By Jennifer Lubell
Lenvatinib, combined with either pembrolizumab or everolimus, outperformed sunitinib monotherapy in progression-free survival (PFS) for patients with advanced renal cell carcinoma (RCC), according to findings presented at the American Society of Clinical Oncology’s 2021 Genitourinary Cancers Symposium.
The combination of lenvatinib and pembrolizumab also bested sunitinib alone in terms of overall survival and objective response rate, supporting the regimen as a potential first-line treatment for advanced RCC, according to Robert J. Motzer, MD, who presented the findings of the phase 3 CLEAR study (Abstract 269).
Lenvatinib and pembrolizumab both have activity as monotherapies for the treatment of patients with advanced RCC, said Dr. Motzer, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Preliminary findings of a phase 1b/2 study of lenvatinib plus pembrolizumab in previously treated RCC patients showed antitumor activity. As a second-line therapy, lenvatinib plus everolimus has prolonged PFS, compared with everolimus alone.
The current open-label, multicenter CLEAR trial investigated lenvatinib plus pembrolizumab and lenvatinib plus everolimus, compared with sunitinib, as first-line treatments.
Investigators randomized 1,069 patients with advanced clear cell RCC and no prior systemic therapy 1:1:1 to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg IV every three weeks; lenvatinib 18 mg plus everolimus 5 mg orally once daily; or sunitinib 50 mg orally once daily (four weeks on and two weeks off). Stratification factors were based on geographic region and prognostic group.
Patient characteristics were balanced among the three arms, Dr. Motzer noted, though there were more patients in Western Europe and North America than the rest of the world. Three-fourth of the patients had a prior nephrectomy.
The primary endpoint was PFS by independent review committee. Secondary endpoints included overall survival, objective response rate, and safety. Investigators based final PFS and interim overall survival analyses on a data cutoff date of Aug. 28, 2020, at a median follow-up of 27 months.
Both lenvatinib combination arms met the primary endpoint by showing a benefit in PFS, compared with sunitinib alone, Dr. Motzer said.
Lenvatinib plus pembrolizumab significantly improved median PFS over sunitinib alone, at 23.9 months versus 9.2 months (Hazard Ratio [HR] 0.39; 95% CI: 0.32–0.49). “The P value was less than 0.001, demonstrating an impressive improvement with PFS,” Dr. Motzer said.
Similarly, lenvatinib plus everolimus had median PFS of 14.7 months, 5.5 months longer than sunitinib (HR 0.65, 95% CI: 0.53–0.80; P < 0.001).
In all key subgroups, both lenvatinib arms showed PFS benefits in comparison to sunitinib.
The lenvatinib plus pembrolizumab arm also yielded significantly higher overall survival in the trial, compared with sunitinib (HR 0.66; 95% CI: 0.49-0.88; P= 0.005). In contrast, the overall survival did not different significantly between the lenvatinib plus everolimus arm and the sunitinib monotherapy arm (HR 1.15; 95% CI: 0.88–1.50; P=0.3). “Benefit was not achieved for LEN plus EVE,” he added.
The objective response rate also favored the lenvatinib combination arms. Lenvatinib plus pembrolizumab achieved an objective response rate of 71%, compared with 54% in the lenvatinib plus everolimus arm, and 36% in the sunitinib arm.
Safety profiles for the lenvatinib combinations “were consistent with each drug’s known profile and manageable, as needed, through dose modifications,” Dr. Motzer said.
Patients experienced more Grade 3 or higher treatment-related adverse events (TRAE) in the lenvatinib arms than the sunitinib arm. Longer treatment duration likely influenced the rate of AEs in the lenvatinib plus pembrolizumab group, he said. The median duration of treatment was 17 months for lenvatinib plus pembrolizumab, compared with 11 months for lenvatinib plus everolimus, and 7.8 months with sunitinib.
Diarrhea, hypertension, and stomatitis were the most common TRAEs reported across all arms in the study.