The CheckMate 025 trial, reported in The New England Journal of Medicine by Robert J. Motzer, MD, and colleagues, showed that treatment with the programmed cell death protein (PD-1) checkpoint inhibitor nivolumab (Opdivo) increased overall survival vs the mTOR inhibitor everolimus (Afinitor) in patients with advanced clear cell renal cell carcinoma who had received one or two prior regimens of antiangiogenic therapy.1
The METEOR trial, reported in The New England Journal of Medicine by Toni K. Choueiri, MD, and colleagues, showed that the multikinase inhibitor cabozantinib (Cometriq) improved progression-free survival vs everolimus in patients with advanced clear cell renal cell carcinoma progressing after vascular endothelial growth factor receptor (VEGFR)-targeted therapy.2 Cabozantinib targets VEGFR, MET, and AXL, the latter two of which are implicated in the development of resistance to VEGFR inhibitors.
Dr. Motzer is Professor of Medicine at Weill Cornell Medical College and Attending Physician at Memorial Sloan Kettering Cancer Center, New York. Dr. Choueiri is Associate Professor of Medicine at Harvard Medical School and Attending Physician at Dana-Farber Cancer Institute, Boston.
CheckMate 025 Trial
In the open-label CheckMate 025 study,1 821 patients from 146 sites in 24 countries in North America, Europe, Australia, South America, and Asia were randomly assigned between October 2012 and March 2014 to receive intravenous nivolumab at 3 mg/kg every 2 weeks (n = 410) or oral everolimus at 10 mg once daily (n = 411). The primary endpoint was overall survival. The nivolumab and everolimus groups were generally balanced for all baseline characteristics assessed.
After a preplanned interim analysis, the study was stopped early on the basis of an independent data monitoring committee assessment concluding that the study had met its endpoint with regard to significant results for overall survival. The minimum follow-up was 14 months.
Survival and Subsequent Therapy
Median overall survival was 25.0 months (95% confidence interval [CI] = 21.8 to not estimable) in the nivolumab group and 19.6 months (95% CI = 17.6–23.1 months) in the everolimus group (hazard ratio [HR] = 0.73, P = .002, meeting the prespecified criterion for superiority of P ≤ .0148). Hazard ratios consistently favored nivolumab in subgroup analyses, including subgroups for region, Memorial Sloan Kettering Cancer Center risk group, and number of previous antiangiogenic regimens.
Analysis by PD-1 ligand (PD-L1) expression level showed a median overall survival of 21.8 vs 18.8 months (HR = 0.79, 95% CI = 0.53–1.17) in patients with ≥ 1% and 27.4 vs 21.2 months (HR = 0.77, 95% CI = 0.60–0.97) in those with < 1%. Similar results were observed among patients with ≥ 5% and < 5% expression.
After progression, subsequent systemic therapy was given to 55% of the nivolumab group (including everolimus in 26%, axitinib [Inlyta] in 24%, and pazopanib [Votrient] in 9%) and 63% of the everolimus group (including axitinib in 36%, pazopanib in 16%, sorafenib [Nexavar] in 9%, and anti–PD-1 therapy in 2%). Study treatment was continued beyond progression in 44% of the nivolumab group and 46% of the everolimus group on the basis of investigator observation of continued clinical benefit.
Response Rate and Progression-Free Survival
The objective response rate was 25% (complete response in four patients) in the nivolumab group vs 5% (complete response in two patients) in the everolimus group (P < .001). Median progression-free survival was 4.6 vs 4.4 months (HR = 0.88, P = 0.11).
In light of a delayed separation of Kaplan-Meier survival curves, an ad hoc sensitivity analysis was performed including 145 nivolumab patients and 129 everolimus patients who had not died or had disease progression at 6 months. This analysis showed a median progression-free survival of 15.6 vs 11.7 months (HR = 0.64, 95% CI = 0.47–0.88).
