Circulating Tumor Cell Number as an Early Response Endpoint for Metastatic Prostate Cancer

1. Circulating Tumor Cell Number as an Early Response Endpoint for Metastatic Prostate Cancer Howard I. Scher, MD, Robert McCormack, MD, Arturo Molina, MD*, Matthew R. Smith, MD, Robert Dreicer, MD, Fred Saad, MD, Ronald de Wit, MD, Dana T. Aftab, MD, Ana Limon-Carrera, MD, Karim Fizazi, MD, PhD, Martin Fleisher, PhD, Johann S. de Bono, MB ChB, PhD, Gary Kelloff, MD, Glenn Heller, PhD February 14, 2019 Presented by: Howard I. Scher, MD

2. Disclosures Consultant: Amgen (U), ESSA Pharma Inc (U), Janssen (U), Menarini Silicon Biosystems (U), Sanofi Aventis (U), WCG Oncology (C) Grant/Research support to MSK: EPIC Sciences, Illumina, Inc, Innocrin Pharma, Menarini Silicon Biosystems, ThermoFisher Board of Directors: Asterias Biotherapeutics Travel reimbursement: Amgen, Janssen, Sanofi Aventis, Menarini Silicon Biosystems U = Uncompensated

3. The Number, Range and Type of Effective Treatment Options for Castration Resistant Prostate Cancer Continues to Increased Dramatically FIX BOX Presented by: Howard I. Scher, MD

4. The Majority of the Drug Approvals Were Based on Time to Event Endpoints That Occur Late Presented by: Howard I. Scher, MD

5. With the Exception of the Control of Pain, No Approvals Were Based on a Favorable Change in a Disease Manifestation Presented by: Howard I. Scher, MD

6. The Presence of Circulating Tumor Cells in Blood Have the Potential to Fulfill The Unmet Need for a Response Indicator Biomarker That is Clinically Meaningful • Well established in patients with prostate,1 breast,2 colorectal3 and other cancers is that the detection of CTCs in blood portends a poor prognosis. • Declines in the number of CTCs post-treatment predicts for an improvement in survival. • Studied in a phase 3 trial, we showed that a 13 week biomarker containing CTC satisfied all 4 Prentice Criteria of a surrogate for overall survival. • Despite rapid technological advances, there remains only one CTC assay that has achieved the level of an FDA clearance. Presented by:

7. CellSearch™: An FDA Cleared CTC Assay (2004) “As an Aid in the Monitoring Patients … In Conjunction with Other Clinical Methods” • CTC definition: • Morphology, CK(+), CD45(-), DAPI(+) • Report: # of cells meeting criteria/7.5 mL of blood • Endpoint: ConversionUnfavorable (> 5 Pre) • Favorable (4 or less Post) Presented by: Howard I. Scher, MD

8. The Association of CTC and PSA Response Endpoints and Survival Was Studied in 5 Phase 3 Registration Trials Covering the Specturm of mCRPC Castration resistant (Lethal) Non-castrate Castration Resistant Metastatic Pre Orteronel - 04 Millenium Castration Resistant Metastatic 1st Line Castration Resistant Metastatic Post- Abiraterone- 301 JNJ Enzalutamide Medivation Orteronel – 05 Millenium – Cabozantinib Exelixis Clinical Metastases: Noncastrate Clinically Localized Disease Rising PSA CTC0 = 1 or more pre-treatment to zero post-treatment Non- Metastatic CRPC Presented by: Howard I. Scher, MD

9. In Addition to the CTC Conversion Endpoint We Explored a New Endpoint - CTC0: The detection of 1 or more CTC pre-treatment and none post-treatment. Presented by:

10. Both CTC0 and CTC Conversion Were More Strongly Associated with Survival Than PSA50 Providing Greater Separation Between Responders and Non-Responders CTC0 PSA50 .83 .74 Evaluable: 75% 51% 95% More patients were evaluable using CTC0 Presented by: Heller et al. JCO 36:572, 2017

