Urothelial Carcinoma Highlights

Transcription

1 Urothelial Carcinoma Highlights Andrea Necchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano European Association of Urology Research Foundation

2 Disclosures Consulting or Advisory Role: Company: Roche, Bayer, Merck & Co. Inc., Astra Zeneca, Pfizer, Astellas/Seattle Genetics, Clovis Oncology Travel, Accommodations, Expenses: Company: Roche, Merck & Co. Inc., Pierre Fabre, PeerVoice Research Funding (Institution): Company: Merck & Co. Inc., Astra Zeneca, Amgen

3 Presentation objectives Review updated anti-pdl1/pd1 trial data and the design of trials in non-metastatic UBC Gain insights on the impact of the data in the future treatment landscape of GU cancers Review emerging novel biomarkers Powles T, Necchi A, Rosen G, et al. CGUC 2017

4 1L metastatic setting

5 Phase II IMvigor210 & KN052 Study Design and Objectives Inoperable locally advanced or metastatic UC 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 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 Endpoints: Primary: confirmed ORR per RECIST v1.1 (central IRF) Key secondary: DOR, OS, safety Balar AV et al, Lancet Jan 7;389(10064):67-76 Balar AV, et al. Lancet Oncol 2017; /S (17)

6 How Emerging Clinical Data Will Impact the European/US Treatment Algorithm for Metastatic Urothelial Cancer FIRST LINE 1,2 Eligible for cisplatin? Yes PS 0-1 GFR 60 ml/min Standard chemotherapy: GC, MVAC, HD-MVAC, PCG PS 2 or GFR <60 ml/min Combination chemotherapy: Carboplatin-based Immune checkpoint inhibitor 3 No PS 2 and GFR <60 ml/min NO combination chemotherapy: Monotherapy, BSC Immune checkpoint inhibitor 3 Consider clinical trial of new or more tolerable therapy 3 SECOND LINE 1,2 PS 0-1 Consider immune checkpoint inhibitor therapy 3 PS 2 Standard second-line chemotherapy BSC Consider clinical trial BSC: best supportive care; GFR: glomerular filtration rate; (HD-)MVAC: (high-dose) methotrexate, vinblastine, doxorubicin, cisplatin; PCG: paclitaxel, cisplatin, gemcitabine. 1. Witjes JA et al. Eur Urol. 2017;71: Witjes JA et al. -Muscle-invasive-and-Metastatic-Bladder-Cancer-Guidelines-2016.pdf. Published Accessed March 3, National Comprehensive Cancer Network (NCCN). Bladder Cancer (Version ). Accessed February 9, 2017.

7 Recruiting Clinical Trials: First-Line Metastatic Bladder Cancer Study Agent Phase and Type Pembrolizumab ± MK / KEYNOTE chemotherapy a vs chemotherapy IMvigor130 2 Atezolizumab ± chemotherapy a DANUBE 3 CheckMate901 4 Galsky MD et al. TPS 539 vs chemotherapy 3 Randomised, controlled 3 Randomised, controlled Durvalumab ± tremelimumab vs SOC chemotherapy 3 Randomised, open label Nivolumab+Ipilimumab vs chemotherapy 3 Randomised, open label Primary Endpoint a GEM-CIS or GEM-carboplatin. SOC: standard of care. 1. ClinicalTrials.gov Identifier: NCT Accessed February 27, ClinicalTrials.gov Identifier: NCT Accessed February 27, ClinicalTrials.gov Identifier: NCT Accessed September 14, ClinicalTrials.gov Identifier: NCT Accessed September 14, 2017 PFS, OS PFS, OS, % with AEs PFS, OS PFS, OS

8 Necchi A, et al. Abstr. #426

9 Summary of the evidences with the use of ICI in first-line therapy Atezolizumab and pembrolizumab are well-tolerated and durable responses are seen in UC patients who are not eligible for cisplatin-based chemotherapy (US-FDA & EMA Approved). However randomised data on the benefit in this setting does not exist If clinical trials are not available and registration permits, treatment with atezolizumab or pembrolizumab could be considered for cisplatin-ineligible first-line patients In candidates for cisplatin-based therapy, there is currently no data to support use of checkpoint inhibitors as first-line treatment outside of clinical trials Currently, there is no evidence supporting the PD-L1 biomarker for selecting patients for ICI therapy in chemotherapy-naive patients SUGGESTION FROM ASCO-GU 2018: Early shift toward second-line immunotherapy or novel agents is recommended (do not administer >4 cycles of platinum-chemo)

