Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

Background: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer.
Methods: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960.
Findings: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug.
Interpretation: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination.
Funding: Exelixis.
Competing Interests: Declaration of interests NA has acted in a consulting or advisory role for Astellas, AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb (BMS), Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Jenssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and received research funding to his institution from AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Jenssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. BM has received grants to his institution from BMS, Calithera, Exelixis, Pfizer, and Seattle Genetics; and personal fees from Astellas, Bayer, BMS, Calithera, Dendreon, EMD Serono, Eisai, Exelixis, Nektar, Pfizer, and Seattle Genetics. BLM has acted in a consulting or advisor role for AbbVie, Astellas, AVEO Oncology, Bayer Oncology, BMS, Clovis, Exelixis, Janssen, Merck, Peloton Therapeutics, Pfizer, and Tempus and has received grants to his institution from Bayer Oncology, BMS, Clovis, Exelixis, Genentech, and Peloton Therapeutics. TBD has acted in a consulting or advisory role for AbbVie, AstraZeneca, Bayer, Exelixis, Janssen, Pfizer, and Seattle Genetics. RRM has received personal fees from Exelixis; has acted in a consulting or advisory role for AstraZeneca, Aveo, Bayer, BMS, Calithera, Caris, Dendreon, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus, and Vividion; and has received research funding from Bayer and Tempus. LP has received financing of scientific research from Pfizer, Exelixis, and Merck. RD has acted in a consulting or advisory role for Astellas, AstraZeneca, Aveo, Bayer, BMS, Exelixis, EMD Serono, Gilead, Hengrui, Hinova, Janssen, Merck, Myovant, Pfizer, Propella, Sanofi Genzyme, Seattle Genetics, and Tavanta. YL has received grants from Celsius, Janssen, and Roche and personal fees from Astellas, AstraZeneca, BMS, Gilead, Janssen, Merck KGaA, MSD, Roche, Pfizer, Sanofi, and Seattle Genetics. UV has received grants from BMS, Exelixis, Merck; and personal fees from AAA, Aveo, Bayer, BMS, Exelixis, Merck, Pfizer, and Sanofi. DC, AP, and MS are employees of Exelixis. TKC has received institutional and personal paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others); has institutional patents filed on molecular mutations and immunotherapy response and ctDNA; has equity in Tempest, Pionyr, Osel, and NuscanDx; and has acted on committees for NCCN, GU Steering Committee, and ASCO/ESMO. SP has acted in a consulting or advisory role for F Hoffman LaRoche and received research funding to his institution from Eisai, Exelixis, Genentech, Roche, and Pfizer. All other authors declare no competing interests.
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