Welcome and Introductions

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1 Welcome and Introductions Ashish M. Kamat, MD, MBBS, FACS Professor of Urologic Oncology Wayne B. Duddlesten Professor of Cancer Research President, International Bladder Cancer Group (IBCG) University of Texas, MD Anderson Cancer Center Houston, TX

2 Evolution of Systemic Therapy for Urothelial Cancer Publication Agency Action BCG 20 MVAC (Ph II) 1 Paclitaxel (Ph II) 2 Docetaxel (Ph II) 4 Gemcitabine + Cisplatin (Ph III) 5 HD-MVAC (Ph III) 6 Gemcitabine + Paclitaxel (Ph II) 7 Vinflunine (Ph III) 9 Gemcitabine + Carboplatin / MCaVi (Ph III) 11 Gemcitabine + Cisplatin + Paclitaxel (Ph III) Gemcitabine authorisation in UK (Oct 26, '95) 3 Gemcitabine EMA harmonisation (Sep 23, '08) 8 Vinflunine EMA approval (Sep 21, '09) 10 Durvalumab FDA breakthrough designation (Feb 17, 2016) 15 Atezolizumab (Ph II) 13 Durvalumab (Ph I/II) 14 Avelumab (Ph I) 17 Nivolumab (Ph II) 18 Pembrolizumab (Ph I/II) Atezolizumab FDA approval (May 18, 2016) 16 Nivolumab FDA approval (Feb 2, 2017) 16 Atezolizumab FDA approval 1st line cis-inelig (Apr 16, 2017) 16 Durvalumab FDA approval (May 1, 2017) 16 Avelumab FDA approval (May 9, 2017) 16 Pembro FDA approval (May 18, 2017) 16 1 Sternberg CN, et al. Cancer. 1989; 2 Roth BJ, et al. J Clin Oncol. 1994; McCaffrey JA, et al. J Clin Oncol. 1997; 5 Von der Maase H, et al. J Clin Oncol. 2000; 6 Sternberg CN, et al. J Clin Oncol. 2001; 7 Meluch AA, et al. J Clin Oncol. 2001; 8 EMA. EMEA/CHMP/512295/2008; ( 9 Bellmunt J, et al. J Clin Oncol. 2009; 10 EMA. EMEA/H/C/000983; 2012 ( 11 De Santis M, et al. J Clin Oncol. 2009; 12 Bellmunt J, et al. J Clin Oncol. 2012; 13 Rosenberg JE, et al. Lancet. 2016; 14 Powles T, et al. Jama Oncol. 2017; 15 FDA.gov; 16 FDA.gov; 17 Apolo AB, et al. J Clin Oncol. 2017; 18 Sharma P, et al. Lancet Oncol. 2017; 19 Balar A, et al. Lancet Oncol. 2017; 20 Witjes JA, et al. Urol Int

3 PD-L1/PD-1 Inhibitors in Bladder Cancer Adapted from Kamat AM, et al. JITC. 2017

4 Kamat AM, et al. JITC. 2017

5 Rationale for Immunotherapy in GU Cancers Robert Dreicer, MD, MS, MACP, FASCO Associate Director for Clinical Research Deputy Director, University of Virginia Cancer Center Section Head, Medical Oncology Co-Director, Paul Mellon Urologic Cancer Institute Professor of Medicine and Urology University of Virginia School of Medicine Charlottesville, Virginia

6 Immunomodulatory Therapeutics in GU Cancers Renal Cancer HD IL2 FDA-approved Interferon alfa Nivolumab Prostate Cancer Sipuleucel T first and only FDA-approved cancer vaccine Bladder Cancer BCG Pembrolizumab, Avelumab, Atezolizumab, Durvalumab, Nivolumab FDA Prescribing Information.

7 Cancer Immunotherapy by Targeting Immune Checkpoints Cancer evades antitumor immune attacks by inhibiting recognition of cancer specific antigens by T-cells and causing dysfunction of CD8 cytotoxic T-cells Immune checkpoint blockade using immune checkpoint inhibitors, such as anti PD-1/PD-L1 mabs and anti CTLA- 4 mabs, are able to reinvigorate dysfunctional/exhausted T-cells by restoring tumor-specific immunity to eliminate cancer cells Bellmunt J, et al. Cancer Treat Rev

8 Cancer Immunotherapy by Targeting Immune Checkpoints To eradicate tumor cells and induce antitumor immunity, T-cells are able to recognize tumor antigens presented to T-cell receptors (TCRs) by antigen-presenting cells (APCs) Following binding to a TCR, a second signal (frequently called a costimulatory signal) is needed for T-cell activation This costimulatory signal comes from binding of CD28 on T-cells with its ligand B-7 on APCs Voena C, et al. Discov Med

9 Cancer Immunotherapy by Targeting Immune Checkpoints CTLA-4, an immune checkpoint (co-inhibitory receptor) is induced after T-cell activation As CTLA-4 has a higher binding affinity for B-7 ligands than CD28, and as CTLA-4 can bind to B7 and displace CD28, this leads to attenuation and termination of T-cell responses and establishment of tolerance Massari F, et al. Cancer Treat Rev

10 Chen DS, Mellman I. Immunity. 2013

11 Anti PD-1/PD-L1 Unleash Cytotoxic CD8+ T-cells T-cell receptor recognizes tumour cell Antibodies block inhibitory signal to PD-1 A separate therapy uses antibodies that bind PD-L1 on the tumour cell PD-L1 PD-L1 binds PD-1, inhibiting T-cell response Hayden EC. Nature

12 Somatic Mutational Burden is High in UBC High mutational complexity rates linked to tobacco/environmental carcinogen exposure. 1 Potential for many neoantigens to be seen as foreign by host immune system. 2 Schumacher TN, Schreiber RD. Science. 2015; 1 Lawrence MS, et al. Nature. 2013; 2 Bellmunt J et al. Cancer Treat Rev

