Cabozantinib Improves Survival in Renal Cell Carcinoma

Toni Choueiri, MD

Cabozantinib (Cabometyx) reduced the risk of death by 34% compared with everolimus (Afinitor) in patients with previously treated advanced renal cell carcinoma (RCC), according to updated data from the phase III METEOR trial presented at the 2016 ASCO Annual meeting.¹

The results, which were simultaneously published in The Lancet Oncology² showed a 4.9-month median OS benefit with cabozantinib. The risk of disease progression was reduced by 49% with the multikinase inhibitor versus everolimus. Based on the METEOR trial, the FDA approved cabozantinib in April 2016 for patients with advanced RCC who had prior antiangiogenic therapy.

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

In the METEOR study, 658 patients with clear cell RCC were randomized in a 1:1 ratio to receive daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). The median age of patients was approximately 62 years (range, 31-86). By MSK criteria, approximately 46% of patients in each arm were in the favorable prognostic risk category, 41% were intermediate, and 13% were poor.

A majority of patients in each arm had received 1 prior VEGFR TKI (71%), with approximately 30% of patients having received ≥2 prior VEGFR TKIs. Use of prior VEGFR TKIs included sunitinib (64% in the cabozantinib arm vs 62% in the everolimus arm), pazopanib (44% vs 41%), axitinib (16% vs 17%), and sorafenib (6% vs 9%). The rates of prior cytokines, PD-1/PD-L1 agents, and bevacizumab between the cabozantinib and everolimus arms were similar as well, at 12% versus 16%, 5% versus 4%, and 2% versus 3%, respectively. Across the study, approximately 33% of patients had received radiotherapy and 86% of patients had undergone nephrectomy.

Median overall survival (OS) was 21.4 months (95% CI, 18.7 to not estimable) for patients receiving cabozantinib versus 16.5 months (95% CI, 14.7-18.8) for those receiving everolimus (HR, 0.66; 95% CI 0.53-0.83; P = .0003). The OS benefit with cabozantinib 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 cabozantinib regardless of MET expression level. This could reflect the broader target profile of cabozantinib.”

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

Among patients with bone metastases, the median OS with cabozantinib was 20.1 months versus 12.1 months with everolimus (HR, 0.54; 95% CI, 0.34-0.84). “We believe that these results due warrant further investigation into the underlying activity of cabozantinib in the bones.”

The updated median PFS by independent review was consistent with the initial PFS analysis at 7.4 months with cabozantinib compared with 3.9 months with everolimus (HR, 0.51; 95% CI, 0.41-0.62; P <.0001). Cabozantinib was superior to everolimus for PFS across all subgroups.

The median duration of treatment with cabozantinib was 8.3 versus 4.4 months with everolimus. The objective response rate (ORR) per independent review was 17% (95% CI, 13-22) in the cabozantinib arm versus 3% (95% CI, 2-6) in the everolimus arm. The stable disease rates were 65% versus 62% and the progressive rates were 12% versus 27%, respectively. The investigator-assessed ORR was 24% (95% CI, 19-29) with cabozantinib compared with 4% (95% CI, 2-7) with everolimus. Stables disease rates per investigator assessment were 63% in both arms and the progressive disease rates were 9% and 27%, respectively.

The updated safety results were consistent with those initially reported. The most common all-grade adverse events (AEs) with cabozantinib were diarrhea (75%), fatigue (59%), nausea (52%), decreased appetite (47%), PPES (43%), hypertension (37%), weight decrease (34%), and vomiting (34%). With everolimus, the most common all-grade AEs were fatigue (48%), anemia (39%), decreased appetite (35%), cough (34%), and dyspnea (30%).

The most common grade 3/4 AEs with cabozantinib were hypertension (15%), diarrhea (13%), and fatigue (11%), compared to anemia (17%), fatigue (7%), and hyperglycemia (5%) with everolimus.

Serious AEs occurred in 39% of the cabozantinib group and 40% of the everolimus arm. Dose reductions were required for 62% and 25% of patients in the cabozantinib and everolimus arms, respectively. Adverse events led to treatment discontinuation in 12% of the cabozantinib arm and 11% of the everolimus arm. There was 1 treatment-related death in the cabozantinib cohort and 2 among patients who received everolimus.

Following treatment discontinuation, some of the subsequent anticancer therapies received included VEGFR TKIs (24% in the cabozantinib arm vs 47% in the everolimus arm), everolimus (29% vs 5%), and PD-1/PD-L1 agents (5% vs 6%).

“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 M. Morrissey, PhD, president and CEO officer of Exelixis, which is codeveloping cabozantinib 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&mdash;now shows consistent survival benefit across all subgroups of patients evaluated in METEOR.”

Exelixis announced in May 2016 that cabozantinib has also demonstrated efficacy in the frontline setting for RCC. In the phase II CABOSUN trial, cabozantinib significantly improved PFS compared with sunitinib 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 cabozantinib indication in RCC.

1. Choueiri TK, Powles T, Escudier BJ, et al. Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib (Cabo) versus everolimus (Eve) in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol 34, 2016 (suppl; abstr 4506).
2. Choueiri TK, Escudier BJ, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial [published online June 5, 2016]. Lancet Oncol. doi: http://dx.doi.org/10.1016/S1470-2045(16)30107-3.

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