Disclosure. Astellas. Research funding. Advisory board (to institute) Roche/Genentech Astra Zeneca/Medimmune Astellas

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1 Disclosure Activity Company Research funding Advisory board (to institute) Astellas Roche/Genentech Astra Zeneca/Medimmune Astellas

2 Immunotherapy for urothelial cell carcinoma A NEW HOPE Michiel van der Heijden

3 Metastatic urothelial cell carcinoma chemotherapy Gemcitabine/Cisplatin vs MVAC (MTX/Vinblastine/Doxorubicine/Cisplatin) Vinflunine vs Best supportive care J ClinOncol; 23 (2005) J ClinOncol; 27 (2009)

4 Immunotherapy in UCC: rationale Mutation load in a range of tumor types

5 Phase Ia Study PCD4989g Clinical Activity of Atezolizumab in UCC Cohort Atezolizumab (anti-pdl1) Tumor cell T cell

6 Phase Ia Study PCD4989g Clinical Activity of Atezolizumab in UCC Cohort IHC Status on immune cells 5% 1 but < 5% < 1% IC2/3 IC1 IC0 Maximum SLD Reduction From Baseline, b % Best response by PD-L1 status immune cells * * * * * IC3 IC2 IC1 IC0 * * * *

7 Feb 2016

8 Presented By Robert Dreicer Feb 2016

9 IMVigor210 Cohort 2 Response rate per PD-L1 IHC score Median follow-up: 17.5 months

10 Atezolizumab: IMvigor211 N = 932 Inclusion criteria Advanced/unresectable or metastatic urothelial cancer PD following first-line platinum-containing regimen for metastatic or inoperable locally advanced disease 2 prior lines of systemic chemotherapy Measurable disease R Atezolizumab 1200 mg IV, q3w Paclitaxel, docetaxel, or vinflunine IV, q3w PRIMARY ENDPOINT OS

11 Pembrolizumab: KEYNOTE-045 N = 470 Inclusion criteria Advanced/unresectable or metastatic urothelial cancer PD following first-line platinum-containing regimen for metastatic or inoperable locally advanced disease 2 prior lines of systemic chemotherapy Measurable disease R Pembrolizumab 200 mg IV, q3w Paclitaxel, docetaxel, or vinflunine IV, q3w PRIMARY ENDPOINT OS PFS

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13 2012

14 IMVigor210 Cohort 1 Response rate per PD-L1 IHC score Median follow-up: 14.4 months Balar et al, ASCO 2016

15 IMVigor210 Cohort 1 Response rate Median follow-up: 14.4 months All IC2/3 IC1 IC0 ORR CR PR 24% 7% 17%

16 IMVigor210 Cohort 1 Response rate by PD-L1 IHC score Median follow-up: 14.4 months All IC2/3 IC1 IC0 ORR CR PR 24% 7% 17% 25% 6% 19%

17 IMVigor210 Cohort 1 Response rate by PD-L1 IHC score Median follow-up: 14.4 months All IC2/3 IC1 IC0 ORR 24% 25% 23% 21% CR 7% 6% 6% 8% PR 17% 19% 17% 13%

18 DANUBE (NCT ) Key eligibility First line metastatic or irresectable cisplatin-eligible/ineligible Tumor PD-L1 status (IHC) confirmed by reference laboratory is required prior to randomization R 1:1:1 Durvalumab (Anti-PD-L1) Durvalumab + Tremelimumab (anti-ctla4) SOC CT: Cisplatin/gemcitabine Carboplatin/gemcitabine

19 PD-L1 Expression, The Cancer Genome Atlas (TCGA) Subtype and Mutational Load Are Independent Predictors of Response to Atezolizumab in Metastatic Urothelial Carcinoma (muc; IMvigor210) Jonathan E. Rosenberg, 1 Daniel P. Petrylak, 2 Michiel S. van Der Heijden, 3 Andrea Necchi 4, Peter H. O Donnell, 5 Yohann Loriot, 6 Margitta Retz, 7 Jose Luis Perez-Gracia, 8 Joaquim Bellmunt, 9 Petros Grivas, 10 Richard Joseph, 11 Lawrence Fong, 12 Edward E. Kadel III, 13 Zachary Boyd, 13 Dorothee Nickles, 13 Garrett Frampton, 14 Richard Bourgon, 13 Priti Hegde, 13 Sanjeev Mariathasan 13 and Thomas Powles 15 \

20 Mutation Load by FoundationOneand Response RECIST v1.1 response responder non-responder 50 Mutation Load/MB All (n = 150) I Luminal II III Basal IV Mutation Load/MB IC0/1 IC2/3 Rosenberg et al., ASCO 2016

21 21 TCGA Subtype II Is Associated With Higher ORR n = 73 n = 52 n = 38 n = 36 RECIST v1.1 response PD SD PR CR ORR, % I II III IV Luminal Basal

22 22 TCGA Subtype T eff Luminal Basal I II III IV Papillary like Squamous Mesenchymal Response IC status TC status FGFR3 CDKN2A KRT5 KRT14 EGFR GATA3 FOXA1 ERBB2 CD8A GZMA GZMB IFNG CXCL9 CXCL10 PRF1 TBX21 Luminal I patients have low T eff gene expression

23 TCGA Subtype T eff Luminal Basal I II III IV Papillary like Squamous Mesenchymal Response IC status TC status FGFR3 CDKN2A KRT5 KRT14 EGFR GATA3 FOXA1 ERBB2 CD8A GZMA GZMB IFNG CXCL9 CXCL10 PRF1 TBX21 Luminal I patients have low T eff gene expression In Luminal II patients with disease progression, a trend toward lower baseline T eff expression was seen, compared with Luminal II responders

24 TCGA Subtype T eff Stromal Luminal Basal I II III IV Papillary like Squamous Mesenchymal Response IC status TC status FGFR3 CDKN2A KRT5 KRT14 EGFR GATA3 FOXA1 ERBB2 CD8A GZMA GZMB IFNG CXCL9 CXCL10 PRF1 TBX21 COL4A1 COL4A2 PDGFRB BGN NUAK1 Subtype II patients tended to have lower stromal gene expression

25 TCGA Subtype T eff Stromal Luminal Basal I II III IV Papillary like Squamous Mesenchymal Response IC status TC status FGFR3 CDKN2A KRT5 KRT14 EGFR GATA3 FOXA1 ERBB2 CD8A GZMA GZMB IFNG CXCL9 CXCL10 PRF1 TBX21 COL4A1 COL4A2 PDGFRB BGN NUAK1 Luminal I tumors have low T eff expression Luminal II tumors have high T eff and low stromal gene expression Basal tumors have high T eff and high stromal gene expression

26 Conclusions Anti-PD-(L)1 has activity in urothelial cell carcinoma Various agents appear equal in (small) studies Differences in response rate reflect patient populations Results Phase 3 (Atezo & Pembro) trials will follow soon First line M+: Atezolizumab 20-25% durable clinical benefit Anti-PD-(L)1 is investigated in many UCC studies. Development: Earlier stages Combinations Biomarker Research

27 Conclusions Anti-PD-(L)1 has activity in urothelial cell carcinoma Various agents appear equal in (small) studies Differences in response rate reflect patient populations Results Phase 3 (Atezo & Pembro) trials will follow soon First line M+: Atezolizumab 20-25% durable clinical benefit Anti-PD-(L)1 is investigated in many UCC studies. Development: Earlier stages Combinations Biomarker Research

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