Two trials could change clinical practice for certain subtypes of renal cell carcinoma (RCC). In one, the combination of lenvatinib and pembrolizumab was superior to sunitinib and to lenvatinib plus everolimus in clear-cell RCC. In the other, cabozantinib was more effective than sunitinib in papillary RCC.

The treatment landscape for renal cell carcinoma (RCC) has been changing rapidly in recent years as more drugs outperform the multikinase inhibitor sunitinib (Sutent; Pfizer) that was long the standard of care. Now, a pair of trials has established two additional options: an immunotherapy combination and a dual MET/VEGF inhibitor.

The phase III CLEAR trial tested the PD-1 inhibitor pembrolizumab (Keytruda; Merck) and the angiogenesis blocker lenvatinib (Lenvima; Eisai) in patients with clear-cell RCC, which accounts for approximately 75% of RCCs (NEJM 2021 Feb 13 [Epub ahead of print]). Each drug had shown promise as a monotherapy, says senior author Toni Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, MA. “We chose the combination with a potential for success.”

The researchers divided 1,069 patients newly diagnosed with advanced disease into three arms: pembrolizumab plus lenvatinib, lenvatinib plus everolimus (Afinitor; Novartis), and sunitinib. Sunitinib was the standard of care when the trial began in 2016, and the lenvatinib–everolimus combination had been approved as a second-line option.

The pembrolizumab combination led to a median progression-free survival (PFS) of 23.9 months and an overall survival (OS) rate of 79.2% at 24 months, compared with 14.7 months and 66.1% for the everolimus combination and 9.2 months and 70% for sunitinib. More than 82% of patients on the pembrolizumab and everolimus arms had grade 3 or higher adverse events, compared with 71.8% of patients on the sunitinib arm.

The effectiveness of pembrolizumab plus lenvatinib “is good news for patients,” Choueiri says, and he predicts that the combination will be approved.

The phase II SWOG 1500 trial tested treatments for papillary RCC (PRCC), a subtype that occurs in about 15% of patients (The Lancet 2021 Feb 13 [Epub ahead of print]). Sunitinib is the current standard of care, but patients with PRCC often have potentially targetable MET alterations. The study included 152 patients with metastatic PRCC who had not received prior MET- or VEGF-directed therapy. The trial compared sunitinib to three MET inhibitors that have shown preliminary promise: crizotinib (Xalkori; Pfizer), savolitinib (Chi-Med), and cabozantinib (Cabometyx; Exelixis). The researchers stopped the savolitinib and crizotinib arms after 2 years due to a lack of efficacy.

Patients treated with cabozantinib had a median PFS of 9 months, a median OS of 20 months, and an objective response rate of 23%, compared with 5.6 months, 16.4 months, and 4% in patients who received sunitinib. Overall, 23% of patients in the cabozantinib group stopped treatment due to side effects, compared with 24% of patients in the sunitinib group.

“This study provides the highest level of evidence to support the use of cabozantinib as the preferred first-line [tyrosine kinase inhibitor] for patients with metastatic PRCC,” says senior author Primo Lara, MD, of the University of California Davis Comprehensive Cancer Center.

Both studies are practice-changing, says Pedro Barata, MD, of the Tulane University School of Medicine in New Orleans, LA, who wasn't connected to either one. The CLEAR trial “shows that lenvatinib plus pembrolizumab significantly improves clinical outcomes of advanced RCC patients,” he says.

Although the study can't determine whether lenvatinib plus pembrolizumab is superior to other immunotherapy combinations in RCC, he adds, the results indicate that “it is a super-active combination with manageable toxicity.” However, sunitinib remains useful for a small percentage of patients with RCC—such as those whose treatment goal is disease control.

As for SWOG 1500, Barata says it clearly demonstrates that “cabozantinib is better than sunitinib for PRCC and should become the new standard of care.” –Mitch Leslie