Neoplasie uroteliali 2017 Highlights. Andrea Necchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

Transcription

1 Neoplasie uroteliali 2017 Highlights Andrea Necchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

2 Disclosures Consulting or Advisory Role: Company: Roche, Bayer, Merck & Co. Inc., Astra Zeneca Travel, Accommodations, Expenses: Company: Roche, Merck & Co. Inc., Pierre Fabre Research Funding (Institution): Company: Merck & Co. Inc., Astra Zeneca, Amgen Available from the ASCO COI website

3 Presentation topics & objectives Bladder and urinary tract tumors Review current translational data from clinical trials/retrospective studies Gain insights on the impact of the latest data and future developments of immunotherapy in UBC

4 Little progress in UBC therapeutic paradigm with the use of old pathological and clinical aids in the last 20 years Grey zone of High Risk NMIBC ± BCG-failure From 2016 White Paper of Bladder Cancer Perioperative (neoadjuvant) systemic therapy is underutilized worldwide Hall et al, Lancet, 1999; updated: J Clin Oncol 2011 Grossman et al, N Engl J Med, 2003 Burger M et al, Eur Urol 2012 Meeks JJ et al, Eur Urol 2012

5 Survival Probability Little progress in UBC therapeutic paradigm with the use of old pathological and clinical aids in the last 20 years A 1.0 Carboplatin Cisplatin P < No. pts at risk Carboplatin Cisplatin Months Necchi A et al, Eur Urol 2016

6 The salvage chemotherapy landscape VFL+BSC (N=253) BSC (N=117) No. of events No. censored (%) 16 (6.3) 2 (1.7) Median in months (95% CI) 6.9 ( ) 4.6 ( ) Hazard ratio (95% CI) 0.88 ( ) p-value a a Stratified log-rank test +2.3 months Bellmunt J et al, Ann Oncol 2013 Sonpavde G et al, J Urol 2015 Mean c-index across bootstrap samples of 0.646

7 Presented By Elizabeth Plimack at 2017 Genitourinary Cancers Symposium

8 Presented By David McConkey and Roland Seiler at 2017 Genitourinary Cancers Symposium

9 Presented By Roland Seiler at 2017 Genitourinary Cancers Symposium N=343 Discovery: 250 Validation: 93

10 Waves of CTinduced clonal tumor evolution Tumor site Time Even mutations in previously reported driver genes, including PIK3CA, KMT2D (MLL2), ATM and TP53, were not consistently shared by matched pre-ct and post-ct tumors Faltas BM et al, Nat Genet 2016

11 Genomic evolution in MIBC after neoadjuvant chemotherapy New neoantigens are detected in post-ct samples 32% of pts had gain or loss in targetable mutations Any driver of chemoresistance? Targeted drug class-2 in the adjuvant setting Targeted drug class-1 in the neoadjuvant setting Liu D et al, ASCO 2016 Jones S et al, Sci Transl Med 2015

12 Genomic Characterization of Upper Tract Urothelial Carcinoma High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB However, there were significant differences in the prevalence of several recurrently mutated genes including FGFR3, HRAS, TP53, and RB1 Sfakianos JP et al, Eur Urol 2016

13 PURE01: an open label, single-arm, phase 2 study of the anti-programmed death (PD)-1 monoclonal antibody (moab) Pembrolizumab for neoadjuvant therapy of muscleinvasive urothelial bladder carcinoma (miubc) ClinicalTrials.gov NCT

14 2 nd line and beyond 1 st line Future development of PD-L1/PD-1 inhibitors in UC Non-muscleinvasive bladder cancer Muscle-invasive bladder cancer Metastatic urothelial cancer Low grade High grade Neoadjuvant Adjuvant Cisplatin-eligible Cisplatin-ineligible In development Pembrolizumab + BCG Atezolizumab Pembro + Chemo Pembrolizumab Atezolizumab Ph III Nivolumab Ph III Durvalumab + Tremelimumab (Ph III) Pembro+GC Atezo+GC Pembrolizumab±CarboG Atezolizumab±CarboG Pembrolizumab Atezolizumab Trimodality Pembrolizumab + RT (Atezolizumab+RT) Maintenance Avelumab (Ph III) Pembrolizumab BCGunresponsive Platinumrefractory Modified from Bellmunt J et al, ESMO 2016 Immuno-Oncology Combinations Personalized medicine

