Beginning in mid-2015, there was an explosion of phase III clinical trials exploring anti-VEGF therapy in combination with immune checkpoint inhibitors as first-line therapy for patients with advanced RCC. There is an empiric rationale for combining these 2 types of agents: Each has their own unique targets and has demonstrated antitumor activity as individual agents with distinct adverse event profiles, so combining them makes sense. However, there is also a more interesting clinical rationale at play as well. Historically, research has suggested that VEGF inhibitors are immunosupportive through various mechanisms, including establishing an immune-permissive tumor microenvironment and increasing potential for T-cell infiltration through tumor vasculature.^1-8

The phase III KEYNOTE-426 was recently published in the New England Journal of Medicine and led to the FDA approval of the first VEGF inhibitor plus immune checkpoint inhibitor combination regimen as first-line treatment for patients with advanced RCC.⁹ This trial showed statistically significant improvements in ORR, PFS, and OS with the combination of axitinib plus pembrolizumab vs sunitinib. After a median follow-up of 12.8 months, the median OS was not reached for either treatment arm, but the risk of death was reduced by 47% with axitinib plus pembrolizumab vs sunitinib (HR: 0.53; 95% CI: 0.38-0.74; P < .0001). Of importance, in this trial, efficacy of axitinib plus pembrolizumab was observed in all patient subgroups examined, including in those with International Metastatic RCC Database Consortium favorable-risk or intermediate-risk/poor-risk disease and regardless of PD-L1 expression level in the tumor biopsy.

Based on these data and the new FDA approval, first-line axitinib plus pembrolizumab represents a new standard of care for patients with advanced RCC. However, this trial compared the combination with sunitinib, which was standard of care at the time of the trial initiation, but we also now have immune checkpoint inhibitor combination therapy with ipilimumab plus nivolumab as a standard of care for intermediate-risk or poor-risk patients with previously untreated advanced RCC. The phase III CheckMate 214 trial compared ipilimumab plus nivolumab with sunitinib and showed significantly improved ORR and OS for intermediate-risk or poor-risk patients in this setting (2 of the primary endpoints of the trial).¹⁰ The median OS was not reached with ipilimumab plus nivolumab and was 26.0 months with sunitinib (HR: 0.63; 99.8% CI: 0.44-0.89; P < .001). Although the FDA approval for first-line ipilimumab plus nivolumab was specifically for intermediate-risk or poor-risk patients based on the trial design of CheckMate 214, if you look at the overall population—which included a group of patients who were favorable risk—there remained an ORR and OS benefit with ipilimumab plus nivolumab.

Both axitinib plus pembrolizumab and ipilimumab plus nivolumab have shown important clinical benefit over single-agent VEGF inhibition and represent optimal first-line treatment choices for the majority of patients with advanced RCC, but without a head-to-head comparison, other factors will come into play for deciding which regimen to recommend for individual patients, for example, adverse event profiles and comorbidities, insurance coverage, and patient preferences. We do know that quality of life seems better with ipilimumab plus nivolumab vs sunitinib,¹⁰ although the major toxicity profile of axitinib plus pembrolizumab is generally driven by the toxicity profile of the VEGF inhibitor.⁹ However, treatment-related adverse events associated with the combination of ipilimumab plus nivolumab remain more difficult to manage vs single-agent PD-1 or PD-L1 inhibitors.

How these data will affect patient care in the clinic will continue to change as the data evolve. As both axitinib plus pembrolizumab and ipilimumab plus nivolumab are integrated into clinical practice, the biggest questions will be: What is the impact of sequencing these agents vs using combination therapy, and how will we treat our patients who progress after combination therapy?