Genomics and Genetics in BC: Precise selection for chemotherapy and Immunotherapy. Raanan Berger MD PhD Sheba Medical Center, Israel

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1 Genomics and Genetics in BC: Precise selection for chemotherapy and Immunotherapy Raanan Berger MD PhD Sheba Medical Center, Israel

2 Disclosures Honoraria, Ad board BMS, MSD, Pfizer, Astra Zeneca, Bayer, Roche, Oncotest-Teva, Astellas, Janssen

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4 1 st line setting No major treatment advances in 20 years in first line OS (mos): GC 14.0 months ( ) MVAC 15.2 months ( ) HR: 1.09 ( ) CDDP-fit First line GC (Gemcitabine-Cisplatin) vs MVAC Von Der Maase H, JCO 2005 CCDP-unfit OS (mos): HR = 0.94(95% CI: ), p=0.64 GCb: 9.3 ( ) M-CAVI: 8.1 ( ) Gemcitabine-Carboplatin Vs M-CAVI De Santis M, JCO 2012

5 2 nd line CT after failure of platinum salt: single-agent ph II trials Author & year of publ. Agent N (evaluable) ORR (%) PFS (mo) OS (mo) Pronzato, NR 0.8 Ifosfamide Witte, Mc Caffrey, NR 9.0 Docetaxel Choueiri, 2012 (1 arm out of 2) 75 (72) Papamichael, NR NR Vaughn, 2002 Paclitaxel Joly, (37) Lorusso, (31) Gemcitabine Albers, (28) Witte, 1998 Topotecan Dodd, 2000 Pyrazoloacridine 14 0 NR 9.0 Roth, 2002 Piritrexim 35 (27) Moore, 2003 Oxaliplatin 18 6 NR NR Dreicer, 2007 Epothilone B 45 (42) Sweeney, 2006 Galsky, 2007 Crevera-Grau, ASCO 2012 Pemetrexed NR 2.9 NR NR 7.2 Sridhar, ASCO GU 2011 Nab-paclitaxel J Lee, ASCO GU 2011 Paclitaxel PM Loriot, ASCO 2012 Pralatrexate (conf.)

6 CPI in Cisplatin Refractory Disease 0

7 One Size Fits All Observation Action Trial and Error Response Medicines attempt to achieve a positive benefit/risk (clinical utility) in large patient populations independent of target status 20-25% Efficacy Walgren et al, JCO 2005

8 Background: Gene Expression/ Subtyping Choi et al. Cancer Cell 2014

9 Slide 23 Siefker-Radtke, Choi et al. GUASCO 2015, EuroUrol 2015

10 Slide 24 Siefker-Radtke, Choi et al. GUASCO 2015, EuroUrol 2015

11 Slide 25 Siefker-Radtke, Choi et al. GUASCO 2015, EuroUrol 2015

12 Slide 26

13 13 The Cancer Genome Atlas (TCGA) Research Network

14 Response by Genomic Subtypes Sharma et al. Lancet Oncology 2017 Rosenberg et al. Lancet 2016

15 PDL1 as a biomarker

16 Overall Survival, (%) Overall Survival, (%) KEYNOTE-045: overall survival and ORR* Outcomes in All Pts Pembro Chemo mos, mos (95% CI)* 10.3 ( ) 7.4 ( ) ORR, % (95% CI)* 21.1 ( ) 11.4 ( ) CR, % PR, % mdor, mos (range) NR ( ) 4.3 ( ) Outcomes in CPS 10% Pembro Chemo mos, mos (95% CI)* 8.0 ( ) 5.2 ( ) ORR, % (95% CI)* 21.6 ( ) 6.7 ( ) CR, % PR, % mdor, mos (range) Pembro Chemo 100 Overall Survival: Total Overall Survival: CPS 10% Pembro 80 Pembro 70 Chemo 70 Chemo HR (95% CI): 0.73 ( ), P= HR (95% CI): 0.57 ( ), P= Time (months) No. at Risk Adapted from Bellmunt et al, No. at Risk Pembro 74 Chemo 90 Time (months) Adapted from Bellmunt et al, *Confirmed ORR and OS were assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: September 7, CPS is the percentage of PD-L1 positive tumor cells and tumor-infiltrating immune cells relative to the total number of tumor cells. 2L, second line; 3L, third line; chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; CR, complete response; HR, hazard ratio; I-O, immuno-oncology; mdor, median duration of response; mos, median overall survival; mos, months; muc, metastatic urothelial carcinoma; NR, not reached; ORR, objective response rate; OS, overall survival; pembro, pembrolizumab; PR, partial response; Pts, patients; RECIST, Response Evaluation Criteria In Solid tumors. 1. Bellmunt J et al. N Engl J Med. 2017;376: Bellmunt J et al. Oral presentation at SITC 2016.