13 Mutation Processes Affect Survival Robertson AG, et al. Cell

14 APOBEC Family of 7 cytosine deaminases: Normal function is in innate immunity as well as in RNA editing Subclass of APOBECs are capable of inducing mutations in chromosomal and mitochondrial DNA APOBEC signature mutations are likely due to APOBEC3A activity Predominant in bladder, cervical, breast, head/neck, and lung cancers Roberts SA, et al. Nat Genet. 2013; Vlachostergios and Faltas. Nat Rev Clin Oncol. 2018

15 OS by TMB Powles T, et al. Lancet

16 PD-L1 Expression in Metastatic Bladder Cancer IHC Score (N=205) PD-L1 Positivity in UBC Tumors by IHC Tumor-Infiltrating Immune Cells n (%) Tumor Cells n (%) IHC 3 18 (9) 14 (7) IHC 2 37 (18) 8 (4) IHC 1 89 (43) 37 (18) IHC 0 61 (30) 146 (71) Powles T, et al. Nature

17 KEYNOTE-045 Study Design (NCT ) Key Eligibility Criteria Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Transitional cell predominant PD after 1 2 lines of platinum-based chemo or recurrence within 12 mo of perioperative platinum-based therapy ECOG PS 0-2 Provision of tumor sample for biomarker assessment Stratification Factors ECOG PS (0/1 vs 2) Hemoglobin level (<10 vs 10 g/dl) Liver metastases (yes vs no) Time from last chemotherapy dose (<3 vs 3 mo) N=270 R (1:1) N=542 N=272 Pembrolizumab 200 mg IV Q3W for 2 years Paclitaxel 175 mg/m 2 Q3W OR Docetaxel 75 mg/m 2 Q3W OR Vinflunine 320 mg/m 2 Q3W Key End Points Primary: OS and PFS in total and PD-L1 CPS 10%populations Secondary: ORR and DOR in total and PD-L1 CPS 10% populations; safety in total population CPS = combined positive score. Bellmunt J, et al. N Engl J Med

18 Confirmed Objective Response and Overall Survival Rates Median Overall Survival (95% CI) Objective Response Rate (95% CI) Pembrolizumab Group (N=270) 10.3 months ( ) 21.1% ( ) Total Population Chemotherapy Group (N=272) 7.4 months ( ) 11.4% ( ) CPS 10% Population Pembrolizumab Group (N=74) 8 months ( ) 21.6% ( ) Chemotherapy Group (N=90) 5.2 months ( ) 6.7% ( ) Bellmunt J, et al. N Engl J Med

19 Hurst CD, et al. Nat Rev Clin Oncol. 2018; Robertson AG, et al. Cell

20 Optimizing Intravesical Immunotherapy Setting the Stage for Systemic Immunotherapy Ashish M. Kamat, MD, MBBS, FACS Professor of Urologic Oncology Wayne B. Duddlesten Professor of Cancer Research President, International Bladder Cancer Group (IBCG) University of Texas, MD Anderson Cancer Center Houston, TX

21 Why is this important? BCG is the ORIGINAL ~ 1.2 Million Doses of BCG Used Globally for Bladder Cancer Böhle A, Brandau S. J Urol

22 We discovered a single case of comprehensive compliance out of 4,790 eligible patients. We did not anticipate that the considerable discordance between established guidelines and routine practice would yield a single case to report. Moreover, those who received at minimum 4 cystoscopies, 4 cytologies and initiation of BCG within 90 days of diagnosis had improved survival when compared with those who did not. Chamie K, et al. Cancer

23 Kamat AM, et al. Eur Urol

24 Myth #1 BCG does not reduce progression rates (only reduces recurrences)

25 Intravesical BCG Progression All Studies With Maintenance Analysis of Progression in 20 Controlled Trials Study Publ Year Author and Group Events / Patients No BCG BCG Statistics (O-E) Var. (BCG OR & CI : No BCG) 1-OR % ± SD 1991 Pagano (Padova) 11 / 63 3 / Badalament (MSKCC) 6 / 46 6 / Lamm (SW8507) 102 / / Palou 2 / 61 3 / Rintala (Finnbl 2) 3 / 90 3 / Rintala (Finnbl 2) 4 / 40 2 / Lamm (SW8795) 24 / / Malmstrom (Sw-N) 22 / / Nogueira (CUETO) 8 / / Rintala (Finnbl 1) 2 / 58 3 / de Reijke (EORTC) 18 / / vd Meijden (EORTC) 19 / / Brosman (UCLA) 0 / 22 0 / Martinez-Pineiro 4 / / Witjes (Eur Bropir) 2 / 25 1 / Jimenez-Cruz 7 / 61 6 / Kalbe 2 / 35 0 / Kalbe 2 / 17 0 / Melekos (Patras) 7 / 99 2 / Ibrahiem (Egypt) 12 / 30 5 / Total 257 / / (14.7 %) (9.5 %) Test for heterogeneity c 2 =9.73, df=18: p= BCG No BCG better better Treatment effect: p= % ±9 reduction Sylvester RJ, et al. J Urol

26 BCG Reduces Progression Only When Maintenance Is Used Meta analysis of 24 RCT of BCG with 4,863 pts Figure 3. Forest plot of progression by BCGT maintenance. Sylvester RJ, et al. J Urol

27 Myth #2 Optimal maintenance schedule is unknown (induction alone is enough)

28 BCG Maintenance Not Created Equal Only SWOG Protocol Shows Clear Benefit Kamat AM and Porten S. Eur Urol

29 Optimal BCG Urinary IL-2 Assay Induction Re-induction de Reijke TM, et al. J Urol

30 Myth #3 BCG is only indicated for high risk disease

31 EORTC BCG Reduces Deaths from Bladder Cancer Epirubicin (n=279) BCG (n=558) Bladder Cancer Deaths 19 (6.8%) 19 (3.4%) Total (n=837) Intermediate Risk (n=497) High Risk (n=323) HR P-value HR P-value HR P-value Sylvester RJ, et al. Eur Urol, 2010.

