Lenvima and Afinitor Approved for Advanced Renal Cell Carcinoma

After a phase 2 study, Lenvima and Afinitor gained FDA approval for the treatment of renal cell carcinoma.

Lenvima (lenvatinib) and Afinitor (everolimus) gained FDA approval for treatment for advanced renal cell carcinoma (RCC) following prior antiangiogeneic therapy, based on progression-free survival (PFS) and overall survival (OS) data from a phase 2 study.

In the trial, known as Study 205, the combination of Lenvima and Afinitor reduced the risk of progression or death by 63 percent compared with the mTOR inhibitor Afinitor alone. Median progression-free survival (PFS) with the combination was 14.6 versus 5.5 months with Afinitor. There was a 33 percent reduction in the risk of death with the combination versus the single-agent Afinitor.

Prior to the approval, the combination of Lenvima and Afinitor 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.

“Lenvima plus Afinitor 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 2 study Robert J. Motzer, 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 Afinitor alone. These noteworthy findings advance the treatment paradigm for this patient population.”

In the open-label phase 2 study, 153 patients were randomized in a 1-1-1 ratio to Lenvima plus Afinitor (51 patients), Lenvima monotherapy (52 patients) or Afinitor monotherapy (50 patients). In the combination arm, Lenvima was administered at 18 mg per day with Afinitor at five mg daily, which is the approved dose. In the single-agent groups, Afinitor was given at 10 mg/day and Lenvima 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 Sutent (sunitinib), at 71 percent, 67 percent and 56 percent in the combination, Lenvima, and Afinitor arms, respectively. Overall, 10 percent, 8 percent and 14 percent of patients in the combination, Lenvima, and Afinitor arms received cytokine therapy or a checkpoint inhibitor, respectively.

Data from the 101 patients who received the Lenvima combination and single-agent Afinitor were included in the FDA-approved label for the medication. In these patients specifically, the median age was 60 years (31 percent were older than 65 years). A majority of patients were male (72 percent), and the ECOG PS was 0 (54 percent) or 1 (46 percent). The primary endpoint of the study was investigator-assessed PFS. Secondary outcomes 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 Afinitor alone. At two years, 51 percent of remained alive in the combination arm versus 26 percent with single-agent Afinitor. The one-year PFS rate was 31 percent with the combination versus 14 percent with Afinitor.

The ORR with the Lenvima combination was 37 percent versus 6 percent with Afinitor alone. One patient in the combination arm experienced a complete response versus none with Afinitor alone.

The label for the combination included safety data from an additional 11 patients who received Lenvima plus Afinitor in a dose escalation portion of the study (62 patients). Median treatment duration with the Lenvima combination was 8.1 months versus 4.1 months with Afinitor 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 percent), dehydration (10 percent), anemia (6 percent), thrombocytopenia (5 percent), diarrhea (5 percent), vomiting (5 percent) and dyspnea (5 percent). AEs led to a dose reduction or interruption for 89 percent of patients in the combination arm versus 54 percent with single-agent Afinitor.

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

“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, co-director, Kidney Cancer Program at City of Hope, said in a statement. “The combination regimen of Lenvima and Afinitor provides a new treatment for patients with advanced RCC whose disease continues to progress despite prior treatment with an antiangiogenic therapy.”