10 2L metastatic setting

11 Outcomes of IMvigor211 - Efficacy US FDA and EMA approval for platinum-treated, advanced UC Powles T. et al, Lancet 2017 & GU-ASCO 2018

12 Outcomes of IMvigor211 - Biomarkers Presented By Thomas Powles at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

13 Outcomes of IMvigor211 - Biomarkers Presented By Thomas Powles at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

14 Outcomes of IMvigor211 - Biomarkers Presented By Thomas Powles at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

15 Mariathasan S, et al. Nature 2018

16 Overall Survival, % KN-045: Overall Survival: Total % 29.8% 27.0% 14.3% No. at risk Time, Months Pembro Chemo Median (95% CI): 10.3 months ( ) 7.3 months ( ) Bellmunt J, et al. Abstr. #410

17 Progression Free Survival, % KN Progression-Free Survival: Total CheckMate-032 PFS Update % 9.5% 12.5% 2.5% Median PFS (95% CI): 3.3 months ( ) 2.1 months ( ) 0 Pembro Chemo Time, Months Sharma P, et al. Abstr. #414 Bellmunt J, et al. Abstr. #410

18 Comparison of main outcomes from the Phase 3 trials IMVIGOR211 1 KEYNOTE452 2 Study drug atezolizumab pembrolizumab Number of patients receiving study drug PS 2 0 1% Bladder primary 69% 86% Liver metastasis 30% 34% Patients with 2 or more risk factors 23% 41% Visceral metastasis 77% 89% 2 or more previous lines of therapy 19% 20% Vinflunine use in control arm 54% 34% PD-L1 positive patients 25% 40% Response rate in ITT 13% 21% OS is PD-L1 postives 0.87 (95%CI: ) 0.59 (95%CI: ) Response rates in PD-L1 positives 23% 22% Overall survival in all comers 0.85 (95% CI: (95%CI: ) 1. Powles T. et al, ASCO-GU 2018; 2. Bellmunt J, et al. ASCO-GU 2018

19 New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab Presented By Gregory Pond at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

20 Pond GR, et al. Abstr. #451

21 Summary 2L Findings confirm that clinical benefit with ICI use is maintained at long term Clinical prognostic factor models derived from noncomparative trials did support the benefit from ICI therapy compared to standard chemotherapy Results from translational studies will likely provide the basis for understanding patient outcome in this setting

22 Ongoing immunotherapy trials as proofof-concepts in early-stage disease

23 Necchi A, et al. Abstr. #TPS533 Necchi A, et al. Abstr. #TPS534 Gupta S, et al. Abstr. #TPS528 Geynisman DM, et al. Abstr. #TPS537

24 Harnessing the neoadjuvant platform in Muscle-Invasive Urothelial Bladder Cancer: the Milano model CT scan, 18 FDG-PET/CT scan mpmr of the bladder Non-responding, Cisplatineligible pts: DD-MVAC x 3 Patients with histologically confirmed TCC (T2-T4a) of the bladder 3 3 weekly cycles of pembrolizumab 200 mg* Cystectomy Post-cystectomy management according to local guidelines Study visits at 4, 12, 24 wks after surgery Survival data collected until 2 y post cystectomy CT scan, 18 FDG-PET/CT scan mpmr of the bladder *Enrolling: PURE01 trial: Primary Endpoint: Pathologic CR rate in T2-T4a N0M0 UBC; N=90 Briganti A, et al. EAU 2018; Necchi A, et al. AUA 2018, AACR 2018

25 Can we predict response and survival after neoadjuvant chemotherapy? Biomarker N Translational relevance Reference ERCC2 mutation 50 Association with pathologic response Van Allen EM, Cancer Discov 2014 ERCC2 mutation Association with improved OS in 2 independent cohorts of cisplatin-treated MIBC patients Liu, et al. JAMA Oncol 2016 Plimack ER et al, Eur Urol 2015 Plimack ER et al, ASCO 2014 ATM/RB1/FANCC mutations 34 Association with improved pt<2 response and OS Plimack ER et al, Eur Urol 2015 ERBB2 mutations 71 Association with pt0 response Groenendijk FH et al, Eur Urol 2015 DNA damage response (DDR) gene alterations 34 Association with pt0/ptis response to DD-GC Iyer G et al, ASCO 2016 Single-sample genomic subtyping classifier 343 Basal tumors benefited the most from neoadjuvant chemotherapy administration Seiler R et al, Eur Urol 2017

26 Geynisman DM, et al. Abstr. #TPS537 Presented By Seth Lerner at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

27 Presented By Seth Lerner at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

28 Ongoing Phase 3 Trials: Postoperative Setting for High-Risk Patients With Bladder or Upper Tract Urothelial Cancer Study Agent ClinicalTrials.gov Identifier PD-L1 Selection Standard Arm IMvigor010 Atezolizumab NCT No Observatio n CheckMate 274 Primary Endpoint Sample Size DFS 700 Nivolumab NCT No PBO DFS 600 Ambassador Pembrolizumab NCT No Observatio n DFS/OS 739 DFS: disease-free survival; PBO: placebo; TBD: to be determined.