32 Tumor Mutational Burden/Neoantigen Burden IMvigor 210 Cohort II; 315 genes Higher mutation load in responding vs non-responding patients (12.4 vs 6.4 per megabase, p <0.0001) Smoking status and TCGA subtype did not correlate with mutational burden Cohort I of IMvigor 210 Improved OS in highest quartile of TMB (>16 to <62.2 mutations per MB) vs quartiles 1 3 Estimated survival probability 75% at 1 year Improvement in OS independent of TCGA subtype; responses noted in all four subgroups; patients in the lowest 3 quartiles similar; top quartile with increased response rate and overall survival benefit;? threshold effect MB, mutational burden; TMB, tumor mutational burden. Balar AV, et al. Lancet. 2017; Rosenberg JE, et al. Lancet

33 Myth #4 Most patients cannot tolerate full course of BCG

34 BCG Is Well Tolerated EORTC Comparison of full dose vs 1/3 dose BCG for 1 year vs 3 years 1355 patients; median follow-up of 7.1 years, < 10% patients discontinued due to toxicity International IPD Survey 971 patients only 5.4% discontinued BCG maintenance due to toxicity. Oddens J, et al. Eur Urol. 2013; Witjes JA, et al. BJU Int

35 Key Fact Duration more crucial than dose (3 years vs 1 year; full dose vs 1/3 dose)

36 Oddens J, et al. Eur Urol EORTC30962 FD vs LD, 1 year vs 3 years Four groups (5-year disease free rates) 3 full dose: 64.2% 3 1/3 dose: 62.6% 1 full dose: 58.8% 1 1/3 dose: 54.5% 1 yr was inferior to 3 yrs (HR 0.75, CI: , p=0.01)

37 BCG Unresponsive NMIBC Persistent high-grade disease at 6 months cysto after ibcg + mbcg Progression of disease from Ta/Tis T1 at 3 mos cysto after ibcg alone Recurrence of HG disease while on BCG maintenance therapy Kamat AM, et al. J Clin Oncol. 2016; Lerner SP, et al. Bladder Cancer

38 Options for Intravesical Therapy after BCG

39 Valrubicin FDA approved in 1998 for BCG-refractory CIS in those who are not candidates for cystectomy CR at 6 months in 18% of patients 2-year DFS only 4% FDA Prescribing Information; Dinney CP, et al. Urol Oncol. 2013; Steinberg G, et al. J Urol

40 Mycobacterium Cell Wall-DNA Complex Reanalysis of subset that was BCG unresponsive 1 yr DFS: 35% in BCG unresponsive vs 25% overall Papillary: 61% and 50% at 1 and 2 years, respectively Li R, et al. Bladder Cancer

41 Instiladrin rad-ifn-cs-003 Phase 3 (n=135) BCGunresponsive NMIBC rad-ifn/syn3 3x10 11 vp/ml Intravesical q3m x 4 3 mo CR PI Boorjian At 12 months: 40 patients (35%) free of high-grade disease No grade 4/5 AE No treatment discontinuation due to AE Shore ND, et al. J Clin Oncol. 2017

42 Pembrolizumab in Patients With Bacillus Calmette Guérin (BCG) Unresponsive, High-Risk Non Muscle-Invasive Bladder Cancer (NMIBC): Phase 2 KEYNOTE-057 Study Ronald de Wit, 1 Ashish M. Kamat, 2 Joaquim Bellmunt, 3 Toni K. Choueiri, 4 Kijoeng Nam, 5 Maria De Santis, 6 Robert Dreicer, 7 Noah M. Hahn, 8 Rodolfo Perini, 5 Arlene Siefker-Radtke, 2 Guru Sonpavde, 9 J. Alfred Witjes, 10 Stephen Keefe, 5 Dean Bajorin 11 1 Erasmus MC Cancer Institute, Rotterdam, Netherlands; 2 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 4 Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA, USA; 5 Merck & Co., Inc., Kenilworth, NJ, USA; 6 University of Warwick, Coventry, United Kingdom; 7 University of Virginia School of Medicine, Charlottesville, VA, USA; 8 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; 9 University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA; 10 Radboud University, Nijmegen, Netherlands; 11 Memorial Sloan Kettering Cancer Center, New York, NY, USA de Wit R, et al. Ann Oncol

43 Localized UC Registration Trials NMIBC S1602 BCG-prime (TICE/Tokyo +/- SQ BCG) (n=969) 1 BCG +/- BC-819 BCG-relapsing (n=470) 1 KEYNOTE-057 Pembrolizumab BCG-unresponsive (n=260) 2 S1605 Atezolizumab BCG-unresponsive (n=148) 1 CG0070 BCG-unresponsive (n=122) 3 BC-819 BCG-unresponsive (n=120) 1 Instiladrin BCG-unresponsive (n=135) 1 Vicinium BCG-unresponsive (n=134) 1 MIBC A Cystectomy +/- Pembrolizumab (n=739) 1 IMvigor010 Cystectomy +/- Atezolizumab (n=700) 1 POUT Nephroureterectomy +/- Adjuvant Chemo (n=345) 1 CheckMate274 Cystectomy +/- Nivolumab (n=640) 1 Q1 Q2 Q3 Q Q1 Q2 Q3 Q Q1 Q2 Q3 Q Q1 Q2 Q3 Q Q1 Q2 Q3 Q Q1 Q2 Q3 Q Slide from Dr. Noah Hahn, Johns Hopkins University, 2017; dewit R, et al. Ann Oncol. 2016; 3 Packiam VT, et al. Urol Oncol. 2017;

