Cancer Treatment Today

The results of two studies investigating combination of ICI and anti-angiogenic therapy compared to sunitinib have been recently published, proving the benefit of the combination over the anti-angiogenic therapy alone: Keynote-426 (3), investigating the combination of pembrolizumab, an anti-PD1, plus axitinib, a VEGFR inhibitor, and Javelin-Renal 101 (4), investigating the combination of avelumab, an anti-PD-L1, plus axitinib.

The primary endpoints of the Keynote-426 were overall survival and progression-free survival in the intention-to-treat population. After a median follow-up of 12.8 months, pembrolizumab plus axitinib resulted in better overall survival (HR 0.53, P<0.0001), median progression free survival (15.1 months in the combination arm versus 11.1 months in the sunitinib arm, HR 0.69, P<0.001) and objective response rate (59.3% in the combination arm versus 35.7% in the sunitinib arm), with a higher percentage of complete response (5.8% in the combination arm versus 1.9% in the sunitinib arm). The percentage of complete response with pembrolizumab plus axitinib were also higher than those obtained with avelumab plus axitinib, both in the PD-L1 positive population (4.4%) and the overall population (3.4%). The only combination to achieve a better rate of complete response is nivolumab plus ipilimumab in the CheckMate-214 (9% in the intermediate and poor risk population) (5). Nonetheless, it should be underlined that in the Keynote-426 a higher percentage of favorable risk patients than in the Javelin-Renal 101 was enrolled (31.9% and 21.7% in the overall population, respectively).

Pembrolizumab plus axitinib proved its efficacy in all the risk categories according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (6), differently to nivolumab plus ipilimumab combination that has been approved only for intermediate and poor risk categories, and independently to PD-L1 expression. Differently, the study Javelin-Renal 101 restricted the evaluation of the primary endpoints PFS and OS to the 63.2% of patients with PD-L1 positivity, thus narrowing the field in which this combination could be used; moreover, it should be underlined that the method of evaluation of PD-L1 is not standardized in RCC thus different methods were used in each trial.
This regimen is included in the NCCN guideline.
Brian I. Rini, M.D., Elizabeth R. Plimack, M.D., Viktor Stus, M.D., Ph.D., Rustem Gafanov, M.D., Robert Hawkins, M.B., B.S., Ph.D., Dmitry Nosov, M.D., D.Sci., Frédéric Pouliot, M.D., Ph.D., Boris Alekseev, M.D., Denis Soulières, M.D., Bohuslav Melichar, M.D., Ph.D., Ihor Vynnychenko, M.D., Ph.D., Anna Kryzhanivska, M.D., et al., for the KEYNOTE-426 Investigators, Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380:1116-1127

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380:1103-15.

Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378:1277-90.

NCCN Kidney Cancer, KID-C,1 2022