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

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

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

1 st line setting No major treatment advances in 20 years in first line OS (mos): GC 14.0 months (12.3-15.5 ) MVAC 15.2 months (13.2-17.3 ) HR: 1.09 (0.88-1.34) CDDP-fit First line GC (Gemcitabine-Cisplatin) vs MVAC Von Der Maase H, JCO 2005 CCDP-unfit OS (mos): HR = 0.94(95% CI: 0.72-1.22), p=0.64 GCb: 9.3 (6.1-10.3) M-CAVI: 8.1 (7.6-11.3) Gemcitabine-Carboplatin Vs M-CAVI De Santis M, JCO 2012

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, 1997 20 5 NR 0.8 Ifosfamide Witte,1997 58 20 2.2 5.1 Mc Caffrey, 1997 30 13 NR 9.0 Docetaxel Choueiri, 2012 (1 arm out of 2) 75 (72) 7 1.6 7.0 Papamichael, 1997 14 7 NR NR Vaughn, 2002 Paclitaxel 31 10 2.2 7.2 Joly, 2009 45 (37) 9 3 7.0 Lorusso, 1998 35 (31) 23 3.8 5.0 Gemcitabine Albers, 2002 30 (28) 11 4.9 8.7 Witte, 1998 Topotecan 44 9 1.4 5.1 Dodd, 2000 Pyrazoloacridine 14 0 NR 9.0 Roth, 2002 Piritrexim 35 (27) 7 2.1 7.0 Moore, 2003 Oxaliplatin 18 6 NR NR Dreicer, 2007 Epothilone B 45 (42) 12 2.7 8 Sweeney, 2006 Galsky, 2007 Crevera-Grau, ASCO 2012 Pemetrexed 45 13 44 28 8 NR 2.9 NR 4.1 9.6 NR 7.2 Sridhar, ASCO GU 2011 Nab-paclitaxel 48 32 6 10.8 J Lee, ASCO GU 2011 Paclitaxel PM 34 21 2.7 6.5 Loriot, ASCO 2012 Pralatrexate 30 3.3 (conf.) 4.0 9.3

CPI in Cisplatin Refractory Disease 0

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

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

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

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

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

Slide 26

13 The Cancer Genome Atlas (TCGA) Research Network

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

PDL1 as a biomarker

Overall Survival, (%) Overall Survival, (%) KEYNOTE-045: overall survival and ORR* Outcomes in All Pts Pembro Chemo mos, mos (95% CI)* 10.3 (8.0 11.8) 7.4 (6.1 8.3) ORR, % (95% CI)* 21.1 (16.4 26.5) 11.4 (7.9 15.8) CR, % 7.0 3.3 PR, % 14.1 8.1 mdor, mos (range) NR (1.6 15.6) 4.3 (1.4 15.4) Outcomes in CPS 10% Pembro Chemo mos, mos (95% CI)* 8.0 (5.0 12.3) 5.2 (4.0 7.4) ORR, % (95% CI)* 21.6 (12.9 32.7) 6.7 (2.5 13.9) CR, % 6.8 2.2 PR, % 14.9 4.4 mdor, mos (range) -- -- Pembro Chemo 100 Overall Survival: Total 1 100 Overall Survival: CPS 10% 2 90 90 80 Pembro 80 Pembro 70 Chemo 70 Chemo 60 60 50 50 40 40 30 30 20 20 10 10 HR (95% CI): 0.73 (0.59 0.91), P=0.002 0 0 HR (95% CI): 0.57 (0.37 0.88), P=0.0048 3 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) No. at Risk 270 226 194 169 147 131 87 54 27 13 4 0 0 272 232 171 138 109 89 55 27 14 3 0 0 0 Adapted from Bellmunt et al, 2017. No. at Risk Pembro 74 Chemo 90 Time (months) 60 51 42 35 31 18 12 7 3 0 0 0 76 51 36 28 24 16 8 4 1 0 0 0 Adapted from Bellmunt et al, 2016. 16 *Confirmed ORR and OS were assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: September 7, 2016. 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;376:1015-1026. 2. Bellmunt J et al. Oral presentation at SITC 2016.

Imvigor 211- Failed to meet endpoint in PDL1 enriched population

Beyond PDL1 as a biomarker

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

Overall Survival (Probability) Overall Survival (Probability) Checkmate 275: OVERALL SURVIVAL BY tumor PD-L1 EXPRESSION AND TMB in 2L Bladder 1.00 0.75 Overall Survival in <1% PD-L1 Subgroup 1 TMB tertile low TMB tertile medium TMB tertile high Shading = 95% CI 1.00 0.75 Overall Survival in 1% PD-L1 Subgroup 1 TMB tertile low TMB tertile medium TMB tertile high Shading = 95% CI 0.50 0.50 0.25 0.25 0 0 3 6 9 12 15 No. at Risk Time (months) Low 25 14 8 7 1 1 Medium 21 14 9 9 5 0 High 23 20 14 13 9 0 0 0 3 6 9 12 15 No. at Risk Low 21 17 12 Time (months) 10 4 0 Medium 25 20 16 15 5 0 High 24 18 15 13 6 2 Adapted from Galsky et al 2017. 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 2017. 848PD. 2. Sharma P et al. Lancet Oncol. 2017;18:312-322. 21

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 = 270 20.0 2.00 (1.87 2.63) TMB evaluable n = 139 20.1 2.00 (1.84 2.86) 8.57 (6.05 11.27) 7.23 (5.49 11.43) <1%, n = 146 15.8 1.87 (1.77 2.04) 5.95 (4.37 8.08) 1%, n = 124 25.0 3.53 (1.94 3.71) 11.63 (9.10 NR) <1%, n = 69 17.4 1.87 (1.68 2.20) 5.68 (4.17 11.30) 1%, n = 70 22.9 2.30 (1.87 3.71) 10.28 (5.85 NR) TMB low n = 46 10.9 1.91 (1.77 3.12) 5.72 (3.61 11.27) <1%, n = 25 0 1.77 (1.64 2.10) 4.96 (2.76 11.27) 1%, n = 21 23.8 3.12 (1.87 5.72) 8.57 (3.61 NR) TMB medium n = 46 TMB high n = 47 17.4 1.87 (1.68 2.30) 9.66 (4.50 NR) 31.9 3.02 (1.84 7.20) 11.63 (5.72 NR) <1%, n = 21 23.8 1.77 (1.41 3.75) 4.53 (2.20 NR) 1%, n = 25 12.0 1.94 (1.61 3.45) 11.30 (5.49 NR) <1%, n = 23 30.4 3.02 (1.71 NR) NR (4.17 NR) 1%, n = 24 33.3 3.52 (1.74 NR) 10.60 (4.60 NR) a ORR based on blinded independent review committee assessment 22

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

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

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