44 Systemic Immunotherapy in Urothelial Cancer Where are We Now and Where are We Going? Arjun Balar, MD Director of Genitourinary Medical Oncology Program NYU Langone Medical Center New York, New York

45 Bladder Cancer Therapeutic Landscape Ta/T1/Tis Non Muscle-Invasive Bladder Cancer (NMIBC) TURBT/Intravesical BCG 70% 80% Normal Urothelium 10% 15% T2-T4 Muscle-Invasive Bladder Cancer (MIBC) Radical cystectomy; <25% get adjuvant/ neoadjuvant (Gem/Cis) Funt SA, et al. Nat Rev Clin Oncol. 2017; Kamat AM, et al. Lancet % 15% First-line Metastatic Gem/Cis or MVAC are SOC in US; Gem/Carbo or Atezolizumab or Pembrolizumab for Cis-ineligible (50%) Second-line Metastatic Avelumab, Atezolizumab, Durvalumab, Nivolumab, Pembrolizumab ORR 15% 19.6% mos: mo Taxanes, gemcitabine, pemetrexed, vinflunine (EU) ORR: 10% mos: 7 9 mo

46 T-cell Activation, Proliferation, and Function are Controlled by Multiple Agonist and Antagonist Signals 1 Co-stimulation via CD28 ligation transduces T-cell activating signals 2 CTLA-4 ligation on activated T-cells down-regulates T-cell responses 3 T-cell function in tissue is subject to feedback inhibition T-cell activation T-cell proliferative block T-cell activation T-cell functional block CTLA-4 T-cell T-cell T-cell PD-1 TCR T-cell TCR PD-1 TCR MHC CD28 B7 Cytokines TCR MHC CD28 CTLA-4 B7 MHC IFNγ MHC PD-L1 APC APC Tumor PD-L1 Tumor or immune cell Adapted from Melero I, et al. Nat Rev Cancer

47 FDA Prescribing Information. Current U.S. FDA-Approved IO Agents in Cancer Anti-PD-1 Antibodies Nivolumab Pembrolizumab Anti-PD-L1 Antibodies Atezolizumab Durvalumab Avelumab Anti-CTLA-4 Antibodies Ipilimumab Very important to become familiar with these agents, as the number and breadth of cancer indications is rapidly changing

48 IMVigor210 Phase II Atezolizumab in Metastatic UC 48 IMvigor210 Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumor tissue evaluable for PD-L1 testing Cohort 1 (N=119) 1L cisplatin ineligible Cohort 2 (N=310) Platinum-treated muc Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression Atezolizumab 1200 mg IV q3w until loss of clinical benefit Co-primary endpoints: (1) Confirmed ORR by RECIST v1.1 and central IRF (2) ORR by investigator-assessed modified RECIST Key secondary endpoints: DOR, PFS, OS, safety Rosenberg JE, et al. Lancet

49 Patients With CR or PR as Best Response Efficacy Atezolizumab in Second-line muc Time to Response First Responses Median follow-up: 17.5 months (range, 0.2 to mo) Months Median time to first response was 2.1 mo Range, 1.6 to 8.3 mo Additional CRs and PRs were observed with longer follow-up 5 PR-to-CR and 2 SDto-PR conversions CR as Best Response PR as Best Response First CR/PR Treatment Discontinuation b Ongoing Response c a Per IRF RECIST v1.1 b Discontinuation symbol does not indicate timing. c No PD or death only. Data cutoff: March 14, Dreicer R, et al. ASCO Abstract

50 KEYNOTE-045 Study Design (NCT ) Key Eligibility Criteria Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Transitional cell predominant PD after 1 2 lines of platinum-based chemo or recurrence within 12 mo of perioperative platinum-based therapy ECOG PS 0-2 Provision of tumor sample for biomarker assessment N = 270 R (1:1) N = 542 N = 272 Pembrolizumab 200 mg IV Q3W for 2 years Paclitaxel 175 mg/m 2 Q3W OR Docetaxel 75 mg/m 2 Q3W OR Vinflunine 320 mg/m 2 Q3W Stratification Factors ECOG PS (0/1 vs 2) Hemoglobin level (<10 vs 10 g/dl) Liver metastases (yes vs no) Time from last chemotherapy dose (<3 vs 3 mo) Key End Points Primary: OS and PFS in total and PD-L1 CPS 10%populations Secondary: ORR and DOR in total and PD-L1 CPS 10% populations; safety in total population CPS = combined positive score Bellmunt J, et al. N Engl J Med

51 KEYNOTE-045 Overall Survival: Update Bellmunt J, et al. N Engl J Med. 2017; Bellmunt J, et al. ASCO Abstract 410.

52 Confirmed Objective Response and Overall Survival Rates Median Overall Survival (95% CI) Objective Response Rate (95% CI) Total Population Pembrolizumab Group (N=270) 10.3 months ( ) 21.1% ( ) Chemotherapy Group (N=272) 7.4 months ( ) 11.4% ( ) CPS >10% Population Pembrolizumab Group (N=74) 8 months ( ) 21.6% ( ) Chemotherapy Group (N=90) 5.2 months ( ) 6.7% ( ) Bellmunt J, et al. N Engl J Med

53 Checkpoint Inhibitors Approved for Use in Urothelial Carcinoma Setting Antibody (Study) N ORR Median OS Atezolizumab 1 (Imvigor210, Cohort 2) % 7.9 months Platinumpretreated Nivolumab 2 (CheckMate 275) Durvalumab 3 (Study 1108) Avelumab 4 (JAVELIN Solid Tumor) % 8.74 months % 18.2 months % 8.2 months a Pembrolizumab arm Pembrolizumab 5 (KEYNOTE-045 [Ph 3]) 270 a 21% 10.3 months 1 Rosenberg JE, et al. Lancet. 2016; 2 Sharma P, et al. Lancet Oncol. 2017; 3 Powles T, et al. JAMA Oncol. 2017; 4 Apolo AB, et al. ESMO Abstract 856P; 5 Bajorin DF, et al. ASCO Abstract 4501.