15 Phase II IMvigor210 Study Design and Objectives Inoperable locally advanced or metastatic UC Predominantly UC histology Tumor tissue evaluable for PD-L1 testing a 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 Key cohort 1 inclusion criteria: No prior treatment for muc (> 12 months since perioperative chemotherapy) ECOG PS 0-2 Cisplatin ineligibility based on 1 of the following: 1 GFR < 60 and > 30 ml/min (Cockcroft- Gault), Grade 2 hearing loss (25 db at 2 contiguous frequencies) or peripheral neuropathy, ECOG PS 2 Cohort 1 specific endpoints: Primary: confirmed ORR per RECIST v1.1 (central IRF) Key secondary: DOR, OS, safety Balar AV et al, Lancet 2017

16 IMvigor210 Study (Cohort 1): OS by PD-L1 Status in Cisplatin- Ineligible Patients Noteworthy survival was observed in octogenarians, those with SD as best RECIST v1.1 response and patients with poor prognostic factors NE, not estimable. Patients at risk of an event are displayed at indicated time points below plot. Censored values are indicated with a plus (+) symbol. Data cut-off: 4 July Balar AV et al, Lancet 2017

17 Phase 2 KEYNOTE-052 Study Design: Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced/Metastatic Urothelial Cancer Results from an interim analysis of the first 100 patients were presented at the 2016 ESMO. Results from the total study population (N = 370) are presented herein (from GU- ASCO 2017 poster) Patients (N = 350) 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 The primary end point was confirmed ORR per RECIST v1.1 by central imaging vendor review Secondary efficacy end points included duration of response, OS, and progression-free survival (PFS) per RECIST v1.1 Safety and tolerability and determination of a cut point for PD-L1 expression were secondary objectives Efficacy and safety were assessed in all patients who received 1 dose of pembrolizumab Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium

18 KEYNOTE-052: ORR by PD-L1 Status Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium

19 Ongoing trials in the first-line metastatic setting MK (Pembro vs Pembro+CT* vs CT) IMvigor130 (Atezo vs Atezo+CT* vs CT) DANUBE (Durva vs Durva+Treme vs CT*) *Consisting of Cis or Carboplatin and Gemcitabine

20 Single-Arm Trials of Salvage Immunotherapy Targeting the PD-1/PD-L1 pathway Pre ASCO-GU17 landscape Phase N Population ORR 1-year OS Atezolizumab IMvigor All comers PCD4989g 2 1a 48 PD-L1 + Avelumab JAVELIN 3 1b 109 All comers Not reported Durvalumab Study PD-L1 + Not reported Nivolumab CheckMate /2 78 All comers CheckMate All comers Not reported Pembrolizumab KEYNOTE b 33 PD-L * % (95% CI) % (95% CI) *Historical ORR for chemotherapy Historical 1-y OS for chemotherapy Loriot Y et al. ESMO 2016; Abstr 783P. 2. Petrylak DP et al. ASCO Patel MR et al. ESMO 2016; Abstr. 777PD. 4. Massard C et al. J Clin Oncol 2016;34: Sharma P et al. Lancet Oncol 2016;217: Galsky MD et al. Lancet Oncol 2017;doi: 7. Plimack ER et al. Lancet Oncol 2017;doi: /S (17) Bellmunt J et al. J Clin Oncol 2009;27: Sonpavde G et al. Lancet Oncol 2010;11: Choueiri TK et al. J Clin Oncol 2012;30: Agarwal N et al. Clin Genitourin Cancer 2014;12:

21 Updated Durvalumab results from MEDI1108 trial Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium

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23 OS, % OS, % Overall Survival Events, n HR (95% CI) P Events, n HR (95% CI) P Pembro Chemo 179 ( ) Pembro ( ) Chemo Median (95% CI) 10.3 mo ( ) 7.4 mo ( ) Median (95% CI) 8.0 mo ( ) 5.2 mo ( ) % 30.7% No. at risk Time, months Total Population No. at risk 39.8% 26.9% Time, months CPS 10% Population Data cutoff date: Sep 7, 2016.

24 ORR, % (95% CI) ORR, % (95% CI) Confirmed Objective Response Rate Total Population CPS 10% Population Δ9.6% P = CR PR % % % 14.1% 11.4% 3.3% 8.1% % 14.9% 6.7% 2.2% 4.4% 0 Pembrolizumab (N = 270) Chemotherapy (N = 272) 0 Pembrolizumab (N = 74) Chemotherapy (N = 90) No alpha allocated to the comparison of ORR in the CPS 10% population. Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: Sep 7, 2016.

25 Meta-Analysis of OS in Studies of Second-Line Immunotherapy For Advanced Urothelial Carcinoma a Nivolumab Phase 2, Galsky, 2016 [1] Atezolizumab Phase 2, Rosenberg, 2016 [2] Nivolumab Phase 1-2, Sharma, 2016 [3] Pembrolizumab Phase 3, ECCO [6.05, not reached] 7.90 [6.58, 9.22] 9.70 [5.34, 14.06] [8.44, 12.16] RE Model 8.96 [7.54, 10.37] Necchi A, et al. Poster Board #: G5 Abstract ID: 341 Median OS, months a Pembrolizumab phase 1 study by Plimack et al (Lancet Oncol 2017;doi: /S (17) ) not included because only patients with PD-L1 + tumors were enrolled. 1. Galsky MD et al. Lancet Oncol 2017;doi: 2. Rosenberg JE et al. Lancet 2016;387: Sharma P et al. Lancet Oncol 2016;17:

26 Presented By Vaughn DJ at 2017 Genitourinary Cancers Symposium

27 Patient Characteristics N = 48 Age Sex Median 58 Range (35-77) Male 41 Female 7 Tumor type Urothelial carcinoma 19 Castration-resistant prostate cancer 9 Urachal adenocarcinoma 4 Germ cell tumor 4 Penile 4 Squamous cell carcinoma of the bladder or urethra 2 Renal cell carcinoma clear cell 2 Renal cell carcinoma sarcomatoid 2 Trophoblastic 1 Sertoli Cell carcinoma 1 Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium

28 Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium

29 Adverse Event CaboNivo N=30 CaboNivoIpi N=18 Any Grade* N (%) Grade 3 N (%) Grade 4 N (%) Any Grade N (%) Grade 3 N (%) Grade 4 N (%) Alanine Aminotransferase Increased 20 (67) (44) 1 (6) 0 Fatigue 19 (63) 2 (7) 0 13 (72) 2 (13) 0 Diarrhea 18 (60) 2 (7) 0 11 (61) 0 0 Hypothyroidism 17 (57) (28) 0 0 Aspartate aminotransferase increased 15 (50) (22) 0 0 Anorexia 14 (47) (61) 1 (6) 0 Hoarseness 12 (40) (22) 0 0 Mucositis 12 (40) (33) 0 0 Hypocalcemia 12 (40) (22) 0 0 Hyponatremia 11 (37) 1 (3) 0 5 (28) 2 (13) 0 Hypophosphatemia 11 (37) 4 (13) 0 8 (44) 3 (17) 0 Palmar plantar erythrodysesthesia 11 (37) (28) 0 0 Thrombocytopenia 11 (37) 1 (3) 1 (3) 6 (33) 0 0 Dysgeusia 9 (30) (44) 0 0 Hypoalbuminemia 9 (30) (17) 0 0 Myalgia 9 (30) (17) 0 0 Nausea 9 (30) (39) 2 (13) 0 Rash 8 (27) (33) 1 (6) 0 Neutropenia 8 (27) 5 (17) 0 4 (22) 0 0 Dry mouth 7 (23) (33) 0 0 Dry skin 7 (23) (22) 0 0 Vomiting 7 (23) 1 (3) 0 4 (22) 0 0 Hypertension 7 (23) 3 (10) 0 3 (17) 3 (17) 0 Hypomagnesemia 7 (23) (11) 0 0 Proteinuria 7 (23) 1 (3) 0 2 (11) 0 0 Headache 7 (23) Anemia 6 (20) 1 (3) 0 4 (22) 0 0 Weight loss 6 (20) (28) 0 0 Abdominal Pain 5 (17) (17) 0 0 Hypokalemia 5 (17) (22) 0 0 Lipase increase 5 (17) 2 (7) 2 (7) 8 (44) 2 (13) 1 (6) Cough 3 (10) (28) 0 0 Dehydration 3 (10) 2 (7) 0 3 (17) 0 0 Hyperthyroidism 3 (10) 1 (3) 0 2 (11) 0 0 Amylase increase 4 (13) 1 (3) 0 1 (6) 0 0 Thromboembolic event 1 (3) 1 (3) Colitis (6) 1 (6) 0 Aseptic meningitis 1 (3) 1 (3) *Reported in at least 10% of patients or > grade 2; Rash includes abdomen/chest rash, acneiform, and maculo-papular Apolo AB, et al. GU ASCO 2017 abstract 293

30 Sharma P et al, SITC 2016

31 Sharma P et al, SITC 2016

32 Sharma P et al, SITC 2016

33 Overall Survival (Probability) Ipilimumab/Nivolumab in muc: Overall Survival Median OS, months (95% CI) NIVO 1 + IPI (4.5 NR) NIVO 3 + IPI ( ) NIVO 1 + IPI NIVO 3 + IPI No. at risk Months NIVO 1 + IPI NIVO 3 + IPI Sharma P et al, SITC 2016

34 What is needed by the bladder cancer patient community The case of second-line therapy Vinflunine. Atezolizumab in 1L and 2L, Nivolumab 2L (Durvalumab and Avelumab granted breakthrough therapy designation) Pembrolizumab

35 @AndreaNecchi