FDA Approves Lenvatinib/Everolimus for Advanced RCC

Robert J. Motzer, MD

The FDA has approved the combination of lenvatinib (Lenvima) and everolimus (Afinitor) as a treatment for patients with advanced renal cell carcinoma (RCC) following prior antiangiogeneic therapy, based on survival and response data from a phase II study.

In the trial, known as Study 205, the combination of lenvatinib and everolimus reduced the risk of progression or death by 63% compared with the mTOR inhibitor everolimus alone. Median progression-free survival (PFS) with the combination was 14.6 versus 5.5 months with everolimus (HR, 0.37; 95% CI, 0.22-0.62). There was a 33% reduction in the risk of death with the combination versus single-agent everolimus.

Prior to the approval, the combination of lenvatinib and everolimus had received a breakthrough therapy designation as a treatment for RCC. The combination was approved earlier than anticipated, under the FDA's priority review program.

“Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade,” lead investigator of the phase II study Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, said in a statement. “This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone. These noteworthy findings advance the treatment paradigm for this patient population.”

In the open-label phase II study, 153 patients were randomized in a 1:1:1 ratio to lenvatinib plus everolimus (n = 51), lenvatinib monotherapy (n = 52), or everolimus monotherapy (n = 50). In the combination arm, lenvatinib was administered at 18 mg per day with everolimus at 5 mg daily, which is the approved dose. In the single-agent groups, everolimus was given at 10 mg/day and lenvatinib was administered at 24 mg/day. Crossover was not permitted in the study.

The most common prior VEGF therapy received by patients in the trial was sunitinib, at 71%, 67%, and 56% in the combination, lenvatinib, and everolimus arms, respectively. Overall, 10%, 8%, and 14% of patients in the combination, lenvatinib, and everolimus arms received cytokine therapy or a checkpoint inhibitor, respectively.

Data from the 101 patients who received the lenvatinib combination and single-agent everolimus were included in the FDA-approved label for the medication. In these patients specifically, the median age was 60 years (31% were >65 years). A majority of patients were male (72%), and the ECOG PS was 0 (54%) or 1 (46%). The primary endpoint of the study was investigator-assessed PFS. Secondary outcome measures included objective response rate (ORR) and overall survival (OS).

The median OS with the combination was 25.5 months compared with 15.4 months with everolimus alone (HR, 0.67; 95% CI, 0.42-1.08). At 2 years, 51% of patients remained alive in the combination arm versus 26% with single-agent everolimus. The 1-year PFS rate was 31% with the combination versus 14% with everolimus.

The ORR with the lenvatinib combination was 37% versus 6% with everolimus alone. One patient in the combination arm experienced a complete response versus none with everolimus alone. 

The label for the combination included safety data from an additional 11 patients who received lenvatinib plus everolimus in a dose escalation portion of the study (N = 62). Median treatment duration with the lenvatinib combination was 8.1 months versus 4.1 months with everolimus alone.

All patients experienced at least one treatment-emergent adverse event (AE) across all treatment arms. The most common serious AEs with the combination were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). AEs led to a dose reduction or interruption for 89% of patients in the combination arm versus 54% with single-agent everolimus.

The most frequently reported grade 3/4 AEs with the combination versus single-agent were diarrhea (19% vs 2%), fatigue (18% vs 2%), hypertension (13% vs 2%), hyponatremia (11% vs 6%), lymphocyte count decrease (10% vs 20%), renal failure (10% vs 2%), proteinuria (8% vs 2%), and hemoglobin decrease (8% vs 16%).

“Rates of renal cell carcinoma have been on the rise over the past several decades, and unfortunately, advanced RCC remains an incurable disease. Since the VEGF pathway is known to be involved in the growth of renal cell tumors, it is important to have a diverse offering of therapeutic options, including treatments that continue to target VEGF inhibition,” Sumanta Kumar Pal, MD, co-director, Kidney Cancer Program at City of Hope, said in a statement. “The combination regimen of lenvatinib and everolimus provides a new treatment for patients with advanced RCC whose disease continues to progress despite prior treatment with an antiangiogenic therapy.”

The FDA initially approved lenvatinib as a treatment for patients with radioactive iodine-refractory, progressive differentiated thyroid cancer in February 2015. The RCC indication is the second for the receptor tyrosine kinase inhibitor, which continues to be assessed across a variety of settings. An application for the combination in RCC is also being considered by European regulatory agencies.