54 Cisplatin-ineligible Patients with Muscle-invasive and Metastatic Urothelial Cancer Cisplatin improves survival (including some cures), however 50% 70% of patients ineligible due to comorbidities PS and Renal Dysfunction Neuropathy/Hearing Loss Heart Failure Cisplatin-ineligible Gem/Carbo (if chemo eligible) Outcomes are very poor 20% 40% or more never treated 1 Median OS: 9 months EORTC Gemcitabine and Carboplatin vs M-CAVI 2 1 Sonpavde G, et al. Clin Genitourin Cancer. 2014; 2 De Santis M, et al. J Clin Oncol

55 First-line Atezolizumab in muc IMvigor210 Study: Cohort 1 IMvigor210 Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumor tissue evaluable for PD-L1 testing Cohort 1 (N=119) 1L cisplatin ineligible Cohort 2 Platinum-treated muc Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression Atezolizumab 1200 mg IV q3w until loss of clinical benefit Cohort 1 specific inclusion criteria No prior treatment for muc (> 12 mo since perioperative chemo) ECOG PS 0-2 Cisplatin ineligibility 1 based on 1 of the following: Renal impairment: GFR <60 and >30 ml/min/1.73m 3 Grade 2 hearing loss or peripheral neuropathy ECOG PS 2 Primary endpoint Confirmed ORR: RECIST v1.1 (per central IRF) Key secondary endpoints DOR, PFS, OS, safety Balar A, et al. Lancet

56 Frontline Therapy for Cisplatin-ineligible muc Old vs New Paradigm 100 Survival, % Gemcitabine and Carboplatin 1 Atezolizumab months 8.1 months 37% ORR: 36% CR rate: 4% Time, Years GC (n=119) M-CAVI (n=119) mos: 9.3 mo. 5-year OS: ~ 0 Overall Survival mos: 15.9 mo. 5-year OS:? 57% Subgroup mos (95% CI) All (N=119) 15.9 mos (10.4, NE) IC0/1 (n=87) 19.1 mos (9.8, NE) IC2/3 (n=32) 12.3 mos (6.0, NE) Time, Months ORR: 23% CR rate: 9% 1 DeSantis M, et al. J Clin Oncol. 2012; 2 Balar A, et al. Lancet

57 KEYNOTE-052 Pembrolizumab as First-line Therapy for Cisplatin-Ineligible Advanced Urothelial Cancer Patients (N=370) Advanced urothelial cancer No prior chemotherapy for metastatic disease ECOG PS 0-2 Ineligible for cisplatin based on 1 of the following CrCl <60 ml/min ECOG PS 2 grade 2 neuropathy or hearing loss NYHA class III CHF Pembrolizumab 200 mg Q3W Primary Endpoints ORR in all patients ORR in patients with PD-L1 positive tumors Primary Endpoints Planned interim analysis in first 100 patients Determine the PD-L1 high expression cut point ORR in all patients and PD-L1 positive population Secondary Endpoints: DOR, PFS, OS, and ORR in all patients, PD-L1 positive and PD-L1 high expressing patients; safety and tolerability Balar AV, et al. Lancet Oncol

58 Baseline Characteristics Characteristic, n (%) N=370 Age, median (range), y 74 (34 94) 80 years 107 (29) Men 286 (77) ECOG performance status a 0 80 (22) (36) (42) Primary tumor location b Upper tract 69 (19) Lower tract 300 (81) Liver metastases 77 (21) Characteristic, n (%) N=370 Metastases location c Lymph node only 51 (14) Visceral disease 315 (85) Prior adjuvant/neoadjuvant platinumbased chemotherapy d 37 (10) Reasons for cisplatin ineligibility Renal dysfunction e 183 (50) ECOG performance status (32) ECOG performance status 2 and renal dysfunction 34 (9) Other reasons f 33 (9) Data cutoff: Mar 9, a 1 patient had an ECOG PS 3. b Unknown for 1 patient. c Unknown for 4 patients. d Adjuvant platinum-based chemotherapy following radical cystectomy or neoadjuvant platinum-based chemotherapy with recurrence >12 months from completion of therapy was allowed. e Renal dysfunction defined as creatinine clearance <60 ml/min. f Other reasons include class III heart failure, grade 2 peripheral neuropathy, and grade 2 hearing loss. Balar AV, et al. Lancet Oncol

59 KEYNOTE-052 Confirmed Objective Response Rate Total Population (N=370) n % (95% CI) Objective response rate % (25 34) Complete response 27 7 (5 10) Partial response (18 27) Stable disease (14 22) Progressive disease (37 47) With longer follow-up 5% increase in ORR 10 additional complete responses 9 additional partial responses O Donnell P, et al. ASCO Abstract Balar AV, et al. Lancet Oncol. 2017; O Donnell PH, et al. ASCO Abstract 4502.

