Toni K. Choueiri, MD
Patients with untreated advanced renal cell carcinoma (RCC) lived significantly longer without disease progression when they received the multikinase inhibitor cabozantinib (Cabometyx) as initial therapy versus sunitinib (Sutent), according to results of an independent review of the randomized CABOSUN trial reported at the 2017 ESMO Congress in Madrid.
Results showed that cabozantinib-treated patients had a median progression-free survival (PFS) of 8.6 months compared with 5.3 months for patients treated initially with sunitinib. The difference represented a 52% reduction in the hazard for progression or death.
The independent review of the data confirmed the primary analysis of the CABOSUN randomized trial, which showed a median PFS of 8.2 months with cabozantinib and 5.6 months with sunitinib by investigator assessment (HR, 0.66; 95% CI, 46%-95%; 1-sided P
“Cabozantinib treatment resulted in clinically meaningful and statistically significant prolongation of progression-free survival per independent review compared with sunitinib as initial targeted therapy in patients with advanced RCC,” Toni Choueiri, MD, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, and collaborators concluded in a poster presentation.
“Subgroup analyses of PFS were consistent with the overall population results,” he added. “The objective response rate per independent review with cabozantinib was twice that observed with sunitinib.”
An updated review of overall survival (OS) showed a numerical advantage in favor of cabozantinib, but the difference did not achieve statistical significance, which was consistent with the initial investigator review of survival.
The CABOSUN trial involved 157 poor- and intermediate-risk patients with advanced RCC, a subgroup of patients with worse prognosis and survival compared with patients who advanced RCC and favorable risk characteristics. Intermediate-risk patients accounted for 81% of the study population.
The patient population had a median age of about 63. Key clinical features included bone metastases in about 36% of patients, prior nephrectomy in 75%, and 3 or more metastatic sites in about 35%. The most common sites of metastasis were lung (70%), lymph nodes (55%), and bone (38%).
Patients were randomized 1:1 to receive oral cabozantinib at 60 mg once daily (n = 79) or oral sunitinib at 50 mg daily for 4 weeks on/2 weeks off (n = 78). Treatment was administered until disease progression or intolerable toxicity.
CABOSUN had a primary endpoint of PFS as assessed by trial investigators. A key secondary endpoint was assessment of PFS by an independent review committee. The review was conducted by means of retrospective blinded review of radiographic images.
The independent review of PFS confirmed the primary analysis, and the 3.3-month absolute difference in favor of cabozantinib remained statistically significant, consistent with the primary analysis (HR, 0.48; 95% CI, 0.31-0.74; P
= 0.0008). A subgroup analysis favored cabozantinib for all prespecified patient groups, including intermediate or poor risk, presence or absence of bone metastases, and positive or negative MET status.
The updated survival analysis occurred after a median follow-up of 30.8 months and showed a median OS of 26.6 months in the cabozantinib arm versus 21.2 months in the sunitinib arm. The difference represented a 20% reduction in the hazard ratio in favor of cabozantinib—a difference that did not achieve statistical significance (HR, 0.80; 95% CI, 0.53-1.21; P = 0.29).
Twice as many patients had objective responses with cabozantinib compared with sunitinib (20% vs 9%). In the cabozantinib group, 16 patients had confirmed partial responses and 43 had stable disease, resulting in a disease control rate (DCR) of 75%. That compared with 7 partial responses, stable disease in 30 patients, and a DCR of 47% in the sunitinib arm. The original report of investigator-assessed outcomes showed DCRs of 78% and 54% for cabozantinib and sunitinib, respectively.
An analysis of adverse events (AEs) showed that treatment with cabozantinib was associated with higher any-grade rates of diarrhea than sunitinib (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%). Treatment with sunitinib versus cabozantinib 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%).
About two-thirds of patients in each group received subsequent cancer therapy at progression.
During a formal discussion of the updated CABOSUN results, Camilo Porta, MD, of the University of Pavia in Italy, said that the study made a convincing case for the superiority of cabozantinib versus sunitinib.
“The progression-free survival benefit survived the independent review committee, and the hazard ratio was even better,” said Porta. “Furthermore, the survival benefit was clinically relevant, though not statistically significant—the trial was underpowered for overall survival.”
In questioning whether cabozantinib could be a novel standard of care for intermediate-risk patients, Porta added, “I wouldn’t be so straightforward, mainly due to the limited number of patients treated. For sure, cabozantinib should be regarded as a choice for these patients.”
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.