Session 2: What is the status of the technologies of "precision medicine? Gideon Blumenthal, MD, Clinical Team Leader, Thoracic and Head/Neck Oncology, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration
Oncology Drug Development in the Era of Precision Medicine: FDA Perspective Gideon Blumenthal, MD Clinical Team Leader Thoracic and Head and Neck Oncology US FDA 2
Disclosure Information I have no financial relationships to disclose 3
Expedited programs 4
Approval Pathways for Drugs and Biologics Traditional (Regular) Approval Based on improvement in a direct measure of clinical benefit: Longer life, better life, or established surrogate Accelerated Approval Initiated in 1992 (HIV crisis using viral load as surrogate) Based on improvement in surrogate endpoint reasonably likely to predict clinical benefit over available therapy Need post marketing studies to confirm benefit Used frequently in Oncology 5
FDA Expedited Programs Fast Track Breakthrough Therapy Priority Review Accelerated Approval Non- Clinical Early Clinical Registration Trial(s) NDA/BLA Submission APPROVAL IND Submission Dose Exploration / Prelim Activity SPA Efficacy and Safety Data FDA Review If considering accelerated approval, post-marketing clinical trials should be underway at the time of approval. 6
Breakthrough therapy designation Signed into law in 2012 (FDASIA) For serious life threatening disease, a drug, based on preliminary clinical evidence, has substantial improvement over available therapy About 40% of BT requests across drug center have been in Oncology About a third of these have been granted Of 9 oncology new molecular entities approved in 2014, 5 were breakthrough designated Pace of breakthrough therapy designations in oncology has continued throughout 2015 7
Breakthrough Therapy: Opportunities and Challenges Opportunities: All Hands on Deck for Transformative Therapies: Aligns and Prioritizes Key FDA review teams (Clinical, Statistics, Manufacturing, Clinical Pharmacology, Toxicology, Inspections) Optimizes communication between FDA and Sponsor Challenges: What is the right threshold for granting a BT designation? What constitutes available therapy? How late is too late? Timing of BT designation request Resource saturation for both FDA and Sponsor? On what basis should we rescind a BT therapy? Manufacturing timelines can be a bottleneck 8
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 Pembrolizumab for PDL1 positive 2 nd line NSCLC based on expansion cohort validation set in Phase 1 Nivolumab for non squamous NSCLC 3.5 month review Osimertinib for T790M EGFR mutation NSCLC after progression on EGFR TKI First in Human to Accelerated Approval 2.5 years 9
Next generation trials 10
Traditional drug development paradigm Linear, sequential, drugs and companion diagnostic development Pharmaceutical R&D process and decision points New Medicines Proposal Target Validation Lead Identification Research ~7yrs Lead Optimization EIH Enabling Pre clinical safety Phase I Early clinical safety Phase IIa Proof of concept Development ~8yrs Phase IIb Early clinical efficacy Phase III Key registration trials Lifecycle management Registration (phase IV) Project initiation Clinical candidate selection Entry into humans Entry into lifecycle management Full development decision Filing decision for first indication Diagnostic development process and milestones Biomarker Discovery Pre clinical assay development ~2yrs BM Dx candidate identified Replication Confirm markers and reproducibility of assay Analytical Development Translation of assay onto a clinical diagnostic platform BM assay on clinical platform Non clinical testperformance Phase I Sensitivity & specificity R&D = Research & Development; BM = Biomarker; PPV = Positive predictive value; NPV = Negative predictive value Clinical validation Clinical Phase ~3yrs Phase II PPV and NPV Clinical utility Phase III Clinical benefit and Cost effectiveness Clinical impact Registration Kapil Dhingra Annals of Oncology, September 2015 11
