Atezolizumab plus cabozantinib not superior to cabozantinib alone after progression on prior immune checkpoint inhibitor treatment in metastatic renal cell carcinoma

The randomised phase III CONTACT-03 trial evaluates the efficacy of atezolizumab plus cabozantinib versus cabozantinib alone in the post immune checkpoint inhibitor (ICI) setting in patients with metastatic renal cell carcinoma. The study reported no improvement in clinical outcomes in patients receiving the combination treatment, and highlighted higher levels of toxicity in patients that progressed on or after previous ICI treatment. Overall this study calls for caution should this approach be used in the treatment of other cancers.

One of the current first line treatments for many cancers involves the use of immune checkpoint inhibitors (ICI), and currently anti-PD-1 and anti-PD-L1 drugs are approved for the treatment of several cancers. Metastatic renal cell carcinoma (mRCC) is the most common form of kidney cancer, and thus there are calls for improvements in treatment strategies. Given that the use of ICI’s are indicated as a first line treatment, questions regarding optimal second line treatments have arisen. Previous research has highlighted the benefit of the use of cabozantinib in patients who were previously treated with ICI-based strategies. More recent research across many cancers suggests that the rechallenging of PD-L1 or PD-1 inhibitors following initial disease progression may be of benefit. To assess this further, the CONTACT-03 study aimed to compare the efficacy of treatment with a PD-L1 inhibitor in a post-ICI setting in patients with mRCC. At ASCO 2023, the current efficacy and safety data arising from the CONTACT-03 study were presented.

Study design

522 patients with advanced/metastatic clear cell or non-clear cell renal cell carcinoma with radiographic progression on or following prior ICI treatment were enrolled and randomised 1:1 into the respective research arms. Arm 1 involved treatment with atezolizumab (1200 mg IV q3w) plus cabozantinib (60 mg/day); arm 2 involved treatment with cabozantinib (60 mg/day) alone. Primary endpoints were independent centrally-assessed progression-free survival (PFS) and overall survival (OS). Key secondary endpoints included investigator-assessed PFS, centrally reviewed overall response rate (ORR), safety and duration of response.

Results

Centrally reviewed median PFS was similar in both arms (10.6 months for the combination treatment and 10.8 months for cabozantinib, HR[95%CI]: 1.03[0.83-1.28], p= 0.784). Interim analysis for OS revealed no difference at the 2 year timepoint (median OS: combination treatment; 25.7 months, cabozantinib; 21.1 months; HR[95%CI]: 0.94[0.7-1.27], p= 0.690). No difference in the centrally-reviewed objective response was noted (respectively 40.5% and 40.9%). Median duration of response was 12.7 months for patients in the combination arm and 14.8 months for patients receiving cabozantinib alone. Subgroup analysis did not identify a subset of patients who may benefit from atezolizumab plus cabozantinib. However, there was a higher incidence of grade 3 or 4 adverse events in the combination treatment (55.3% vs. 47.3%), as well as serious treatment-related adverse events (24.0% vs. 11.7%). The most common adverse event reported was diarrhoea (65.3% in combination treatment arm vs. 70.7% in cabozantinib arm).

Conclusion

The addition of atezolizumab to cabozantinib did not improve clinical outcomes in patients with mRCC who progressed on or after prior ICI treatment. The combination treatment resulted in increased toxicity, however, no new safety signals were identified. This study highlights the importance of randomised, prospective assessment of rechallenging with ICI in RCC and other tumour types.

Reference

Choueiri T, et al. Efficacy and safety of atezolizumab plus cabozantinib versus cabozantinib alone after progression with prior immune checkpoint inhibitor treatment in metastatic renal cell carcinoma. Presented at ASCO 2023; Abstract LBA4500.