1. Drug Development at CINJ Evolving challenges

3. Phase 1 Studies at CINJ Early drug trials– Fits easily in scope for single or limited number of institutions. CINJ the only NCI phase I Operator Dose escalations occur in cohorts with delays to assess toxicities; thus we need multiple phase I studies active to meet need All new agents or new combinations of new or existing agents Objective to find the maximum tolerable dose Needs very close scrutiny for any toxicities; weekly meeting to discuss clinical course and events Assess pharmacokinetics (what the patient does to drug) Assess pharmacodynamics (what the drug does to patient) Recommend dose for Phase II studies

4. Phase II studies at CINJ Overlaps with phase Ib (expanded dose or disease specific cohort) Phase II usually in specific disease or disease subgroup Can be single institution, but usually multiple or cooperative group Objective to define preliminary activity above defined threshold with 90 or 95% confidence Usually designed with two-step: go or no-go (exlcudes lower threshold) Often conducted with (exploratory) correlative studies, biomarkers, etc, unless the biomarker defines the endpoint Randomized phase II studies, usually multi-institutional: Distributes experience across institutions Often designed to pick “winner” for further study Can serve as basis for phase III studies

5. Phase III studies Large, randomized studies against concurrent (standard) control N in the hundreds to thousands depending on endpoint Overall survival = the “gold standard” Surrogates include: PFS, % alive at given interval, objective response frequencies New studies progressively incorporate integrated biomarkers Accrual takes years, Follow-up often prolonged Usually not feasible in (most) single institutions Accrual rate needs careful scrutiny Requires independent DMC with interim safety and futility analysis Needs sponsor: Cooperative Groups, Industry (via CRO) Remains the defining standard for FDA approval

14. Problems with the Classic Pathway to Drug Development Too inefficient, too expensive, and too long High failure rate competes away patient resources on drugs that fail High cost of development indirectly drives drug price Long time to approval derives patients of potential benefit Long time to development shortens patent life and drives price High cost and long time lessens commercial enthusiasm for “older” agents i.e. those published or patened previoulsy as in academics

15. Evolving Problems in Drug Development New technology such as genomic profiling Diseases are progressively splitting into ever smaller distinct subgroups NSCLC: mutations EGFR, ALK,ROS-1, ERB-2. RAF, MET The Lung Cancer Mutation Consortium now tests for ~30 genes Each distinct subgroup showing differential prognostic and predictive impact Low frequency subgroups may not distribute evenly in phase III studies New therapeutic classes may target unique subpopulataions New Imaging approaches may alter classic endpoints

16. Examples of some Approaches for improvement Phase I: increase number of participating institutions Use of adaptive dosing algorythms Expanded cohorts (Ib) to focus on specific disease subgroup, etc Phase II Randomized phase II studies to lessen the phase III time and expense by promoting apparent “winners” Use of Bayesian approach Phase III Define more homogeneous populations Integrate Bayesian statistics The expedited review

17. The FDA Expedited Approval Review The FDA opened an expedited review process for marketing approval To offer patients earlier access to promising agents with limited options Allows “early” data for consideration Usually requires an “unmet need” Requires an eventual confirmatory phase III trial Requires completion within a defined time-line Lack of positive phase III data can lead to removal of approval Some examples of expedited approvals

18. Phase 1 Study of Crizotinib for ALK Mutated NSCLC 2010 N Engl J Med 363;18

19. Randomized confirmation trial for Crizotinib v. Chemotherapy in ALK mutated NSCLC N Engl J Med 2014; 371:2167-2177

20. The Lancet 2014 384, 1109-1117DOI: (10.1016/S0140-6736(14)60958-2) Phase I Study of 2 doses of Pembrolizumab for metastatic melanoma RAF wt

21. Figure 3 The Lancet 2014 384, 1109-1117DOI: (10.1016/S0140-6736(14)60958-2) Copyright © 2014 Elsevier Ltd Phase 1 study of 2 doses of pembriluzomab for metastatic melanoma Lancet 2014 384, 1109

22. Kaplan-Meier curves of (A) overall survival and (B) progression-free survival in 107 nivolumab- treated patients with melanoma and (C) response duration in 33 objective responders. Suzanne L. Topalian et al. JCO 2014;32:1020-1030 ©2014 by American Society of Clinical Oncology

23. Phase 1 study Crizotinib for ROS-1 mutated NSCLC

24. Phase 1 Study Crizotinib for ROS-1 mutated NSCLC

25. Evolving Problems in Drug Devlopment As unique disease subgroups become progressively smaller Confirmatory phase III trials become ever more difficult to complete Requires ever larger population from which to extract the subgroups Requires ever larger investigator pool As new therapeutic classes evolve, the identification of the subgroup to benefit often lags behind EGFR inhibitors arrived before the EGFR mutations were identified The subgroup most likely to benefit from checkpoint inhibitors remains a topic of current investigation

26. Do We Always Really Need Confirmatory Phase III Trials? In the cited examples Is the effect size sufficient to conclude validation? Do we expect to see failure when the response and TTF or OS show the magnitude of effect in the “early” trials Is it ethical to deny someone in the unique subgroup an alternative control? Will cross-over to the new agent produce a sufficient “rescue” Does an early relapse produce adverse effect The challenge to the statistical community:

27. Can we develop a statistical model for validation of “earlier “ data short of a randomized phase III trial? Will the FDA listen?