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Clinical Trial
. 2020 Oct 1;26(19):5120-5128.
doi: 10.1158/1078-0432.CCR-19-4162. Epub 2020 Jun 12.

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Matthew D Galsky  1 , Abdel Saci #  2 , Peter M Szabo  2 , G Celine Han  2 , Gary Grossfeld  2 , Sandra Collette  2 , Arlene Siefker-Radtke  3 , Andrea Necchi  4 , Padmanee Sharma  3
Affiliations
Clinical Trial

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Matthew D Galsky et al. Clin Cancer Res. .

Abstract

Purpose: We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC).

Patients and methods: Patients received nivolumab 3 mg/kg once every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was objective response rate (ORR) per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were progression-free survival (PFS) per BIRC using RECIST v1.1 and overall survival (OS) in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures.

Results: Of 270 treated patients, 139 had evaluable TMB. With 33.7 months' minimum follow-up, ORR per BIRC, median PFS, and median OS [95% confidence interval (CI)] in all treated patients were 20.7% (16.1-26.1), 1.9 months (1.9-2.3), and 8.6 months (6.1-11.3), respectively. No new safety signals were identified. Higher TMB was associated (P < 0.05) with improved ORR [OR (95% CI): 2.13 (1.26-3.60)], PFS [HR: 0.75 (0.61-0.92)], and OS [HR: 0.73 (0.58-0.91)]. TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB.

Conclusions: These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted.See related commentary by Swami et al., p. 5059.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Dr. Galsky reports personal fees from BioMotiv, Glaxo Smith Kline, Janssen, Lilly, Astellas, Novartis, Pfizer, Seattle Genetics, Inctye, Dracen, Inovio, and Aileron, and grants and personal fees from Dendreon, Merck, Genentech, and Bristol Myers Squibb, outside the submitted work.

Dr. Saci has nothing to disclose.

Dr. Szabo reports employment and stock ownership from Bristol Myers Squibb.

Dr. Han reports employment from Bristol Myers Squibb.

Dr. Grossfeld reports employment and stock ownership from Bristol Myers Squibb.

Dr. Collette reports employment and stock ownership from Bristol Myers Squibb.

Dr. Siefker-Radtke reports personal fees from Merck, Bavarian Nordic, Seattle Genetics, Genentech, Mirati, AstraZeneca, Nektar Therapeutics, Pfizer, and Janssen.

Dr. Necchi reports personal fees from Bayer and Seattle Genetics, grants from Roche and AstraZeneca, and grants and personal fees from Merck and Bristol Myers Squibb.

Dr. Sharma reports consultancy from Oncolytics, Jounce, BioAtla, Forty-Seven, Polaris, Marker, Codiak, ImaginAb, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, and Infinity, patents from Jounce, and stock in Constellation, Oncolytics, Apricity Health, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, Jounce, Neon, BioAtla, Forty-Seven, Polaris, Marker, Codiak, and ImaginAb.

Figures

Figure 1.
Figure 1.
Time to and duration of response per BIRC in all treated patients with response.
Figure 2.
Figure 2.
Landmark analysis of overall survival by best response within the first 12 months. This analysis included 100 treated patients still alive at 12 months with best overall response of CR, PR, SD, or PD within the first 12 months. Abbreviations: CR, complete response; NE, not estimable; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 3.
Figure 3.
OS in (A) all treated patients and by PD-L1 expression, and by TMB tertiles in (B) patients with PD-L1 expression <1% and (C) ≥1%.
Figure 4.
Figure 4.
Association of TMB with (A) best overall response and (B) objective response. Abbreviation: OR, overall response.
See this image and copyright information in PMC

Comment in

References

    1. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Bladder cancer, version 3.2019. April 23, 2019
    1. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18:312–22. - PubMed
    1. OPDIVO® (nivolumab) [package insert]. Bristol Myers Squibb Company, Princeton, NJ; 2019.
    1. OPDIVO. https://www.ema.europa.eu/en/medicines/human/EPAR/opdivo. Accessed June 27, 2019.
    1. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124–8. - PMC - PubMed

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