29 Ongoing neoadjuvant trials for non-metastatic UTUC: Agents Sponsor ClinicalTrials.gov Identifier Gem-Cis Durvalumab + Tremelimumab Xiangya Hospital of Central South University MDACC, MedImmune NCT NCT Gem-Cis MSKCC NCT Patient Selection High grade UTUC High risk UTUC, CDDPineligible High grade UTUC Design Single arm Phase 2 Primary Endpoint Sample Size OS 50 Single arm Phase 2 Safety 15 Single arm Phase 2 Path Response 54 Gem-Carbo; DD-MVAC ECOG-ACRIN NCT High grade UTUC Non-randomized Phase 2 pcr 60

30 Biomarker findings & New drugs

31 IMvigor210: TCGA Subtype in muc Immune desert Luminal Basal I II III IV Papillary like Squamous Mesenchymal Inflamed Immune suppressed a Response IC status TC status IMvigor210 subtypes have distinct tumor-immune landscapes that reflect responsiveness to atezolizumab Tumor stroma Tumor cells TIL/immune cells Increased responses TIL, tumor-infiltrating lymphocyte. a High myeloid, inflammatory, activated stromal/fibroblast markers. Data cutoff: March 14, Rosenberg J et al, ASCO 2016

32 Is FGFR Mut/Fus a favorable feature in MIBC? Robertson et al., 2017, Cell 171, 1 17 McConkey D, et al. Hematol Oncol Clin North Am. 2015;29: ; Sharma P, et al. Lancet Oncol. 2017;18: ; Rosenberg JE, et al. Lancet. 2016;387: ; Balar AV, et al. Lancet. 2017;389:67-76; Siefker-Radtke AO, et al Genitourinary Cancers Symposium, Abstr 450

33 Nassar A, et al. Abstr. #465

34 Maximum Reduction From Baseline (%) Most Patients Receiving 8 mg Continuous Dose Erdafitinib Had Tumor Shrinkage 100 FGFR Mutation FGFR Fusion Regimen 1 10 mg intermittent dose Regimen 2 6 mg continuous dose Regimen 3 8 mg continuous dose Evaluable patients, n ORR confirmed, n (%) CR PR SD 8 (24) 2 (6) 6 (18) 16 (49) 27 (35) 2 (3) 25 (32) 30 (39) 25 (42) 3 (5) 22 (37) 23 (39) Total 60 (35) 7 (4) 53 (31) 69 (41) DCR confirmed, n (%) 24 (73) 57 (73) 48 (81) 129 (76) DoR, median months PFS, median months Survival rate at 1 year 31% 32% 57% 38% Patient Loriot Y, et al. Abstract

35 Responses Were Maintained mg Treatment ongoing Treatment discontinuation Among patients receiving 8 mg continuous dose erdafitinib: 42% of patients had an objective response Median DoR was 5.4 months Many responses are ongoing Responder (confirmed CR/PR) Uptitrated patient Complete response Partial response Stable disease Progressive disease 0 20 Weeks Loriot Y, et al. Abstract 411 6

36 Joeger M, et al. Abstr. #494

37 Patient journey and therapeutic options across the clinical stages MIBC/1L metastatic Neoadjuvant/A djuvant/1l Cisplatin-base chemo first Cisineligible/treate d pts, FGFRmutation/fusio n + tumor pan-fgfr inhibitor-first? Cisineligible/treate d pts, FGFR wild-type tumors ICI first option (IO combo?) ICI progression, FGFR wild-type Ramucirumabdocetaxel first 1 Continue ICI Salvage chemo FGFR: fibroblas growth-factor receptor; ICI: immune checkpoint inhibitors; IO: immuneoncology; MIBC: muscle-invasive bladder cancer 1. Petrylak DP, et al. Lancet Sep 12. pii: S (17)

38 @AndreaNecchi