FDA Approves Frontline Cabozantinib for Advanced RCC

Toni K. Choueiri, MD

The FDA has approved cabozantinib (Cabometyx) for previously untreated patients with advanced renal cell carcinoma (RCC), based on a meaningful improvement in progression-free survival (PFS) versus sunitinib (Sutent) in the CABOSUN trial.

In the phase II study, first-line treatment with cabozantinib reduced the risk of progression or death by 52% compared with sunitinib for patients with advanced RCC. The median PFS was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74; P = .0008). The approval was granted approximately 2 months ahead of an FDA deadline.

“The CABOSUN trial enrolled treatment-naïve patients with advanced kidney cancer, including those who are known to fare poorly, such as patients with intermediate- or poor-prognostic factors and those with bone metastases or multiple sites of metastatic disease,” lead investigator Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, said in a statement. “Physicians are already experienced in using Cabometyx in the second-line advanced RCC setting, and it is a much-needed advance to also now have Cabometyx as an option for their patients with previously untreated advanced RCC.”

The CABOSUN trial randomized 157 patients with poor- and intermediate-risk advanced RCC to receive cabozantinib at 60 mg once daily (n = 79) or sunitinib at 50 mg daily for 4 weeks on/2 weeks off (n = 78). Intermediate-risk patients accounted for 81% of the study population. Baseline characteristics were similar between the two arms.

In the cabozantinib group, the median age of patients was 63 years (range, 40-82). Patients had an ECOG performance status of 0 (46%), 1 (42%) and 2 (13%). Thirty-seven percent of patients had bone metastases and 72% had received a prior nephrectomy. The median diameter of lesions was 7.2 cm and the primary metastatic sites were the lung (70%), lymph nodes (57%), and bone (39%). The median number of metastatic sites was ≥3 for 32% of patients.

The objective response rate (all partial responses) with cabozantinib was 20% compared with 9% for sunitinib. When including those with stable disease, the over disease control rate was 75% with cabozantinib versus 47% for sunitinib. A reduction in target lesion size of any magnitude was recorded for 80% of patients in the cabozantinib arm versus 50% with sunitinib.

Cabozantinib showed similar superiority to sunitinib across all prespecified patient subgroups, including risk, bone metastases, and MET status. In those with poor-risk disease, there was a 69% reduction in disease progression or death (HR, 0.31; 95% Ci, 0.11-0.92). In the intermediate group, the HR for PFS was 0.52 in favor of cabozantinib (95% CI, 0.32-0.82).

The median duration of treatment exposure was doubled in the cabozantinib arm (6.5 vs 3.1 months) with fewer dose reductions required with cabozantinib (46% vs 35%). Treatment discontinuation due to adverse events (AEs) was similar between each group (21% vs 22%). Subsequent therapies were similar between each group.

The rate of grade 3/4 AEs was similar between the cabozantinib and sunitinib arms, respectively (68% vs 65%). Grade 5 AEs, regardless of cause, were experienced by 4% of patients in the cabozantinib arm compared with 10% in the sunitinib group.

When compared with cabozantinib, sunitinib led to higher rates thrombocytopenia (61% vs 38%), anemia (46% vs 33%), nausea (39% vs 32%), neutropenia (35% vs 15%), and leukopenia (35% vs 12%). However, compared with sunitinib, cabozantinib was associated with more diarrhea (73% vs 55%), hypertension (67% vs 44%), liver enzyme elevation (AST, 60% vs 31%; ALT, 55% vs 28%), decreased appetite (47% vs 32%) and weight loss (32% vs 17%, dysgeusia (41% vs 29%), and palmar-plantar erythrodysesthesia (42% vs 33%).

“We at the Alliance for Clinical Trials in Oncology are very gratified that the CABOSUN study supported the approval of Cabometyx for the potential first-line treatment of all patients with advanced renal cell carcinoma," senior author of the study Michael J. Morris, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and Chair of the Alliance Genitourinary (GU) Committee, said in a statement. "This trial exemplifies how NCI-sponsored studies can be efficient, accrue rapidly, and yield results highly relevant to the field."

Cabozantinib was initially approved by the FDA as a treatment for advanced RCC following one prior anti-angiogenic therapy in April 2016. This indication was based on findings from the phase III METEOR trial, in which cabozantinib showed a 4.9-month median OS benefit versus everolimus as a second-line therapy for advanced RCC. The risk of disease progression or death was reduced by 49% with cabozantinib over everolimus.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.

After 30.8 months of follow-up, the median overall survival was 26.6 months (95% CI, 14.6-not evaluable) in the cabozantinib arm versus 21.2 months (95% CI, 16.3-27.4) in the sunitinib arm, representing a nonstatistically significant 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21; P = 0.29).