60 KN052 vs IMVigor 210 Cohort 1 Key Subgroups Atezolizumab IMVIGOR 210 Cohort 1 1 Pembrolizumab KEYNOTE Subgroup ORR ORR ITT Population PD-L1+ Visceral Liver Prior Perioperative Tx Survival NR-not released; data will be presented at ASCO18 23% 28% (IC 2/3) 14% 8% 36% 15.9 months (median) 57% 12 months OS Rate 29% 51% (CPS 10%) 26% 18% NR NR NR Balar AV, et al. Lancet. 2017; O Donnell PH, et al. ASCO

61 Checkpoint Inhibitors Approved for Use in Urothelial Carcinoma 7 U.S. FDA Approvals To Date Setting Antibody Approval Status First-line (cisplatinineligible) Platinumpretreated Atezolizumab Accelerated approval granted in April 2017 Pembrolizumab Accelerated approval granted in May 2017 Atezolizumab Accelerated approval granted in May In May 2017, the subsequent phase 3 IMvigor211 trial did not meet primary endpoint of overall survival Nivolumab Accelerated approval granted in February 2017 Durvalumab Accelerated approval granted in May 2017 Avelumab Accelerated approval granted in May 2017 Pembrolizumab Full approval granted in May 2017

62 Immune Checkpoint Inhibitors in muc A Clinical Perspective Administration: intravenous over minutes, no premedications required Dosing Schedules Variable Q2, Q3, and Q4 weeks dosing Anti PD-1 vs Anti PD-L1 Disease monitoring Scans should be repeated every 8 10 weeks Responses tend to be early (first or second scan) Pseudoprogression is uncommon (<5%), and diagnosed clinically Progression on imaging is thus most likely real Consider pseudoprogression if clinical improvement (pain, appetite, energy) and stable to improved labs Necchi A, et al. Ann Oncol

63 Treatment Beyond Progression: The Atezolizumab Experience 220 patients with RECIST confirmed PD of 310 total patients included in analysis 4% ORR in 137 patients received post-pd Tx None of the 4% were initial responders Pre-PD responders maintain decrease in SLDs with continued treatment Necchi A, et al. Ann Oncol

64 Immune Checkpoint Inhibitors in muc First-line vs second-line: Unanswered questions Ideal patient population Sequencing Who should receive chemotherapy vs immunotherapy first? Chemotherapy-ineligible patients now have an option Minority respond to single agent PD-1 axis inhibition Outcomes appear binary Focus on novel combinations to improve engagement of immune system in single-agent IO refractory patients

65 Novel Combinations in Metastatic Bladder Cancer Immune Stimulating/Synergizing Combinations CTLA-4 IDO VEGF Radiation/ Chemo Targeted Therapy Combinations Exploratory FGFR3 DNA Damage Repair

66 Muscle Invasive Bladder Cancer Platform for Testing Chemoradiation added to PD-1 Blockade Chemoradiation is a standard in non-surgical candidates or those refusing radical cystectomy Radiation Immunogenic cell death Radiation may enhance T-cell priming/type 1 IFN convert noninflamed tumors and enable response to PD-1 blockade Best chemotherapy to pair is radiosensitizing at low-doses to minimize systemic toxicity Gemcitabine highly radiosensitizing at <5% of systemic dose

67 PACIFIC Immunotherapy after ChemoRT in Stage III NSCLC Antonia SJ, et al. N Engl J Med

68 PACIFIC: Efficacy Durvalumab Placebo HR/RR P Value Median PFS 16.8 mon 5.6 mon 0.52 <.0001 Time to distant metastasis or death 23.2 mon 14.6 mon 0.52 <.0001 ORR 28% 16% 1.78 <.001 Antonia SJ, et al. N Engl J Med

69 Phase II Trial of Pembrolizumab, Gemcitabine, and Hypofractionated RT as Bladder Sparing Treatment for MIBC E N R O L L M E N T Immunotherapy Pembrolizumab 200 mg IV Maximal 2 3 Wks 3 4 Wks TURBT Radiation Therapy 52 Gy over 4 weeks (5 days/week = 20 fractions) Chemotherapy Gemcitabine 27 mg/m2 IV Twice 12 Weeks Weekly Immunotherapy Pembrolizumab 200 mg IV every 3 weeks x 3 doses TUR of Tumor Bed N=54 (safety lead-in = 6) Primary Endpoint: BIDFS Participating Sites: 4 Clinicaltrials.gov. NCT

70 Phase III Randomized Trial of Concurrent Chemoradiotherapy with or without Atezolizumab in Localized MIBC Drs. Singh, Lerner, Efstathiou, et al.;

71 Current Clinical Development of Anti PD-1/L1 in NMIBC Identifier NCT WO29635 NCT NCT S1605 NCT NCT NCT Trial Phase Ib/II Safety and Pharmacology Study of Atezolizumab Alone and in Combination with BCG in High-Risk NMIBC Phase II Study of Atezolizumab in Subjects with Non-Metastatic TCC of the Bladder (PI: L Fong, UCSF) Phase II Study of Atezolizumab in Recurrent BCG-Unresponsive NMIBC (PI: P. Black) ADAPT-BLADDER: Durvalumab Monotherapy (cohort 1) and Durvalumab + BCG (cohort 2a) and EBRT (cohort 2b) in BCG-Unresponsive NMIBC (PI: N. Hahn) Phase II Durvalumab for BCG-Refractory Urothelial Carcinoma in Situ of the Bladder Phase II Nivolumab +/- BCG in BCG-Unresponsive NMIBC (CheckMate 9UT) NCT KEYNOTE 57 Phase II Study of Pembrolizumab in BCG-Refractory High-Risk NMIBC (ESMO 2018) NCT Phase I/II Marker Lesion Study Assessing Safety, Tolerability, and Efficacy of Pembrolizumab in Intermediate-Risk Recurrent NMIBC Clinicaltrials.gov;

72 Immunotherapy in UC Conclusions Pace of progress in urothelial carcinoma treatment is unprecedented Immunotherapy is a well tolerated and active treatment for our patients Reliable predictive biomarkers for clinical decision making are lacking Several other novel therapies and combinations are in clinical development in metastatic disease Potential for even greater impact in localized disease for patients refractory to standard therapies in NMIBC or refusing/ineligible for surgery in MIBC

73 As a Urologist, Where Will Checkpoint Inhibitors Fit into My Practice? Neal D. Shore, MD, FACS Medical Director, CPI Carolina Urologic Research Center Atlantic Urology Clinics Myrtle Beach, South Carolina

74 Why Should Urologists Be Interested in IO? Relevant real-world disease demographics Immediate impact on your practice IO patient selection considerations Current role Metastatic disease Platinum-refractory, ineligible Prospective future roles First-line MIBC Bladder-sparing strategies NMIBC, both BCG-naïve and unresponsive

75 Hurdles to Immunotherapy Integration in Urology 1. Do I maintain an applicable patient population? Clinical appropriateness of practice setting Demographic considerations

76 Patient Population LUGPA Experience Administering all 5 approved IO therapies since 2016 Phase II/III sequencing/combination trials, including PARPi, IDO, FGFR, and IO+IO All FDA-approved CRPC therapies since 2010 (Sip-T, Abi, Enza, Rad 223, Apa, Cabz) In 2018, 50% of LUGPA s 150 member practices (2500 physicians) have APC clinics Gateway to advanced bladder cancer (ABC) clinics?