Vision for drug development in Oncology X New Target New Drug Candidate Exploratory Biomarkers Fail Early Exploratory Human Trials (POM, POE) Surrogate Endpoints Surrogate Biomarkers Companion Diagnostics Confirmatory Studies Limited Approval Additional Approvals Companion Diagnostics Exploratory Biomarkers New Hypotheses Post-Marketing Surveillance Translational Research POM = Proof of mechanism; POE = Proof of efficacy Kapil Dhingra Annals of Oncology, September 2015
Challenges with old paradigm MET p53 KRAS ROS1 EGFR ALK N=800-1200 Platinum doublet Platinum doublet + drug X HIGH RISK PHASE 3 FAILURE OR CLINICALLY SMALL EFFECT Challenges with new paradigm ALK Targeted Therapy N=100-200 Large, Clinically Meaningful Effect 1% Prevalence of even common tumors: Number needed to screen > 100 patients need to reduce screen failure rate 1 drug/ 1 biomarker per trial unsustainable Need common multianalyte platform(s) Need Rapid Learning/ Failure/ Confirmation 13
Rare is common and the long tail phenomenon 30 25 20 15 10 5 All Common (5% or greater) Intermediate (2 5%) Rare (Less than 2%) Patients with TARGET Gene events by category (%) 0 25 50 75 100 0 00 TP53 BRAF PIK3CA CDKN2A KRAS NF1 EPHA3 ERBB4 ATM CREBBP EGFR EPHA5 PTEN ROS1 NOTCH2 SMARCA4 APC KDR MLL BRCA2 NOTCH1 NRAS PDGFRA ATR DDR2 EZH2 FLT3 NTRK3 RB1 RET CDH1 FBXW7 PIK3R1 ASXL1 BCL2 CTNNB1 ERBB2 JAK2 MET MTOR STK11 CDKN1B GNAS MAP2K1 SMAD4 SYK ABL1 BRCA1 ERBB3 MYC PTCH1 RUNX1 ALK BRD4 CDK4 ERG FGFR2 IGF1R MSH2 MSH6 NFKBIA AKT1 ETV6 PDGFRB SMO TSC2 WT1 XPO1 AR FGFR1 KIT MDM4 MEN1 CDKN2B CRKL MAP2K4 MDM2 SMAD2 TET2 BAP1 CCND1 CCND2 DNMT3A ESR1 ETV1 EWSR1 FGFR3 GNAQ HRAS IDH1 JAK3 MLH1 RAF1 RARA AURKA BRD3 CCND3 CCNE1 IDH2 MAP2K2 MITF NF2 TMPRSS2 TSC1 VHL BRD2 ETV4 ETV5 MPL SMARCB1 ARAF GNA11 MCL1 NKX2 1 AKT2 AKT3 CDK6 CDKN1A CEBPA TARGET gene alterations (%) Van Allen et al., Nature Med (2014) Lawrence et al, Nature (2014) 14
Master Protocols Umbrella Test impact of different drugs on different mutations in a single type of cancer BATTLE I SPY2 Lung MAP Basket Test the effect of a drug(s) on a single mutation(s) in a variety of cancer types ImatinibBasket BRAF+ NCI MATCH 15
Public Private Partnership: Novel Collaboration in Oncology Clinical Research Alliance SWOG S1400 Master Protocol ECOG ACRIN NCI C NRG 16
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Incorporating the patient voice 18
Traditional Oncology Endpoints Direct Clinical Benefit Surrogate PRO Measures symptoms/ function Challenges include missing data, un blinding PFS Accounts for stable disease Ascertainment bias/ Informed censoring Magnitude important!! Can not be assessed in single arm trials ORR Smaller/ quicker Binary No stable disease Can be assessed in single arm trials OS Bigger and longer studies Confounded by crossover and subsequent therapies Can not be assessed in single arm trials Subjective Objective 19
Efforts to incorporate patient voice Validating lung cancer specific patient reported outcome (PRO) as a drug development tool Patient focused drug development meeting June, 28, 2013 The voice of the Patient: http://www.fda.gov/downloads/forindustry/userfees/pres criptiondruguserfee/ucm379698.pdf Lung cancer twitter chat 20
Its been a busy time in lung cancer. 21
Acknowledgements Richard Pazdur Patricia Keegan Thoracic & Head/Neck Team Sean Khozin Diko Kazandjian Lee Pai Scherf Erin Larkins Barbara Scepura Luckson Mathieu 22