Is There a Role for “Salvage” Immunotherapy in Advanced Renal Cell Cancer?

For untreated metastatic clear cell renal cancer, immune-checkpoint–based combinations with ipilimumab and nivolumab or an immune checkpoint inhibitor and a VEGF-tyrosine kinase inhibitor (TKI) are first-line standard-of-care options. Most patients, however, either fail to respond or ultimately experience disease progression, and some receive subsequent VEGF-TKI therapy. Immune checkpoint-based therapies are used as salvage therapy by some clinicians, but there is limited evidence for this practice, and it is not an established standard of care.

Based on provocative phase 2 results on combined PD-L1 and VEGF-TKI therapy in the salvage setting, investigators conducted an industry-sponsored, open-label randomized phase 3 trial comparing treatment with the PD-L1 inhibitor atezolizumab plus the VEGF-TKI cabozantinib versus cabozantinib alone in patients with locally advanced or metastatic clear or nonclear cell renal cancer, good performance status, and evidence of disease progression during or after first- or second-line immune checkpoint inhibitor therapy. The two primary endpoints were progression-free survival and overall survival.

Of 522 randomized patients, median age was approximately 63 years, roughly three quarters had clear cell cancer without sarcomatoid differentiation, and most were classified as having intermediate risk. At a median follow-up of 15.2 months, 65% of patients receiving atezolizumab/cabozantinib and 64% receiving cabozantinib alone had disease progression or died. Median progression-free survival was 10.6 months in the combination arm and 10.8 in the control arm (hazard ratio, 1.03; P=0.78). Overall survival did not differ between groups (HR for death, 0.94; 95% CI, 0.70–1.27; P=0.69). Serious adverse events were more common in the combination arm than the control arm (48% vs. 33%).