Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial

Background Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. Methods CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. Findings From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15 center dot 2 months (IQR 10 center dot 7-19 center dot 3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10 center dot 6 months (95% CI 9 center dot 8-12 center dot 3) with atezolizumab-cabozantinib and 10 center dot 8 months (10 center dot 0-12 center dot 5) with cabozantinib (hazard ratio [HR] for disease progression or death 1 center dot 03 [95% CI 0 center dot 83-1 center dot 28]; p=0 center dot 78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25 center dot 7 months (95% CI 21 center dot 5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21 center dot 1-not evaluable) with cabozantinib (HR for death 0 center dot 94 [95% CI 0 center dot 70-1 center dot 27]; p=0 center dot 69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab- cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. Interpretation The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. Funding F Hoffmann-La Roche and Exelixis. Copyright (c) 2023 Elsevier Ltd. All rights reserved. June S0140-6736(23)00922-4 See Oncology, Comprehensive of Sciences, d'Hebron Oncology, Vall Cancer Oncology Octubre, of and Clinical of dei

Automated summary

The study aimed to investigate the efficacy of adding atezolizumab to cabozantinib in delaying disease progression and prolonging survival in patients with metastatic renal cell carcinoma. However, the results showed that this combination did not improve clinical outcomes and led to increased toxicity, discouraging the sequential use of immune checkpoint inhibitors in these patients outside of clinical trials.