11. Here we Explored Different CTC and PSA Response Endgpoints as “Transitional” Surrogates for Overall Survival Using Data From 5 Phase 3 Randomized Trials Presented by: Howard I. Scher, MD

12. Why “Transitional” as Opposed to “Traditional”? • Transitional is used because the endpoints were studied in a phase 2 setting – not phase 3. • Each arm of a trial was considered independently – a total of 10 trials. • Patient Level Discrimination: The separation between between responder and non-responder survival curves. • Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial Presented by: Howard I. Scher, MD

13. The Question: How well does a response endpoint measured at 3 months predict survival at 6 to 18 months after the start of treatment? The response endpoints studied: CTC0 PSA50 CTC0 or PSA50 CTC0 and PSA50 Presented by:

14. BEST: A Glossary that Captures Distinctions BetweenBiomarkers and Their Clinical Assessment for Use in Research, Practice and Product Development Diagnostic Monitoring Pharmacodynamic/Response Predictive Prognostic Reasonably likely surrogate Validated Surrogate Endpoint https://www.ncbi.nlm.nih.gov/books/NBK326791/pdf/Bookshelf_NBK326791.pdf Presented by: Howard I. Scher, MD

15. Consort Diagram and Response Rates Randomly Assigned Patients (N=6,081) Patients who survived > 13 weeks (N=5,660) Patients who survived > 13 weeks with CTC > 1 & PSA > 5 ng/dl (N=3080) Achieved CTC 0 (N=591) 19% Achieved PSA 50 (N=659) 21% Presented by: Howard I. Scher, MD

16. PSA50 Response Rates Were Modestly Higher in theExperimental Arm with Little Difference in The Control Arms Presented by: Howard I. Scher, MD

17. The Analyses Were Conducted at the Patient Level and Separately at the Trial Level • The endpoints were studied in a phase 2 setting – not traditional surrogacy which is done in phase 3. • Each arm of a trial was considered independently – a total of 10 trials. • Patient Level - Discrimination: The separation between between responder and non-responder survival curves. • Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial Presented by: Howard I. Scher, MD

18. Survival Probability Estimates Over Months 6 to 18With Difference in Outcomes at 12 and 15 Months CTC0 PSA50 0.89 0.84 0.84 0.76 0.38 0.32 0.44 0.35 0.51 0.52 0.40 0.41 Black line indicates responders and red line, non-responders. Presented by: Howard I. Scher, MD

19. The Analyses Were Conducted at the Patient Level and Separately at the Trial Level • The endpoints were studied in a phase 2 setting – not traditional surrogacy which is done in phase 3. • Each arm of a trial was considered independently – a total of 10 trials. • Patient Level - Discrimination: The separation between between responder and non-responder survival curves. • Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial Presented by: Howard I. Scher, MD

20. The 3 Month CTC0 Endpoint Provides an Early Indicator of Clinical Benefit Explaining Over 60% of the Variation in Survival and is More Informative Than PSA50 – And/Or Did Not Add 12 Mos. 0.67 0.59 Presented by: Howard I. Scher, MD

21. The 95% Confidence Intervals Around the Difference in R2 Values of CTC0 and PSA50 Endpoints Falls Below Unity:Attaining Trial Level Transitional Surrogacy Falls Short Presented by:

22. Based on More Recent Guidance We Have Revised the Context of Use of our Qualification Program to a Response Measure that Reflects Clinical Benefit Presented by:

23. Conclusions • CTC0 is an improved measure of response relative to PSA • The result can be used to aid the management of the individual patient – failure to decline portends a poor prognosis. • For a population in a phase 2 trial the proportion of patients in whom CTC0 is achieved provides a meaningful measure of efficacy. • The result can be used to inform the decision to continue development. Presented by: Howard I. Scher, MD

24. Conclusions 2 5. CTC0 on its own it does not meet new guidance for a reasonably likely surrogate. 6. Differences are not significant due to small number of trials. Presented by:

25. Acknowledgements