Immune-checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 or CTLA4 are components of various FDA-approved treatment regimens for metastatic renal cell carcinoma (mRCC). Despite the promising efficacy of these regimens, disease progression is inevitable for most patients. Now, data from two retrospective studies shed light on the safety and clinical activity of ICI rechallenge in this setting.
Gul et al. focused specifically on salvage therapy with nivolumab plus ipilimumab (nivo + ipi) in 45 patients previously treated with PD-1 or PD-L1 inhibitors, predominantly as monotherapy (in 60%) or in combination with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI; 18%). The objective response rate (ORR) with salvage nivo + ipi was 20%, all partial responses (PRs), with stable disease (SD) in a further 16% of patients. Responses were observed regardless of whether patients had an objective response, SD or progressive disease (PD) with prior ICI therapy (ORR 17%, 25% and 22%, respectively). The median duration of response was 7 months, and the median progression-free survival duration was 4 months. Interestingly, only 1 of 11 patients who had previously received a VEFGR-TKI, either with an ICI or alone in the most recent line of therapy, had a PR with nivo + ipi (ORR 9%).
Ravi et al. evaluated the outcomes of 69 patients, most of whom had previously received an ICI plus a VEGF pathway-targeted agent (42%), ICI monotherapy (39%) or dual ICI therapy (13%). ICI rechallenge was not restricted to any particular agent or combination, and most patients received single-agent ICI (38%) or dual ICI (32%) salvage therapy. The overall ORR was 23%, and the rate of SD was 41%. ORRs were similar in patients who received ICI monotherapy (30%), dual ICI therapy (25%) or an ICI plus a targeted agent (23%), as well as in those who had received prior dual ICI (33%) or VEGF pathway-targeted (17%) therapy. The ORR was 29% among patients with a response to prior ICI therapy (versus 15% and 21% in those with prior SD and PD, respectively) and was 38% in those who discontinued prior ICI therapy owing to toxicities.
Grade 3–4 immune-related adverse events (irAEs), including hepatotoxicity, pneumonitis and colitis, occurred in 13% and 16% of patients after ICI rechallenge in each study, respectively, with any-grade irAEs in 64% and 45%. Ravi et al. found that prior irAEs were associated with a higher risk of irAEs upon rechallenge (41% versus 20%).
“The observation of responses regardless of treatment type and sequence emphasizes the need for predictive biomarkers”
These findings indicate that ICI rechallenge in patients with mRCC is generally safe. The observation of responses regardless of treatment type and sequence emphasizes the need for predictive biomarkers.
Gul, A. et al. Salvage ipilimumab and nivolumab in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitors. J. Clin. Oncol. https://doi.org/10.1200/JCO.19.03315 (2020)
Ravi, P. et al. Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2020.2169 (2020)