Cabozantinib Bests Everolimus Across High-Risk RCC Subgroups for PFS Improvement

Cabozantinib High-Risk RCC

Bernard Escudier, MD

In a comparison study, cabozantinib (Cometriq) significantly boosted progression-free survival (PFS) against everolimus (Afinitor) in patients with renal cell carcinoma (RCC) regardless of metastases degree, type, number of prior treatments, or patient risk status, according to a subgroup analysis of the phase III METEOR trial.¹

Data from the analysis of the trial were presented at a presscast held in advance of the 2016 Genitourinary Cancers Symposium.

“Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope to patients with this aggressive cancer,” lead study author Bernard Escudier, MD, chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France, said in a statement.

The METEOR study randomized 658 patients in a 1:1 ratio to receive daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). The primary endpoint of progression-free survival (PFS) was assessed on the first 375 patients enrolled in the trial. In this portion of the study, 187 patients were randomized to cabozantinib and 188 received everolimus.

The median age of patients was approximately 62 years (range, 31-86) and a majority had received one prior VEGFR TKI (73%), with 27% of patients having received ≥2 prior therapies. Previous systemic therapy primarily consisted of sunitinib (62%), pazopanib (43%), and axitinib (16%). By MSK criteria, 46% of patients were in the favorable prognostic risk category, 41% were intermediate, and 13% were poor.

After a minimum of 11 months of follow-up, the median PFS for the initial 375-patient analysis was 7.4 months with cabozantinib compared with 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75;P<.001).²The updated PFS data for all 658 patients reported on the presscast were comparable to the interim data: 7.4 versus 3.9 months (HR, 0.52; 95% CI, 0.43-0.64;P<.001).

The PFS benefit for cabozantinib over everolimus held up across the majority of predetermined patient subgroups. Most notable, were the benefits observed in those patients at greatest risk.

In patients with &ge;3 metastases sites, the median PFS was 7.3 months versus 3.7 months for cabozantinib versus everolimus, respectively (HR, 0.38; 0.29-0.50). Cabozantinib reduced the risk of disease progression by 74% in patients with visceral and bone metastases (5.6 vs 1.9 months; HR, 0.26; 95% CI, 0.16-0.43). Further, the HR for PFS favored cabozantinib across metastases sites, including lung (HR, 0.47), liver (HR, 0.53), and bone (HR, 0.50).

In those labeled as &ldquo;poor&rdquo; prognostic risk by the MSKCC scale, the benefit was 5.4 versus 3.5 months with cabozantinib versus everolimus, respectively (HR, 0.70; 95% CI, 0.42-1.16).

&ldquo;It looks as though cabozantinib works very well in some challenging clinical scenarios,&rdquo; said Sumanta Pal, MD, City of Hope, who moderated the presscast.

The number of prior VEGFR TKIs did not impact the PFS benefit of cabozantinib. The median PFS was 7.4 versus 3.8 months and 7.4 versus 4.0 months among patients who received 1 or &ge;2 prior VEGFR TKIs, respectively.

The type of prior VEGFR TKI, however, might have an impact on the benefit of cabozantinib. In patients whose only prior VEGFR TKI was pazopanib, the median PFS was 7.4 versus 5.1 months (HR, 0.67). However, in patients whose only previous VEGFR TKI was sunitinib, the median PFS was 9.1 versus 3.7 months (HR, 0.43).

Patients benefited from cabozantinib, regardless of prior treatment with a PD-1/PD-L1 inhibitor; however, the benefit was greater in patients who had received immunotherapy. The HR for PFS was 0.22 in favor of cabozantinib in patients treated with an anti—PD-1/PD-L1 agent compared with 0.54 in those patients with no prior checkpoint inhibitor treatment.

In the overall study population, tumor shrinkage occurred in 75% of the cabozantinib arm versus 48% of the everolimus arm, according to a statement released by ASCO.

At the interim analysis of the full study population, a trend toward improvement in overall survival (OS) was observed; however, this did not pass a high bar for statistical significance (HR, 0.67; 95% CI, 0.51-0.89;P= .005). APvalue of &le;.0019 was required to achieve significance. The survival follow-up will continue until the data mature.

Commenting on the PFS and OS data he has seen thus far, Pal is optimistic about the potential for cabozantinib in RCC.

&ldquo;The magnitude of benefit that patients get from cabozantinib far exceeds—in my opinion&mdash;what we have seen to date in this setting in terms of both delay in tumor growth and improving survival. Patients who received cabozantinib had nearly double the delay in cancer growth [versus ] the comparator,&rdquo; said Pal.

Safety results with the 2 drugs were comparable to outcomes observed in previous studies.

Grade 3/4 AEs occurred in 68% of patients treated with cabozantinib versus 58% in those who received everolimus. The most common grade 3/4 AEs with cabozantinib were hypertension (15%), diarrhea (11%), and fatigue (9%) versus anemia (16%), fatigue (7%), and hyperglycemia (5%) with everolimus. Grade 5 AEs occurred in 7% of patients treated with cabozantinib and in 8% of those who received everolimus.

The most common serious AEs in the cabozantinib arm were abdominal pain (3%), pleural effusion (3%), and diarrhea (2%). In the everolimus group, the most common serious AEs were anemia (4%), dyspnea (4%), and pneumonia (4%). Dose reductions were required for 60% and 25% of patients, in the cabozantinib and everolimus arms, respectively. The discontinuation rate due to adverse events (AEs) was 9% in the cabozantinib arm versus 10% with everolimus.

Based on data from the METEOR trial, the manufacturer of cabozantinib, Exelixis, recently completed an FDA new drug application (NDA) for use of the multikinase inhibitor as a treatment for patients with advanced RCC who have received 1 prior therapy. The NDA was submitted on a rolling basis as part of a breakthrough therapy designation granted in August 2015.

The FDA initially approved cabozantinib as a treatment for patients with metastatic medullary thyroid cancer in November 2012. The agent continues to be explored in a number of solid tumors, including the phase III CELESTIAL trial, which is comparing cabozantinib to placebo for patients with HCC following treatment with sorafenib (NCT01908426).

ReferencesEscudier BJ, Motzer RJ, Powles T, et al. Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients (pts) with advanced renal cell carcinoma (RCC). 2016 Genitourinary Cancers Symposium Presscast; January 4, 2016. Abstract 499.Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823.