The results of the phase 2 Study 218 indicated that the lower starting dose of 14 mg of lenvatinib (Lenvima) did not meet the threshold for non-inferiority compared to the FDA-approved starting dose of 18 mg.
The lower starting dose of 14 mg of lenvatinib (Lenvima) in combination with everolimus (Afinitor) in patients with clear-cell renal cell carcinoma (RCC) following treatment with an anti-angiogenic therapy, with prior anti-PD-1/PD-L1 therapy permitted, did not meet the threshold for non-inferiority compared to the FDA-approved starting dose of 18 mg.
The doses were evaluated in the phase 2 Study 218, designed to compare the safety and efficacy of the 2 different starting doses were. Results were presented by Eisai during an oral presentation at the International Kidney Cancer Symposium (IKCS) 2020.
Of note, Study 218 was conducted as a post-marketing commitment to the FDA and the EMA following priority review designation in the US and the approval of lenvatinib plus everolimus for the treatment of patients with advanced RCC who were previously treated with an anti-angiogenic therapy.
"With the influx of options for patients in the advanced RCC space, it is important that we continue to evaluate data in order to determine the most effective course of action that may help maximize therapeutic effects while managing tolerability for patients," lead study investigator Sumanta Pal, MD, co-director of the Kidney Cancer Program and clinical professor in the department of Medical Oncology & Therapeutics at City of Hope Comprehensive Cancer Center in Duarte, California. "The results from Study 218 show the potential benefit of [lenvatinib] plus everolimus in patients with advanced RCC, while providing a similar safety profile seen in previous studies."
In this randomized, open-label, phase 2 trial (NCT03173560), the primary efficacy end point was noninferiority of 14 mg of lenvatinib versus 18 mg for objective response rate (ORR) at week 24 (OR, > 0.76; P ≤ .045) based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. The primary safety end point was superiority of the proportion of patients with intolerable grade 2 or any grade 3 or higher treatment-emergent adverse events (TEAEs) within 24 weeks after randomization in the 14 mg versus 18 mg treatment arms.
Additionally, key secondary end points included overall ORR, progression-free survival (PFS) overall survival (OS), and safety. The study enrolled a total of 343 patients.
In the primary efficacy analysis, which included a total of 311 patients, the ORR at week 24 for patients treated with lenvatinib at the lower starting dose of 14 mg was not non-inferior to the ORR at week 24 for patients treated with the approved starting dose of 18 mg) (ORORRWK24, 0.88; 90% CI, 0.59-1.32; P = .2676). Moreover, the ORR at week 24 for patients starting with 14 mg and 18 mg was 32.1% (95% CI, 24.7-39.4) and 34.8% (95% CI, 27.3-42.3), respectively.
In the primary safety analysis, which included 309 patients, the occurrence of intolerable grade 2 or any grade 3 or higher TEAEs was found to be similar between the 14 mg and 18 mg treatment arms (82.8% vs. 79.6% [P = .4763], respectively). Notably, the 18 mg starting dose of lenvatinib plus 5 mg of everolimus also demonstrated a similar safety profile as seen in the previous phase 2 trial, Study 205.
In the full safety analysis set consisting of all patients who were randomized and received at least 2 doses of the study drug (n = 341), TEAEs resulted in:
Further, the overall ORR based on the primary efficacy analysis set of 311 patients for those starting with 14 mg and 18 mg of lenvatinib was 34.6% (95% CI, 27.1-42.1) and 40.6% (95% CI, 32.9-48.4), respectively (OR, 0.77; 90% CI, 0.52-1.14). Median PFS indicated a numerical benefit for patients treated with lenvatinib at 18 mg compared to lenvatinib at 14 mg, with the median PFS being 11.1 months (95% CI, 9.0-12.9) for patients treated with 14 mg versus 14.7 months (95% CI, 11.1-20.3) for patients treated with 18 mg. Median OS also indicated a numerical benefit for those treated with 18 mg of lenvatinib, with a median OS of 27.0 months (95% CI, 18.3-NE) observed for patients treated with 14 mg versus NE (95% CI: 23.8-NE) for patients treated with 18 mg.
Importantly, some of the most common any-grade TEAEs (≥ 20%) across the 14 mg and 18 mg treatment arms included diarrhea (68.2% vs. 72.0%), hypertension (30.1% vs. 35.7%), proteinuria (22.5% vs. 35.7%), decreased appetite (35.3% vs. 34.5%), and nausea (30.6% vs. 31.0%). Serious TEAEs (≥ 2%) also occurred in 49.1% of patients who received 14 mg of lenvatinib and 48.8% of patients who received 18 mg of lenvatinib.
"This research demonstrates our commitment to advancing our understanding of our oncology compounds and generates key insights for the medical community to help inform treatment decisions around dosing," Corina Dutcus, MD, vice president of Clinical Research for the Oncology Business Group at Eisai, said in the release. "This study, in which 343 patients received [lenvatinib] plus everolimus, helps to contribute to the growing body of evidence supporting the role of this TKI-mTOR combination in the advanced RCC treatment paradigm."
EISAI ANNOUNCES NEW INVESTIGATIONAL DATA EVALUATING TKI-MTOR INHIBITOR REGIMEN LENVIMA® (LENVATINIB) PLUS EVEROLIMUS IN ADVANCED RENAL CELL CARCINOMA (RCC) AT IKCS 2020 [news release]. Woodcliff Lake, New Jersey. Published November 7, 2020. Accessed November 9, 2020.