77 Establishing an Advanced Bladder Cancer Clinic Neal D. Shore, MD, FACS President Large Urology Group Practice (LUGPA) Carolina Urologic Research Center/Atlantic Urology Clinics Myrtle Beach, South Carolina Noah M. Hahn, MD Associate Professor of Medicine, Department of Oncology and Urology Director, Medical Oncology Bladder Cancer Program Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland Ashish M. Kamat, MD, MBBS, FACS Professor of Urology; Wayne B. Duddlesten Professor in Cancer Research, Division of Surgery The University of Texas MD Anderson Cancer Center Houston, Texas Jonathan Henderson, MD Secretary Large Urology Group Practice (LUGPA) CEO, Regional Urology, LLC Shreveport, Louisiana

78 Hurdles to Immunotherapy Integration in Urology 1. Do I maintain an applicable patient population? Clinical appropriateness of practice setting Demographic considerations 2. Do I possess the required level of commitment? Educational strategies (CME) Adaptability within an evolving treatment landscape Training to monitor and manage toxicities Appropriately identify pts for approved indications as well as clinical trial candidates

79 Commitment The Integral Role of Education Continuing Medical Education (CME) Imperative for practice adaptability Central impetus for therapeutic advancement Many resources: AUA, ASCO GU, BCAN, LUGPA, SUO Web-based training: Role of Immune Checkpoint Inhibitors in Advanced or Metastatic Bladder Cancer: A Urologists Perspective embedded-media html Innovative Delivery Formats Multi-disciplinary events Integration of urology, medical oncology, and radiation oncology Novel Approaches LUGPA On-site Bladder Cancer Academy (BCA)

80 Bladder Cancer Academy (BCA) Inaugural academy: June 2017; Chicago, IL Educational symposia: focused on diagnosis and therapeutic management of bladder and kidney cancer 50 LUGPA members & 50 Urology/MedOncology Fellows, alongside international expert faculty Urologists/Medical Oncologists 2 nd Bladder Cancer Academy: March 1-3, 2018; St Louis, MO

81 2017 LUGPA CME Program Updates for Optimizing GU Oncology Cancer Clinics of Excellence

82 LUGPA OnSite New in 2018, LUGPA will organize and conduct educational programs at member practices Expert presentations on topics such as: Advanced Cancer Treatment for Bladder Prostate Kidney OPTIONAL two-hour CME COURSE on one of the Organ-Targeted Therapy Cancer Topics Management Hot Topics Group Culture and decision making How to expand service lines Physician Compensation Expanding the use of NPs and PAs better physician workflow Physician and Administrator leadership development

83 Hurdles to Immunotherapy Integration in Urology 1. Do I maintain an applicable patient population? Clinical appropriateness of practice setting Demographic considerations 2. Do I possess the required level of commitment? Educational strategies (CME) Adaptability within an evolving treatment landscape Training to monitor and manage toxicities Appropriately identify pts for approved indications as well as clinical trial candidates 3. Do I have access to necessary tools and resources? Staffing/administration Billing and reimbursement concerns Medico-legal issues

84 Resources Administrative / Nursing Roles Administration and nursing teams must work closely together to develop protocols (SOPs) for the administration of immunotherapeutics Administrative team members can also provide resources to patients who are unable to afford treatment Patient assistance programs are available for all of the previously mentioned therapies through the drug manufacturer and independent assistance foundations Consider clinical trials

85 What Must I Know about Immune-related Adverse Events in Urology Practice? Robert Dreicer, MD, MS, MACP, FASCO Associate Director for Clinical Research Deputy Director, University of Virginia Cancer Center Section Head, Medical Oncology Co-Director, Paul Mellon Urologic Cancer Institute Professor of Medicine and Urology University of Virginia School of Medicine Charlottesville, Virginia

86 Current Status IO Therapy In Urothelial/Renal Cancer Urothelial Front-line cisplatin ineligible (CPI standard of care) Post platinum (CPI standard of care) CTLA4 + CPI (investigational) Renal Front-line intermediate/poor risk clear cell (ipilimumab + nivolumab pending FDA approval) Post TKI (CPI standard of care) FDA Prescribing Information; Clinicaltrials.gov.

