First-line lenvatinib-pembrolizumab combination improves OS, PFS in advanced kidney cancer
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The combination of lenvatinib and pembrolizumab significantly prolonged OS and PFS compared with sunitinib among previously untreated patients with advanced renal cell carcinoma, according to results of the phase 3 CLEAR trial.
The results, presented at Genitourinary Cancers Symposium and simultaneously published in The New England Journal of Medicine, also showed the combination of lenvatinib (Lenvima, Eisai) and everolimus (Afinitor, Novartis) conferred longer PFS than sunitinib (Sutent, Pfizer), but this combination did not extend OS.
“Lenvatinib and pembrolizumab [Keytruda, Merck] have activity as monotherapies for the treatment of patients with advanced renal cell carcinoma,” Robert J. Motzer, MD, kidney cancer section head in the genitourinary oncology service and Jack and Dorothy Byrne chair in clinical oncology at Memorial Sloan Kettering Cancer Center, said during his presentation. “Also, lenvatinib plus everolimus prolonged PFS compared with everolimus alone as second-line therapy.”
Thus, Motzer and colleagues compared lenvatinib plus pembrolizumab or everolimus with sunitinib as first-line treatment of 1,069 patients with advanced clear-cell renal cell carcinoma.
Researchers randomly assigned patients 1:1:1 to receive 20 mg oral lenvatinib daily plus 200 mg IV pembrolizumab every 3 weeks (n = 355; median age, 64 years; 71.8% men), 18 mg oral lenvatinib daily plus 5 mg oral everolimus daily (n = 357; median age, 62 years; 74.5% men) or 50 mg oral sunitinib daily in a 4-weeks-on, 2-weeks-off schedule (n = 357; median age, 61 years; 77% men).
PFS, measured by an independent review committee using RECIST version 1.1, served as the study’s primary endpoint. Secondary endpoints included OS, objective response rate and safety.
Median follow-up was 26.6 months.
Median PFS was 23.9 months with lenvatinib plus pembrolizumab, which represented an “impressive improvement” over the 9.2-month median PFS observed in the sunitinib group (HR = 0.39; 95% CI, 0.32-0.49), Motzer said, adding that this benefit persisted across key patient subgroups, including all International Metastatic RCC Database Consortium risk groups.
The median PFS in the lenvatinib plus everolimus group of 14.7 months also represented a significant improvement compared with sunitinib (HR = 0.65; 95% CI, 0.53-0.8), and this benefit persisted across patient subgroups.
“Both lenvatinib combination arms met their primary endpoint by showing a benefit in PFS over sunitinib,” Motzer said.
The interim analysis for OS showed significant improvement in the lenvatinib-pembrolizumab group compared with sunitinib (HR = 0.66; 95% CI, 0.49-0.88), with medians not reached for either group. The HRs for OS favored lenvatinib-pembrolizumab for all key patient subgroups with the exception of patients with favorable-risk disease, who represented 31% of the population but had few OS events (lenvatinib-pembrolizumab, 14; sunitinib, 15).
OS for lenvatinib plus everolimus did not reach significance compared with sunitinib (median, not reached; HR = 1.15; 95% CI, 0.88-1.5).
Researchers reported confirmed ORRs of 71% (95% CI, 66.3-75.7) for lenvatinib-pembrolizumab, 53.5% (95% CI, 48.3-58.7) for lenvatinib-everolimus and 36.1% (95% CI, 31.2-41.1) for sunitinib. RRs for achieving response were significantly higher for lenvatinib-pembrolizumab (1.97; 95% CI, 1.69-2.29) and lenvatinib-everolimus (1.48; 95% CI, 1.26-1.74) compared with sunitinib.
Motzer noted the “high” confirmed complete response rate of 16.1% in the lenvatinib-pembrolizumab group, with only 5.4% of patients in that cohort demonstrating progressive disease as their best response. Complete response occurred among 9.8% of the lenvatinib-everolimus group and 4.2% of the sunitinib group.
Median duration of response was 25.8 months with lenvatinib-pembrolizumab, 16.6 months with lenvatinib-everolimus and 14.6 months with sunitinib.
Nearly all patients experienced any-grade treatment-related adverse events, with grade 3 or worse events occurring among 71.6% of the lenvatinib-pembrolizumab group, 73% of the lenvatinib-everolimus group and 58.8% of the sunitinib group.
“However, adverse events to lenvatinib-pembrolizumab were influenced by the longer median treatment duration [17 months vs. 11 months vs. 7.8 months],” Motzer said.
Diarrhea, hypertension, elevated lipase and hypertriglyceridemia were the most common grade 3 or higher adverse events across groups.
“The relatively low rates of hepatic toxicity, lack of myelosuppression and low high-grade hand-foot syndrome are attractive features of lenvatinib tyrosine kinase inhibitor in combination,” Motzer said.
“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced renal cell carcinoma,” he added.
The CLEAR study is a “step forward” because it provides data to help clinicians choose between combinations of immunotherapy plus a VEGFR TKI as an alternative to nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb), Alain Ravaud, MD, PhD, of Hospital Saint-André and University Hospital Center Bordeux in France, wrote in an editorial accompanying the NEJM publication.
“Rapid progression of the disease, especially in symptomatic patients who have involvement of an unfavorable metastatic site (eg, liver or large mediastinal lymph nodes) requiring a rapid response to treatment, favors combining two modes of action,” Ravaud wrote. “Treatment with an anti-PD-1 drug plus a VEGFR [TKI] has been associated with lower percentages of patients having disease progression in the first 3 to 6 months than has treatment with nivolumab plus ipilimumab ...
“Slow progression or a favorable metastatic location (eg, lung), on the other hand, does not always necessitate rapid control of the disease, and in such situations other factors that distinguish the treatments from one another (eg, toxicity) may provide a more valuable basis for choosing therapy,” he wrote, adding that biomarker-driven studies should be the next step in research to help make individualized treatment decisions.
References:
- Motzer RJ, et al. Abstract 269. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
- Motzer RJ, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2035716.
- Ravaud A. N Engl J Med. 2021;doi:10.1056/NEJMe2101777.
Perspective
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Pooja Ghatalia, MD
The ORR of 71% in the randomized phase 3 CLEAR trial was very impressive, including 16% of patients experiencing a complete response in the lenvatinib-pembrolizumab group. The investigators should be commended for their use of a reasonable comparator arm such as lenvatinib-everolimus, which is an effective treatment in post-second-line settings. Although toxicities reported in the study were manageable, a 20 mg starting dose of lenvatinib with pembrolizumab may be toxic based on prior experience with lenvatinib.
Lenvatinib-pembrolizumab now joins other combinations, such as pembrolizumab and axitinib (Inlyta, Pfizer), nivolumab plus cabozantinib (Cabometyx, Exelixis) and ipilimumab plus nivolumab, as a standard front-line option for patients with metastatic renal cell carcinoma.
Lenvatinib-pembrolizumab also demonstrated a 59% response rate among patients previously treated with immunotherapy plus a TKI in a phase 2 clinical trial presented at ASCO20 Virtual Scientific Program. How to sequence these treatments in clinic remains an area of active investigation.
Reference:
Lee C-H, et al. Abstract 5008. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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Motzer RJ, et al. Abstract 269. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
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