Metastatic renal cell carcinoma (mRCC) is usually, depending on risk classification and on the performance status, treated with a combination of tumor-specific drugs, either two infusions of immunotherapy (IO) with nivolumab and ipilimumab or combination immunotherapy with avelumab, pembrolizumab or nivolumab plus a vascular endothelial growth factor receptor (VEGFR). However, tyrosine kinase inhibitor (TKI) monotherapy is the first-choice alternative therapy if IO is not tolerated or inapplicable.

At the 2023 ASCO annual meeting, the final prespecified overall survival (OS) analysis of the phase 3 CLEAR trial was presented. The extended 4‑year follow-up of lenvatinib plus pembrolizumab showed sustained superiority over sunitinib for OS and progression-free survival (PFS) in previously untreated advanced kidney cancer patients [1, 2].

However, the difference between survival for the combination compared to sunitinib had decreased significantly. The average time to when the cancer started growing again was nearly 2 years with combination therapy, compared to just over 9 months for sunitinib. Reasons for this may be the effect of following treatments, stopping pembrolizumab at 2 years, or patients coming off combination treatment because of side effects or other reasons. Nearly three quarters of patients on the tyrosine kinase inhibitor IO combination arm had serious or, much more rarely, life-threatening side effects compared to 60% of patients on sunitinib.

There are demonstrated benefits to lenvatinib plus pembrolizumab in all risk groups, but the impact of this combination and other combinations—whether ipilimumab plus nivolumab or other IO/TKI combinations—on OS in this setting is much smaller in the favorable-risk vs the intermediate- and poor-risk subgroups. (Tables 1, 2 and 3).

In another presentation, Dr. Brian Rini discussed the 5‑year analysis of KEYNOTE-426, a phase 3 study, assessing pembrolizumab plus axitinib vs sunitinib as first-line therapy for advanced clear cell renal cell carcinoma [4, 5].

KEYNOTE-426 represents the longest follow-up to date of the combination of an IO plus a VEGFR/TKI in the first-line setting. A substantial percentage of patients completed 35 cycles of pembrolizumab with good long-term outcomes.

At the prolonged analysis (median follow-up 67.2 months), first-line pembrolizumab plus axitinib showed statistically significant PFS in the intention-to-treat (ITT) population continued to favor pembrolizumab plus axitinib vs sunitinib (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.59–0.81). The 60-month PFS rates were 18.3% vs 7.3%, respectively.

The reported OS (HR 0.53, 95% CI 0.38–0.74), the reported PFs and the ORR in the entire population was (HR 0.69, 95% CI 0.57–0.84), and objective response rates (ORR; 59.3% vs 35.7%) over sunitinib for advanced clear cell carcinoma [4].

The doublet induced an ORR of 60.6% in the ITT population, which comprised a complete response (CR) rate of 11.6%, a partial response (PR) rate of 46.1%, and a stable disease (SD) rate of 22.7%; 11.6% of patients experienced disease progression.

Among patients with IMDC favorable-risk disease, there was no difference in OS (HR 1.10, 95% CI 0.79–1.54) or PFS (HR 0.76, 95% CI 0.57–1.02) for pembrolizumab plus axitinib vs sunitinib, with a slight benefit for pembrolizumab plus axitinib (68.8%) vs sunitinib (50.4%) with regard to ORR. Contrarily, among patients with IMDC intermediate/poor risk disease, there was a significant benefit in OS (HR 0.76, 95% CI 0.62–0.93) and PFS (HR 0.68, 95% CI 0.56–0.82) for IO/TKI combination vs TKI monotherapy [4].

It should be noted that this is the longest follow-up of a TKI/IO combination study showing that some patients in the front-line setting receiving the IO/TKI combination are going to have durable disease control rate.

Thus, there is a demonstrated benefit of TKI/IO combinations in all risk groups, but the impact of this combination or other combinations, ipilimumab plus nivolumab, on OS in this setting is much smaller in the favorable-risk versus intermediate- and poor-risk subgroups, which is why none of these studies can help us answer the critical question of which combination of treatments is best for an individual patient with advanced/metastatic RCC.