87 Toxicity of Immune Checkpoint Blockade Major side effects of immunotherapy are related to development of autoimmunity Immune-related adverse events (iraes) may occur in any organ system Certain events may be life threatening or fatal Prompt recognition of potentially severe iraes improves outcomes Combining checkpoint inhibitors with agents such as CTLA4 inhibitors significantly increases iraes FDA Prescribing Information; Teply BA, Lipson EJ. Oncology

88 Postow M, et al. NEJM. 2018; FDA Prescribing Info. Organs Affected by Checkpoint Blockade Thyroiditis 0.6-9% (All Grades) <1% (Grades 3-4) Rash 11-20% (All Grades) % (Grades 3-4) Pneumonitis % (All Grades) % (Grades 3-4) UTI 15-22% (All Grades) 4-9% (Grades 3-4) Diarrhea 12-25% (All Grades) % (Grades 3-4)

89 Puzanov I, et al. J Immunother Cancer. 2017; Michot JM, et al. Eur J Cancer

90 Clinical Management of Immune-related Events in Patient Management Assessment of IO toxicity in the context of disease management The treatment should not be worse than the disease Steroids used to manage IO toxicity does not impact on therapeutic dose Role of comorbid disease Pneumonitis in the setting of COPD Significant response to IO therapy vs toxicity Winer A, et al. J Thorac Dis

91 Management Beyond Steroids Anti-TNFα chimeric Mab (infliximab) binds circulating TNFα Indications include ankylosing spondylitis, Crohn s, psoriasis/psoriatic arthritis, rheumatoid arthritis, ulcerative colitis Dosing Standard (rheumatologic conditions): 5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks for maintenance For iraes, 5 mg/kg IV x 1 or 2 doses often is sufficient to control symptoms Naidoo J, et al. Ann Oncol. 2015; Naidoo J, et al. Ann Oncol. 2016; FDA Prescribing Information.

92 Immune-Related Adverse Events Caveats Immune checkpoint inhibitor therapy is NOT chemotherapy Patient education, close follow-up MANDATORY Education of our colleagues (i.e., Hospital Medicine, Family Medicine, ER, and Internal Medicine) is critical Colitis Combination IO therapies has potential to improve outcomes, but with a potential price in toxicity Implications for an older patient population Need better coordination between urology/med oncology as IO moves into earlier disease stages

93 Practical Implications of Checkpoint Inhibitors in Urothelial Cancer: Case Discussions Neal D. Shore, MD, FACS, Moderator, with Faculty Panel

94 Case 1 A 59-year-old female with gross hematuria 1 pack/day smoker CT urogram: normal upper tracts, bladder mass Cystoscopy: 3 cm right bladder wall tumor

95 Case 1 TURBT Complete resection Pathology: T1, high grade, lymphovascular invasion (LVI), carcinoma in situ (CIS) Base of tumor muscle, no invasion, no tumor

96 Case 1: Which of the following would be the most appropriate next step? A. Repeat TURBT B. BCG x 6 weeks, followed by maintenance C. Cystectomy

97 Case 1 Patient undergoes repeat TURBT: Persistent CIS and NO muscle invasion She receives BCG for 6 weeks. Cystoscopy and cytology at 3 months is negative She receives BCG for 3 weeks at 3 months. Cystoscopy and cytology at 6 months is negative/atypical She receives BCG for 3 weeks at 6 months. Cystoscopy at 9 months shows diffuse erythema, biopsy shows CIS

98 Case 1: What would you recommend next? A. BCG x 6 B. BCG + INF x 6 C. Valrubicin x 6 D. Clinical trial E. Cystectomy

99 Case 2 A 75-year-old male with a 45 pack-yr smoking history Intermittent gross hematuria, 6 months of progressive fatigue, loss of appetite, 20 lbs weight loss, and pelvic pain Cystoscopy: 4.5 cm sessile mass at base of the bladder and trigone CT CAP: mass seen + bilateral pelvic, retroperitoneal lymphadenopathy, + pulmonary nodules TURBT: high-grade UC invasive to muscularis propria and prostatic stroma

100 Case 2: The patient has metastatic UC to lymph nodes and lung. He presented with ECOG PS 2 and CrCl of 42 ml/min. Which of the following treatment options would you recommend for this patient? A. Gemcitabine and carboplatin B. Anti PD-1/PD-L1 antibody C. Gemcitabine and cisplatin D. Single-agent chemotherapy E. Best supportive care

101 Case 2: The pt has metastatic UC to lymph nodes and lung. He presented with ECOG PS 2 and CrCl of 53 ml/min, and has a history of rheumatoid arthritis well controlled on hydroxychloroquine. Which of the following treatment options would you recommend for this patient? A. Gemcitabine and carboplatin B. Anti PD-1/PD-L1 antibody C. Gemcitabine and cisplatin D. Single-agent chemotherapy E. Best supportive care

102 Case 3 63-year-old male with newly diagnosed metastatic urothelial cancer. He quit smoking 23 years ago, 1 pack/day x 20 years history CT CAP enlarged pelvic, RP and mediastinal lymph nodes measuring up to 4 cm 3 cm mass in the right lateral wall of the bladder A bone scan shows no evidence of osseous disease. ECOG PS is 0, and CBC and comprehensive metabolic profile are within normal limits. His estimated GFR is 80 cc/min.

103 Case 3: Which of the following treatment options would be most appropriate for this patient? A. Hospice care B. Radical cystectomy and pelvic lymph node dissection C. Paclitaxel D. Radiation E. Gemcitabine and cisplatin F. Anti PD-1/PD-L1 antibody

104 Case 4 A 79-year-old male has an initial diagnosis of T2 N0 M0 that is managed with chemoradiotherapy (5FU/mitomycin) and 6660 cgy. Six months following EBRT, surveillance imaging reveals new hepatic lesions Fine needle aspiration finds metastatic urothelial cancer. ECOG 1; creatinine is 1.4 (52 ml/min) AST/ALT, ALP, and bilirubin are all within normal limits

105 Case 4 Baseline S/P 4 doses pembrolizumab

106 Case 4 Baseline S/P 4 doses pembrolizumab

107 Case 4 Baseline S/P 4 doses pembrolizumab

108 Case 4 He presents for cycle 5 of pembrolizumab. He feels well. Liver function tests indicate an AST of 888 U/L, an ALT of 765 U/L, and a bilirubin of 1.2

109 Case 4: Which of the following would be the most appropriate next step? A. Proceed with pembrolizumab B. Start prednisone, proceed with pembrolizumab C. Start prednisone, switch to atezolizumab D. Convert therapy to carboplatin/gemcitabine E. Hospice referral F. Start prednisone