Adverse Events
The most common treatment-related adverse events were fatigue (33%), nausea (14%), and pruritus (14%) in the nivolumab group and fatigue (34%), stomatitis (29%), and anemia (24%) in the everolimus group. Grade 3 or 4 treatment-related adverse events occurred in 19% vs 37%, with the most common being fatigue (2%) with nivolumab and anemia (8%) with everolimus.
Dose reductions occurred in 26% of everolimus patients. No reductions in nivolumab dose were permitted. Treatment-related adverse events led to treatment discontinuation in 8% vs 13% in the everolimus and nivolumab groups, respectively. Death considered related to treatment occurred in zero and two patients (due to septic shock and acute bowel ischemia).
The investigators concluded: “Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus.”
METEOR Trial
In the open-label METEOR trial,2 658 patients from 173 sites in 26 countries with disease progression after VEGFR-targeted therapy were randomly assigned between August 2013 and November 2014 to receive oral cabozantinib at 60 mg/d (n = 330) or oral everolimus at 10 mg/d (n = 328). The primary endpoint was progression-free survival.
The first 375 randomized patients (187 assigned to cabozantinib and 188 assigned to everolimus) constituted the progression-free survival population for the primary endpoint analysis. An interim analysis of overall survival, a secondary endpoint, was performed among the entire study population. The progression-free survival population cabozantinib and everolimus groups were generally balanced for all baseline characteristics assessed.
Progression-Free Survival
Minimum follow-up was 11 months in the progression-free survival population. Median progression-free survival on independent review was 7.4 months (95% CI = 5.6–9.1 months) in the cabozantinib group vs 3.8 months (95% CI = 3.7–5.4 months) in the everolimus group (HR = 0.58, P < .001).
A consistent benefit of cabozantinib was observed across subgroups defined by the number of prior VEGFR inhibitors and Memorial Sloan Kettering risk category. A post hoc analysis among 153 patients who received only sunitinib as VEGFR-targeted therapy showed a median progression-free survival of 9.1 vs 3.7 months (HR = 0.41).
Response Rate and Overall Survival
The objective response rate in the progression-free survival population was 21% with cabozantinib vs 5% with everolimus (all partial responses, P < .001). Objective response was observed in 22% (17/76) of cabozantinib recipients and 3% (2/77) of everolimus recipients who had received sunitinib as their only VEGFR inhibitor.
An interim analysis of overall survival in the entire population, with a minimum follow-up of 6 months, showed a benefit of cabozantinib (HR = 0.67, P = .005), but the difference did not cross the significance boundary for the interim analysis (P ≤ .0019). Follow-up continues for the final analysis of overall survival.
After progression, subsequent anticancer therapy was used in 38% of the cabozantinib group and 47% of the everolimus group. The most common subsequent treatments were everolimus (23%) in the cabozantinib group and axitinib (23%) in the everolimus group.
Adverse Events
The most common adverse events of any grade, irrespective of causal relationship to study drug, were diarrhea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), and palmar-plantar erythrodysesthesia syndrome (42%) in the cabozantinib group and fatigue (46%), anemia (38%), and decreased appetite (34%) in the everolimus group. Grade 3 or 4 adverse events occurred in 68% vs 58%; the most common in the cabozantinib group were hypertension (15%), diarrhea (11%), and fatigue (9%), and the most common in the everolimus group were anemia (16%), fatigue (7%), and hyperglycemia (5%).
Dose reductions occurred in 60% and 25% of patients, with the most common causes being diarrhea (16%), palmar-plantar erythrodysesthesia syndrome (11%), and fatigue (10%) in the cabozantinib group and pneumonitis (4%), fatigue (3%), and stomatitis (3%) in the everolimus group. Adverse events led to treatment discontinuation in 9% vs 10%. Death considered related to study treatment occurred in one patient in the cabozantinib group (death not otherwise specified) and in two patients in the everolimus group (aspergillosis and aspiration pneumonia).
The investigators concluded: “Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.” ■
Disclosure: The CheckMate 025 trial was funded by Bristol-Myers Squibb. The METEOR trial was funded by Exelixis. For full disclosures of the study authors, visit www.nejm.org.
References
1. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).
2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).
