Combining anti-angiogenic drugs with immune checkpoint inhibitors (ICI) after progression on ICIs represents a promising therapeutic approach in renal cell carcinoma (RCC). To further explore this strategy, the phase 3 CONTACT-03 trial evaluated the combination of cabozantinib and atezolizumab in RCC patients who have received prior ICI therapy. The results of this trial, recently published in The Lancet, showed that the addition of atezolizumab to cabozantinib does not improve clinical outcomes and leads to increased toxicity. As such, this combination should not be used in patients with RCC outside of clinical trials.
The combination of anti-angiogenic drugs with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic approach in renal cell carcinoma (RCC) after ICI progression. The anti-PD-L1 atezolizumab antibody has shown encouraging activity in combination with anti-angiogenic therapy after prior progression with ICI. Cabozantinib, a tyrosine kinase inhibitor (TKI) with activity against VEGFR2, c-MET and RET, may promote an immune-permissive environment and enhance atezolizumab activity. In the phase Ib COSMIC-021 trial, the combination of cabozantinib plus atezolizumab showed favourable safety and efficacy results in clear-cell(cc) RCC and non(n)-ccRCC patients. The phase III CONTACT-03 study further evaluated cabozantinib plus atezolizumab in second/third-line RCC after prior ICC therapy, compared to cabozantinib monotherapy.
The phase 3 CONTACT-03 trial was conducted across 135 different sites from 15 countries in Asia, Europe, North America, and South America. Eligible patients were adults (≥aged 18 years) with locally advanced or metastatic RCC whose disease had progressed under ICI therapy. In total, 522 patients were randomly assigned (1:1) to receive atezolizumab plus cabozantinib (n=263) or cabozantinib alone (n=259). The two primary endpoints were progression-free survival (PFS) and overall survival (OS).
After a median follow-up of 15.2 months, no significant difference in PFS was observed between the two groups (10.6 vs. 10.8 months with atezolizumab-cabozantinib and cabozantinib, respectively; HR[95%CI]: 1.03 [0.83-1.28]; p=0.78). Similarly, the results did not reveal any significant differences in median OS (25.7 months vs. not evaluable in the atezolizumab-cabozantinib and cabozantinib cohorts, respectively; HR[95%CI]: 0.94 [0.70-1.27]; p=0.69). In total, 171 (65%) and 166 (64%) patients receiving the combination or cabozantinib alone had disease progression or died, respectively. Of those, 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Serious adverse events occurred in 48% and 33% of patients treated with atezolizumab-cabozantinib and cabozantinib monotherapy, respectively. Adverse events leading to death occurred in 6% vs. 4% of patients in each group.
In conclusion, the addition of atezolizumab to cabozantinib did not lead to improved clinical outcomes and was associated with increased toxicity. These results discourage the sequential use of immune checkpoint inhibitors in patients with RCC outside clinical trials.
Pal SK, Albiges L, Tomczak P et al. 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. Lancet;402(10397):185-95.