Lenvatinib plus pembrolizumab improves PFS, OS and ORR in advanced clear-cell RCC

Lenvatinib plus pembrolizumab significantly improves progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) vs sunitinib in treatment-naïve patients with advanced clear-cell renal cell carcinoma (RCC), results of the phase III CLEAR study have shown.

“In the study, lenvatinib plus everolimus significantly improved PFS and ORR, but not OS, vs sunitinib,” said investigator Dr Robert Motzer of the Memorial Sloan Kettering Cancer Center, New York, US, at ASCO GU 2021. [Motzer R, et al, ASCO GU 2021, abstract 269; N Engl J Med 2021, doi: 10.1056/NEJMoa2035716]

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” he suggested.

In the study, 1,069 patients with previously untreated advanced clear-cell RCC, Karnofsky performance status ≥70, measurable disease and adequate organ function were randomized (1:1:1) to receive lenvatinib 20 mg orally QD plus pembrolizumab 200 mg intravenously Q3W (n=355; median age, 64 years), lenvatinib 18 mg orally QD plus everolimus 5 mg orally QD (n=357; median age, 62 years), or sunitinib 50 mg orally QD (4 weeks on, 2 weeks off) (n=357; median age, 61 years).

“The primary endpoint of PFS was met with both combination regimens,” said Motzer.

Median PFS was 23.9 months in the lenvatinib-pembrolizumab arm (hazard ratio [HR], 0.39; 95 percent confidence interval [CI], 0.32 to 0.49; p<0.001) and 14.7 months in the lenvatinib-everolimus arm (HR, 0.65; 95 percent CI, 0.53 to 0.80; p<0.001), compared with 9.2 months in the sunitinib arm

“The PFS improvement with lenvatinib-pembrolizumab vs sunitinib was impressive,” noted Motzer.

“The PFS benefit of both combination regimens extended across all key subgroups analyzed, including International Metastatic RCC Database Consortium [IMDC] risk groups,” he added.

With lenvatinib-pembrolizumab, the PFS HR for patients with IMDC favourable, intermediate or poor risk was 0.41 (95 percent CI, 0.28 to 0.62), 0.39 (95 percent CI, 0.29 to 0.52) and 0.28 (95 percent CI, 0.13 to 0.60), respectively. With lenvatinib-everolimus, the corresponding PFS HRs were 0.55 (95 percent CI, 0.38 to 0.81), 0.67 (95 percent CI, 0.51 to 0.88) and 0.73 (95 percent CI, 0.42 to 1.29), respectively.

OS was also significantly improved with lenvatinib-pembrolizumab vs sunitinib (median, not reached [NR] vs NR; HR, 0.66; 95 percent CI, 0.49 to 0.88; p=0.005), but not with lenvatinib-everolimus (median, NR vs NR; HR, 1.15; 95 percent CI, 0.88 to 1.50; p=0.3).

“OS favoured lenvatinib-pembrolizumab vs sunitinib in all key subgroups analyzed, except in patients with IMDC favourable risk, who comprised 31 percent of the population. In this subgroup, there were only 14 vs 15 OS events in those who received lenvatinib-pembrolizumab vs sunitinib [HR, 1.15; 95 percent CI, 0.55 to 2.40],” Motzer noted.

Confirmed ORR was 71 percent with lenvatinib-pembrolizumab, 53.5 percent with lenvatinib-everolimus, and 36.1 percent with sunitinib. “Complete response as best overall response was observed in 16.1 percent of lenvatinib-pembrolizumab recipients, compared with 9.8 percent and 4.2 percent of lenvatinib-everolimus and sunitinib recipients, respectively,” said Motzer. “Only 5.4 percent of lenvatinib-pembrolizumab recipients had progressive disease as best overall response, compared with 7.3 percent and 14 percent of those who received lenvatinib-everolimus and sunitinib, respectively.”

Grade ≥3 treatment-related adverse events (TRAEs) were reported by 71.6 percent, 73 percent and 58.8 percent of patients in the lenvatinib-pembrolizumab, lenvatinib-everolimus, and sunitinib arms, respectively.

“The median duration of treatment was 17 months with lenvatinib-pembrolizumab, 11 months with lenvatinib-everolimus, and 7.8 months with sunitinib. Rates of TRAEs in the lenvatinib-pembrolizumab arm were influenced by the longer treatment duration,” pointed out Motzer.