Cabometyx Improves Survival in Renal Cell Carcinoma

Cabometyx (Cabozantinib) reduced the risk of death by 34 percent compared with Afinitor (everolimus) in patients with previously treated advanced renal cell carcinoma (RCC), according to updated data from the phase 3 METEOR trial presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

The results, which were simultaneously published in The Lancet Oncology showed a 4.9-month median overall survival (OS) benefit with the multikinase inhibitor Cabometyx. The risk of disease progression was reduced by 49 percent with Cabometyx versus Afinitor.

Based on the METEOR trial, the FDA approved Cabometyx in April 2016 for patients with advanced RCC who had prior antiangiogenic therapy.

“In the phase 3 METEOR trial, treatment with Cabometyx was associated with a significant improvement in overall survival, as well as progression-free survival and objective response rate compared with Afinitor in patients with advanced renal cell carcinoma. Cabometyx is a new standard for patients with advanced RCC after prior antiangiogenic therapy,” said lead author Toni Choueiri, clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute.

In the METEOR study, 658 patients with clear cell RCC were randomized and given either Cabometyx or Afinitor daily. The median age of patients was approximately 62 years.

A majority of patients in each arm had received one prior vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), with approximately 30 percent of patients having received two or greater prior VEGFR TKIs. Use of prior VEGFR TKIs included Sutent (sunitinib), Votrient (pazopanib), Inlyta (axitinib) and Nexavar (sorafenib). The rates of prior cytokines, PD-1/PD-L1 agents and Avastin (bevacizumab) between the Cabometyx and Afinitor arms were similar as well, at 12 percent versus 16 percent, 5 percent versus 4 percent and 2 percent versus 3 percent, respectively.

Across the study, approximately 33 percent of patients had received radiotherapy and 86 percent of patients had undergone surgery to remove the kidneys.

Median OS was 21.4 months for patients receiving Cabometyx versus 16.5 months for those receiving Afinitor. The OS benefit with Cabometyx was sustained across all prespecified patient subgroups, including MSKCC risk groups, prior VEGFR TKIs, bone metastases, visceral bone metastases and tumor MET status.

Commenting on the MET subgroup, Choueiri said, “The hazard ratio for overall survival in the MET-high versus MET-low expression group does suggest that patients do experience clinical benefit with Cabometyx regardless of MET expression level. This could reflect the broader target profile of Cabometyx.”

He also noted that there was a similar OS benefit between patients whose only prior VEGFR TKI was either Sutent or Votrient. The hazard ratio for OS was 0.66 for both subgroups.

Among patients with bone metastases, the median OS with Cabometyx was 20.1 months versus 12.1 months with Afinitor. “We believe that these results due warrant further investigation into the underlying activity of Cabometyx in the bones,” said Choueiri.

The updated median PFS by independent review was consistent with the initial progression-free survival (PFS) analysis at 7.4 months with Cabometyx compared with 3.9 months with Afinitor. Cabometyx was superior to Afinitor for PFS across all subgroups.

The median duration of treatment with Cabometyx was 8.3 versus 4.4 months with Afinitor. The objective response rate (ORR) per independent review was 17 percent in the Cabometyx arm versus 3 percent in the Afinitor arm.

The stable disease rates were 65 percent versus 62 percent and the progressive rates were 12 percent versus 27 percent, respectively. The investigator-assessed ORR was 24 percent with Cabometyx compared with 4 percent with Afinitor. Stables disease rates per investigator assessment were 63 percent in both arms and the progressive disease rates were 9 percent and 27 percent, respectively.

The updated safety results were consistent with those initially reported. The most common all-grade side effects with Cabometyx were diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, hypertension, weight loss and vomiting. With Afinitor, the most common all-grade side effects were fatigue, anemia, decreased appetite, cough and difficulty breathing.

The most common grade ¾ side effects with Cabometyx were hypertension, diarrhea and fatigue, compared to anemia, fatigue and hyperglycemia with Afinitor.

Serious side effects occurred in 39 percent of the Cabometyx group and 40 percent of the Afinitor arm. Dose reductions were required for 62 percent and 25 percent of patients in the Cabometyz and Afinitor arms, respectively. Side effects led to treatment discontinuation in 12 percent of the Cabometyx arm and 11 percent of the Afinitor arm. There was one treatment-related death in the Cabometyx cohort and two among patients who received Afinitor. Following treatment discontinuation, some of the subsequent anticancer therapies received included VEGFR TKIs, Afinitor and PD-1/PD-L1 agents.

“We [were] excited to share the detailed overall survival results from the METEOR trial with the oncology community at this year’s ASCO Annual Meeting,” Michael Morrissey, president and CEO officer of Exelixis, which is codeveloping Cabometyx with Ipsen, said in a statement.

“The five-year survival rate for patients diagnosed with advanced kidney cancer is only 12 percent, underscoring the need for new treatment options that help patients live longer while delaying the progression of their disease. Critically, Cabometyx—the first FDA-approved therapy to demonstrate a benefit in all three key efficacy parameters—now shows consistent survival benefit across all subgroups of patients evaluated in METEOR.”

Exelixis announced in May 2016 that Cabometyx has also demonstrated efficacy in the frontline setting for RCC. In the phase 2 CABOSUN trial, Cabometyx significantly improved PFS compared with Sutent in treatment-naive patients with advanced RCC. Exelixis plans to submit the full CABOSUN results for presentation at an upcoming medical meeting and communicate with regulatory authorities about a potential first-line Cabometyx indication in RCC.