Highlight 2017 TUMORI GENITOURINARI Francesco Pantano MD, PhD Università Campus Bio-Medico Roma

Principali novità e aggiornamenti Neoplasia renale: CheckMate 214: Efficacy and Safety of Nivolumab plus Ipilimumab vs Sunitinib in first-line mRCC CaboSun: final results Neoplasia prostatica Latitude: Phase III Trial of Abiraterone in newly diagnosed metastatic prostate cancer Stampede: update results Neoplasia vescicale Keynote-045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma Range: Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy Imvigor211: A Phase III Randomized Study Examining Atezolizumab vs. Chemotherapy for Platinum-Treated Advanced Urothelial Carcinoma

Neoplasia renale (1)

Neoplasia renale (1)

Neoplasia renale (1)

Neoplasia renale (1)

Neoplasia renale (2)

HR=0.48 (95% CI: 0.31-0.74), p=0.0008 (2-sided) Neoplasia renale (2) CABOSUN: Final results Favors cabozantinib Favors sunitinib Subgroup Analyses of PFS per IRC Median PFS No. of Events Cabozantinib (N=79) 8.6 mo 43 Sunitinib (N=78) 5.3 mo 49 HR=0.48 (95% CI: 0.31-0.74), p=0.0008 (2-sided) Probability of PFS No. at risk Time Since Randomization (Months) Cabozantinib Sunitinib Overall Survival (OS) HR=0.80 (95% CI: 0.53-1.21); p=0.29 (2-sided) Median OS: Cabozantinib 26.6 mo, Sunitinib 21.2 mo Data cutoff for PFS: Sep 15, 2016; for OS: July 1, 2017.

Original Report1 Investigator September 2016 Cutoff Investigator2 Neoplasia renale (2) CABOSUN: consistency across different analyses Original Report1 Investigator September 2016 Cutoff Investigator2 September 2016 Cutoff IRC2 Cabozantinib N = 79 Sunitinib N = 78 Progression-free survival Median PFS, months 8.2 5.6 8.3 5.4 8.6 5.3 Stratified HR (95% CI) 0.66 (0.46-0.95) 0.56 (0.37-0.83) 0.48 (0.31-0.74) P-value 0.012 (1-sided) 0.0042 (2-sided) 0.0008 (2-sided) Tumor Response Objective response rate (95% CI),3 % 46 (34-57) 18 (10-28) 33 (23-44) 12 (5-21) 20 (12-31) 9 (4-18) Disease control rate,4 % 78 54 76 49 75 47 Progressive disease, % 18 26 24 29 Not evaluable or missing, % 4 21 6 27 85 235 Any reduction in target lesions, % 87 44 38 80 50 1 Data cutoff: April 11, 2016; Choueiri TK, et al. J Clin Oncol 2017;35:591-7; 2 Data cutoff: Sep 15, 2016; 3 One CR was observed with Cabozantinib for both investigator assessments, and one CR was observed with Sunitinib for the JCO investigator assessment; all other responses were PRs; 4 CR + PR + SD; 5 Not evaluable or missing for the following reasons – Cabozantinib (6 patients): adverse event (5), withdrew consent (1); Sunitinib (18 patients): adverse event (6), death (2), disease progression (1), withdrew consent (9).

Neoplasia prostatica (1) LATITUDE: Phase III Trial of Abiraterone in newly diagnosed metastatic prostate cancer (n=1,199) High-risk defined as meeting at least 2 of 3 high-risk criteria: Gleason score of ≥ 8 Presence of ≥ 3 lesions on bone scan Presence of measurable visceral lesion Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results Fizazi K et al. N Engl J Med. 2017;377(4):352‒60.

LATITUDE: Co-primary End Points Neoplasia prostatica (1) LATITUDE: Co-primary End Points Fizazi K et al. N Engl J Med. 2017;377(4):352‒60.

LATITUDE: Co-primary End Points Fizazi K et al. N Engl J Med. 2017;377(4):352‒60.

Statistically significant improvement in all secondary end points Fizazi K et al. N Engl J Med. 2017;377(4):352‒60.