17 Imvigor 211- Failed to meet endpoint in PDL1 enriched population

18 Beyond PDL1 as a biomarker

19 Mutation Load and Survival With Immunotherapy Presented By Sandy Srinivas at 2018 ASCO Annual Meeting

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21 Overall Survival (Probability) Overall Survival (Probability) Checkmate 275: OVERALL SURVIVAL BY tumor PD-L1 EXPRESSION AND TMB in 2L Bladder Overall Survival in <1% PD-L1 Subgroup 1 TMB tertile low TMB tertile medium TMB tertile high Shading = 95% CI Overall Survival in 1% PD-L1 Subgroup 1 TMB tertile low TMB tertile medium TMB tertile high Shading = 95% CI No. at Risk Time (months) Low Medium High No. at Risk Low Time (months) Medium High Adapted from Galsky et al Checkmate 275 is a phase 2, single-arm trial of nivolumab 3 mg/kg IV q2w, with a primary endpoint of ORR by BICR using RECIST v1.1 (in all treated and in PD-L1+* patients) High TMB was significantly associated with higher ORR, longer mpfs, and longer OS across tumor PD-L1 levels TMB-high patients with PD-L1 expression >1% (n=24): ORR=33.3%, mpfs=3.52 months, mos=10.6 months TMB demonstrated a clearer association with OS among patients with <1% tumor PD-L1 expression TRAEs were evaluated in 270 patients who received nivolumab; any Grade TRAEs: 64% and Grade 3 4 TRAEs: 18% 2 *Tumor PD-L1 expression of 1% or 5% or greater. Median follow-up was 11.5 months for Galsky et al, and 7.0 months for Sharma et al. 3 patients died due to TRAEs 1,2 2L, second line; AE, adverse event; BIRC, blinded independent review committee; IV, intravenously; mos, median OS; mpfs, median PFS; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; TMB, tumor mutation burden. 1. Galsky MD et al. Oral presentation at ESMO PD. 2. Sharma P et al. Lancet Oncol. 2017;18:

22 Results ORR, OS, and PFSin all patients and TMB/PD-L1 subgroups Population ORR, % a Median PFS, months (95% CI) Median OS, months (95% CI) Tumor PD-L1 expression ORR,% a Median PFS, months (95% CI) Median OS, months (95% CI) CheckMate 275 study N = ( ) TMB evaluable n = ( ) 8.57 ( ) 7.23 ( ) <1%, n = ( ) 5.95 ( ) 1%, n = ( ) (9.10 NR) <1%, n = ( ) 5.68 ( ) 1%, n = ( ) (5.85 NR) TMB low n = ( ) 5.72 ( ) <1%, n = ( ) 4.96 ( ) 1%, n = ( ) 8.57 (3.61 NR) TMB medium n = 46 TMB high n = ( ) 9.66 (4.50 NR) ( ) (5.72 NR) <1%, n = ( ) 4.53 (2.20 NR) 1%, n = ( ) (5.49 NR) <1%, n = (1.71 NR) NR (4.17 NR) 1%, n = (1.74 NR) (4.60 NR) a ORR based on blinded independent review committee assessment 22

23 Association of High Tissue Tumor Mutational Burden (TMB) and Atezolizumab Efficacy Across Multiple Tumor Types Presented By David Gandara at 2018 ASCO Annual Meeting

24 TMB at 16 mut/mb Identifies a Patient Population <br />Distinct from PD-L1 IHC Presented By David Gandara at 2018 ASCO Annual Meeting

25 MMR-Deficient Tumors Respond Better to Pembrolizumab Than MMR-Proficient Tumors Le DT et al. NEJM 2015

26 Deletrious DDR Alterations and Response to CPI

27 pcr as prognostic factor 27

28 Slide 1 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

29 Slide 4 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

30 Slide 8 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

31 Slide 6 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

32 Slide 11 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

33 Slide 12 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

34 Slide 14 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

35 Slide 13 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

36 Slide 15 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

37 Slide 16 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

38 Conclusion Urothelial Cancer is no Longer Just One Disease

39 Thanks