The designation was based on findings from an open-label three-arm phase II study that demonstrated an improvement in progression-free survival (PFS) for lenvatinib compared with everolimus (Afinitor) in patients with advanced RCC. In findings presented at the 2015 ASCO Annual Meeting, lenvatinib monotherapy improved PFS by 39% versus everolimus monotherapy (HR = 0.61; 95% CI, 0.38-0.98; P = .048). Additionally, the combination of lenvatinib and everolimus demonstrated a 60% improvement in PFS over everolimus alone (HR = 0.40; 95% CI, 0.24-0.68; P <.001).
"We are excited and honored that the FDA has granted breakthrough therapy designation to lenvatinib for patients with metastatic renal cell carcinoma," Kenichi Nomoto, PhD, president, Oncology Product Creation Unit at Eisai, said in a statement. "We look forward to working closely with the FDA to expedite this clinical program and hope to offer an important additional treatment option to patients in need."
In the phase II open-label study, 153 patients were randomized in a 1:1:1 ratio to lenvatinib (18 mg/day) plus everolimus (5 mg/day), lenvatinib monotherapy (24 mg/day) or everolimus monotherapy (10 mg/day). No crossover was permitted within the context of the study. The primary endpoint of the study was to compare PFS in the lenvatinib arms with single agent everolimus.
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. The remaining patients had received either pazopanib or sorafenib. Thirteen percent of patients had received a prior cytokine or checkpoint inhibitor therapy, at 10%, 8%, and 14%, in the combination, lenvatinib, and everolimus arms, respectively.
The median PFS was 14.6 months for lenvatinib plus everolimus (n = 51), 7.4 months for lenvatinib alone (n = 52), and 5.5 months for everolimus (n = 50). The ORR in the combination arm was 43%, with lenvatinib it was 27%, and with everolimus it was 6%.
The median overall survival (OS) was 25.5 months in the combination arm, 19.1 months in the lenvatinib monotherapy arm, and 15.4 months in the single-agent everolimus arm. The combination of lenvatinib and everolimus reduced the risk of death by 49% compared with everolimus alone (HR = 0.51; 95% CI, 0.30-0.88; P = .024). Single-agent lenvatinib improved OS by 32% versus single-agent everolimus (HR = 0.68; 95% CI; 0.41-1.14); however this was not statistically significant (P = .118).
All patients experienced at least one treatment-emergent adverse event (AE) in each treatment arm. Treatment-related grade 3 AEs occurred in 71% of patients in the combination arm, 83% in the single-agent lenvatinib arm, and 52% in the everolimus arm. There were relatively few grade 4 events in any of the three arms.
Diarrhea was the most frequently occurring all-grade AE in the lenvatinib arms, at 84% in the combination arm and 71% with monotherapy. Grade 3 diarrhea occurred in 20% of patients in the combination arm compared with 12% for single-agent lenvatinib and 2% with everolimus. Outside of diarrhea, other common grade ≥3 AEs with the combination included hypertension (14%) and fatigue (10%).
"The high-response rate and the longer OS results speak to the high-level of efficacy observed in the study for the combination," lead investigator Robert Motzer, MD, an attending physician, Memorial Sloan Kettering Cancer Center, said when the findings were presented. "Adverse events were generally higher for the lenvatinib-containing arms compared with everolimus. These adverse events were predictable, and generally managed with dose modifications."
Dose reductions were required in 73% of patients treated the combination, 62% treated with single-agent lenvatinib, and for 26% in the everolimus alone arm. AEs were the cause of treatment discontinuation for 9%, 11%, and 5% of patients in the combination, single-agent lenvatinib, and everolimus arm, respectively.
The FDA initially approved Lenvatinib as a treatment for patients with progressive, radioactive iodine-refractory differentiated thyroid cancer in February 2015. The FDA's breakthrough therapy designation will help further expedite the development of the therapy for patients with advanced RCC.
Studies continue to assess lenvatinib for patients with RCC, including a phase I investigation of the combination of lenvatinib and everolimus in patients with unresectable advanced RCC (NCT02454478). Additionally, a phase Ib/II study is exploring lenvatinib in combination with the PD-1 inhibitor pembrolizumab (Keytruda) for patients with solid tumors, including RCC (NCT02501096).
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