LBA23 - Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361

Background

The open-label, phase III KEYNOTE-361 study compares efficacy and safety of 1L P + C vs C for advanced UC (NCT02853305).

Methods

Eligible pts had advanced/unresectable or metastatic UC, ECOG PS 0-2, and no prior systemic therapy for advanced disease. Pts from 201 sites in 21 countries were randomized 1:1:1 to P 200 mg Q3W for ≤35 cycles, P for ≤35 cycles + C for ≤6 cycles (investigator’s choice [IC] of gemcitabine + either cisplatin or carboplatin), or IC of C for ≤6 cycles. Randomization was stratified by IC of platinum and PD-L1 combined positive score (CPS) (≥10 vs <10). Dual primary endpoints were PFS by blinded central review and OS. A sequential testing strategy was used, beginning with superiority testing of PFS and OS for P + C vs C in the total population (P-value threshold of ≤0.0019 for PFS and ≤0.0142 for OS as adjusted for α spent at interim analyses to maintain overall α=2.5% [one-sided] with 0.5% and 2.0% allocated to PFS and OS, respectively), followed by noninferiority and superiority testing of OS for P vs C in pts with CPS≥10 and total pts only if OS for P + C was statistically superior to C.

Results

1010 pts were randomized between Oct 19, 2016 and Jun 29, 2018: 351 to P + C, 307 to P, and 352 to C. As of Apr 29, 2020, median (range) time from randomization to cutoff was 31.7 (22.0-42.3) mo. Baseline characteristics were generally well-balanced across arms. Median PFS for P + C, P, and C for total pts was 8.3 mo, 3.9 mo, and 7.1 mo, respectively; median OS was 17.0 mo, 15.6 mo, and 14.3 mo, respectively. HR (95% CI) for P + C vs C was 0.78 (0.65-0.93, P = 0.0033) for PFS and 0.86 (0.72-1.02, P = 0.0407) for OS. ORR was 54.7% for P + C, 30.3% for P, and 44.9% for C. Median DOR (range) was 8.5 (2.0+-35.5+) mo, 28.2 (2.1+-36.1+) mo, and 6.2 (1.8+-36.3+) mo, respectively. 35.3%, 41.0%, and 61.1% of total pts in P+C, P, and C arms received subsequent therapy (6.6%, 4.6%, and 48.0% of total pts received anti–PD-[L]1), respectively. Grade 3-5 TRAE rate was 75.1% with P + C, 16.9% with P, and 71.6% with C; discontinuation rate of any drug due to an AE was 30.9%, 15.9%, and 18.1%, respectively.

Conclusions

PFS and OS benefit upon addition of P to C vs C did not reach statistical significance. Due to statistical design, OS noninferiority/superiority of P vs C was not tested.

Clinical trial identification

NCT02853305, August 2, 2016.

Editorial acknowledgement

Ina Nikolaeva of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A. Alva: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: EMD Serono; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Progenics; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Esanik; Research grant/Funding (institution): Ionis; Research grant/Funding (institution): Argus Biosciences; Research grant/Funding (institution): Prometheus; Full/Part-time employment: University of Michigan. T. Csőszi: Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. M. Ozguroglu: Honoraria (self): Roche; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. N. Matsubara: Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): MSD, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy, Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Chigai; Advisory/Consultancy: Sanofi. L. Geczi: Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. S.Y-S. Cheng: Advisory/Consultancy, Research grant/Funding (institution): Merck & Co., Inc.; Advisory/Consultancy: BMS; Advisory/Consultancy: AstraZeneca. Y. Fradet: Advisory/Consultancy: Merck & Co., Inc.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Tersera; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Astellas. S. Oudard: Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: BMS; Honoraria (self), Travel/Accommodation/Expenses: Merck & Co., Inc.; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Travel/Accommodation/Expenses: Astellas; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Research grant/Funding (self): Ipsen; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. C. Vulsteke: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self): Janssen; Honoraria (institution), Travel/Accommodation/Expenses: Roche; Honoraria (institution): Leo Pharma; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Astellas; Travel/Accommodation/Expenses: Novartis. R. Morales Barrera: Honoraria (self), Advisory/Consultancy: Sanofi Aventis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Asofarma; Travel/Accommodation/Expenses: Pharmacyclics; Travel/Accommodation/Expenses: Clovis; Travel/Accommodation/Expenses: Lilly. A. Fléchon: Honoraria (self), Travel/Accommodation/Expenses: Astellas; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca. S. Gunduz: Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Y. Loriot: Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self): Astellas; Honoraria (self), Honoraria (institution), Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (self): Seattle Genetics; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self): Ipsen. A. Rodriguez-Vida: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Travel/Accommodation/Expenses: Sanofi-Aventis; Advisory/Consultancy: Clovis; Research grant/Funding (institution): Takeda. R. Mamtani: Honoraria (self): Med Learning Group; Advisory/Consultancy: Flatiron Health; Advisory/Consultancy: Roche/Genetech; Advisory/Consultancy: Seattle Genetics/Astellas; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. E.Y. Yu: Advisory/Consultancy: AbbVie; Advisory/Consultancy: Advanced Accelerator Applications; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Clovis; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Blue Earth; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Dendreon; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Taiho. K. Nam: Full/Part-time employment: Merck & Co., Inc. K. Imai: Full/Part-time employment: Merck & C., Inc. B.H. Moreno: Full/Part-time employment: Merck & Co., Inc. T.B. Powles: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (institution), Advisory/Consultancy: BMS; Honoraria (institution), Advisory/Consultancy: Seattle Genetics; Honoraria (institution), Advisory/Consultancy: Ipsen; Honoraria (institution), Advisory/Consultancy: MSD, a subsidiary of Merck & Co., Inc.; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche.