is there a need for centralized infrastructure for diagnostic testing, IRB, or umbrella protocols? Is cross validation of tumor-based testing or blood-based testing pre-competitive? What is the threshold of rarity that defines the need for national scale investigation (NCTN or private sector)?

Recommendations Establish trials of multiple novel agents against a common control Investment in centralized diagnostic testing platforms, cross-validation to credential multiple drugs, multiple platforms Investment in federated registries to understand predictive/prognostic implications of rare biomarker subsets, link ‘omics data to clinical outcome data