Conference Coverage

Combo delivers ‘impressive’ survival results in first-line RCC setting



The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Robert J. Motzer, MD, head of the kidney cancer section, genitourinary oncology service,  Memorial Sloan Kettering Cancer Center, New York Courtesy of Memorial Sloan Kettering Cancer Center

Dr. Robert J. Motzer

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

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

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.


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