Lenvatinib plus pembrolizumab achieve CLEAR survival advantage for clear cell RCC
medwireNews: The CLEAR study has demonstrated a significant progression-free survival (PFS) gain with use of lenvatinib plus pembrolizumab for the first-line treatment of advanced clear cell renal cell carcinoma (RCC).
The final PFS results of the open-label phase 3 trial, after a median follow-up of 27 months, were presented at the 2021 Genitourinary Cancers Symposium to coincide with publication in The New England Journal of Medicine.
Robert Motzer (Memorial Sloan Kettering Cancer Center, New York, USA) explained that around three-quarters of patients had previously undergone nephrectomy and the majority had an intermediate or favorable MSKCC prognosis and intermediate or favorable IMDC risk classification.
The primary endpoint of median PFS was 23.9 months for the 355 patients who were randomly assigned to receive lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks versus 9.2 months for the 357 patients instead given sunitinib 50 mg/day given on a 4-week on, 2-week off schedule.
This gave a significant hazard ratio (HR) for progression or death of 0.39 in favor of the combination regimen, which Motzer said demonstrated an “impressive improvement in PFS” compared with sunitinib.
The 357 patients who were assigned to receive a third regimen of lenvatinib 18 mg/day plus everolimus 5 mg/day also achieved a significant PFS benefit compared with sunitinib, at a median of 14.7 versus 9.2 months and a HR of 0.65.
The significant PFS benefit for lenvatinib plus pembrolizumab versus sunitinib was true for all assessed patient subgroups, including across all IMDC risk groups and by PD-L1 expression, whereas lenvatinib plus everolimus did not show a significant benefit for IMDC poor risk patients and those without prior nephrectomy or with sarcomatoid features.
Interim analysis indicated that median overall survival (OS) was unreached in all three groups and significantly better with lenvatinib plus pembrolizumab than sunitinib (HR=0.66), whereas no significant difference was found between lenvatinib plus everolimus and sunitinib.
Further OS analysis favored lenvatinib plus pembrolizumab over sunitinib in all key subgroups except for IMDC intermediate or favorable risk patients; Motzer noted that favorable risk patients made up 31% of the study population but that there were just 29 events in these two treatment arms, and the confidence intervals were wide, at 0.55–2.40.
Both the pembrolizumab and everolimus combinations with lenvatinib had significantly higher objective response rates than sunitinib, at 71.0% and 53.5% versus 36.1%, and relative risks of 1.97 and 1.48, respectively.
Motzer highlighted the “high” complete response rate of 16.1% with lenvatinib plus pembrolizumab versus 9.8% and 4.2% with lenvatinib plus everolimus and sunitinib, respectively, and the corresponding rates of progressive disease of 5.4% and 7.3% versus 14.0%.
Median duration of response was 25.8 months with lenvatinib plus pembrolizumab, 16.6 months with lenvatinib plus everolimus, and 14.6 months with sunitinib.
Rates of grade 3 or 4 adverse events (AEs) were “modestly higher” with the lenvatinib plus pembrolizumab and lenvatinib plus everolimus combinations than with sunitinib (71.6, 73.0, and 58.8%, respectively), Motzer said.
But he remarked that the AE rates for patients given lenvatinib plus pembrolizumab “were influenced by the longer treatment duration,” at a median 17.0 months versus 11.0 and 7.8 months for the lenvatinib plus everolimus and sunitinib groups, respectively.
Treatment-related AEs leading to discontinuation of lenvatinib or pembrolizumab occurred in 9.7% of patients, lenvatinib or everolimus in 13.5%, and sunitinib in 10.0%, with the safety profiles of the lenvatinib combination arms both “consistent with each drug’s known profile and manageable, as needed, through dose modifications,” Motzer summarized.
He concluded: “These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC.”
Discussing the efficacy and safety results at the session, Stephanie Berg (Loyola University Chicago, Illinois, USA) said that lenvatinib plus pembrolizumab “is another novel combination to have in our armamentarium for first-line clear cell RCC.”
Placing the combination alongside nivolumab–cabozantinib, avelumab–axitinib, and pembrolizumab–axitinib, she suggested that characteristics of these different regimens, such as health-related quality of life, physician familiarity of agents, and detection of a high tumor burden or slow growing disease, “may become important to choose the best first-line option for our patients.”
Berg added that if “patients start with combination immunotherapy it becomes an automatic choice to use a VEGF–TKI second-line.”
“These trials establish that [immuno-oncology]–TKI combination therapy is now standard of care and our second-line choice is less clear, therefore data is needed on the most suitable order of therapy for the entire population as well as specific groups in the future,” she concluded.
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