Cometriq (cabozantinib) significantly improved progression-free survival (PFS) versus Afinitor (everolimus) in patients with renal cell carcinoma (RCC) regardless of the degree of metastases, type or number of prior treatments, or patient risk status, according to a subgroup analysis of the phase 3 METEOR trial.1
The data were presented during a presscast held in advance of the 2016 Genitourinary Cancers Symposium, a meeting of hundreds of oncologists and oncology professionals held January 7-9 in San Francisco.
“Our preliminary results suggest that [Cometriq] may help overcome treatment resistance and provide new hope to patients with this aggressive cancer,” lead study author Bernard Escudier, 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 one-to-one ratio to receive daily Cometriq at 60 mg (330 patients) or Afinitor at 10 mg (328 patients). 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 Cometriq and 188 received Afinitor.
The median age of patients was approximately 62 years (ranging from 31 to 86) and a majority had received one prior VEGFR TKI (73 percent), with 27 percent of patients having received at least two prior therapies. Previous systemic therapy primarily consisted of Sutent (sunitinib, 62 percent), Votrient (pazopanib; 43 percent) and Inlyta (axitinib; 16 percent). By Memorial Sloan Kettering (MSK) Cancer Center criteria, 46 percent of patients were in the favorable prognostic risk category, 41 percent were intermediate, and 13 percent 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 Cometriq compared with 3.8 months with Afinitor.2 The updated PFS data for all 658 patients reported on the presscast were comparable to the interim data: 7.4 versus 3.9 months.
The PFS benefit for Cometriq over Afinitor held up across the majority of predetermined patient subgroups. Most notable, were the benefits observed in those patients at greatest risk.
In patients with at least three metastases sites, the median PFS was 7.3 months versus 3.7 months for Cometriq versus Afinitor, respectively. Cometriq reduced the risk of disease progression by 74 percent in patients with visceral and bone metastases (5.6 vs 1.9 months). Further, the benefit for PFS was observed across metastases sites, including lung, liver and bone.
In those labeled as “poor” prognostic risk by the MSK criteria, the benefit was 5.4 versus 3.5 months with Cometriq versus Afinitor, respectively.
“It looks as though [Cometriq] works very well in some challenging clinical scenarios,” said Sumanta Pal, from City of Hope, who moderated the presscast.
The number of prior VEGFR TKIs did not impact the PFS benefit of Cometriq. The median PFS was 7.4 versus 3.8 months and 7.4 versus 4.0 months among patients who received one or at least two prior VEGFR TKIs, respectively.
The type of prior VEGFR TKI, however, might have an impact on the benefit of Cometriq. In patients whose only prior VEGFR TKI was Votrient, the median PFS was 7.4 versus 5.1 months. However, in patients whose only previous VEGFR TKI was Sutent, the median PFS was 9.1 versus 3.7 months.
Patients benefited from Cometriq, regardless of prior treatment with a PD-1/PD-L1 inhibitor; however, the benefit was greater in patients who had received immunotherapy.
In the overall study population, tumor shrinkage occurred in 75 percent of the Cometriq arm versus 48 percent of the Afinitor 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. 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 Cometriq in RCC.
“The magnitude of benefit that patients get from [Cometriq] far exceeds — in my opinion — what we have seen to date in this setting in terms of both delay in tumor growth and improving survival. Patients who received [Cometriq] had nearly double the delay in cancer growth [versus] the comparator,” said Pal.
Safety results with the 2 drugs were comparable to outcomes observed in previous studies.
Grade 3/4 AEs occurred in 68 percent of patients treated with Cometriq versus 58 percent in those who received Afinitor. The most common grade 3/4 AEs with Cometriq were hypertension (15 percent), diarrhea (11 percent), and fatigue (9 percent) versus anemia (16 percent), fatigue (7 percent), and hyperglycemia (5 percent) with Afinitor. Grade 5 AEs occurred in 7 percent of patients treated with Cometriq and in 8 percent of those who received Afinitor.
The most common serious AEs in the Cometriq arm were abdominal pain (3 percent), pleural effusion (3 percent), and diarrhea (2 percent). In the Afinitor group, the most common serious AEs were anemia (4 percent), dyspnea (4 percent), and pneumonia (4 percent). Dose reductions were required for 60 percent and 25 percent of patients, in the Cometriq and Afinitor arms, respectively. The discontinuation rate due to adverse events (AEs) was 9 percent in the Cometriq arm versus 10 percent with Afinitor.
Based on data from the METEOR trial, the manufacturer of Cometriq, 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 Cometriq 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 3 CELESTIAL trial, which is comparing Cometriq to placebo for patients with HCC following treatment with sorafenib (NCT01908426).