Neoplasia prostatica (2)

STAMPEDE. Multi-Arm Multi-Stage platform design

1,917 pts (95% newly- diagnosed) treated with SOC+Abi vs SOC 52% metastatic,20% N+M0, 28% N0M0* The treatment duration depended on disease stage and intent for radical radiotherapy: M0 with no RT planned and for patients M1 treatment continued until PSA, radiologic, or clinical progression or until another treatment was started; for patients with nonmetastatic disease with radiotherapy planned, treatment was to continue for 2 years or until any type of progression, whichever came first Primary end point: OS * Pts were included if had at least two of following: T3-4 , Gleason ≥ 8, PSA ≥ 40 James N, ASCO 2017

James N, ASCO 2017

James N, ASCO 2017

Valutazione non pre-pianificata

Neoplasia vescicale (1) Keynote-045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma 542 pazienti arruolati Bellmunt J et al, N Engl J Med 2017; 376: 1015-1026

Neoplasia vescicale (1)

Neoplasia vescicale (2) Valutazione dello sperimentatore Valutazione indipendente centralizzata Petrylak DP, et al. Lancet 2017 (epub ahead of print)

Neoplasia vescicale (2) Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial Valutazione dello sperimentatore Valutazione indipendente centralizzata Petrylak DP, et al. Lancet 2017 (epub ahead of print)

Neoplasia vescicale (3) Imvigor211: A Phase III Randomized Study Examining Atezolizumab vs. Chemotherapy for Platinum-Treated Advanced Urothelial Carcinoma Key Eligibility Criteriaa mUC with progression during or following platinum-based chemotherapy ≤ 2 prior lines of therapy Measurable disease per RECIST v1.1 ECOG PS 0-1 Evaluable sample for PD-L1 testing TCC histology as primary component (N = 931) Atezolizumab 1200 mg q3w Loss of clinical benefit R 1:1 Survival follow-up No crossover permitted per protocol Chemotherapy (investigator’s choice) Vinflunine q3w Docetaxel q3w Paclitaxel q3w RECIST v1.1 progression Stratification Factors No. of risk factorsb (0 vs. 1/2/3) Liver metastases (yes vs. no) PD-L1 status (0/1 vs. 2/3) Chemotherapy (vinflunine vs. taxanes) Primary endpoint OS, tested hierarchically in pre-specified populations Additional endpoints Efficacy: RECIST v1.1 ORR, PFS and DORc Safety PROs: EORTC QLQ-C30 Powles T, et al. EAS 2017, IMvigor211.

Neoplasia vescicale (3) Obiettivo primario: sopravvivenza globale nella popolazione PDL-1 IC2/3

Imvigor211: A Phase III Randomized Study Examining Atezolizumab vs Imvigor211: A Phase III Randomized Study Examining Atezolizumab vs. Chemotherapy for Platinum-Treated Advanced Urothelial Carcinoma Disegno dello studio oggetto di critiche: obiettivo primario solo sulla popolazione iperesprimente PDL-1 Efficacia inaspettata della chemioterapia (soprattutto vinflunina) nella popolazione iperesprimente PDL-1 Durata mediana della risposta superiore nei pazienti trattati con atezolizumab (circa 3 volte superiore) Confermata una buona tollerabilità dell’atezolizumab

Take home messagge Neoplasia renale: Neoplasia prostatica: CheckMate 214: beneficio in termini di OS nei pz intermediate/poor risk nel braccio IPI+ NIVO vs. sunitinib (change in practice) , risposte significative soprattutto nei pz con PD-L1 ≥ 1% Cabosun: L’indipendet radiology review cometee ( IRC) conferma il vantaggio in PFS del Cabozantinib vs. sunitnib nei pz intermediate/poor risk Neoplasia prostatica: I risultati dello studio LATITUDE e STAMPEDE indicano che l’aggiunta di AA+ P all’ADT potrebbe essere considerato il nuovo Standar of Care nei mHSPC ad alto rischio

Take home messagge Neoplasia vescica: Immunoterapia: dati di efficacia oramai consolidati in prima linea nella malattia metastatica non fit per cisplatino e in seconda linea nei pazienti refrattari alla chemioterapia a base di platino (pembro) Siamo in attesa dei dati in prima linea nei pazienti fit per cisplatino L’espressione di PD-1/PDL-1 non sembra promettente come biomarker predittivo Ramucirumab più docetaxel potrebbe diventare un’opzione terapeutica nei pazienti platino-refrattari