Abstract
BackgroundCombination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.MethodsPatients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.ResultsArm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached.Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.ConclusionsThe addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.Trial registrationClinicaltrials.gov identifier: NCT01472081. Registered 16 November 2011.
Highlights
Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma
While there was no adverse impact on response and the overall survival (OS) outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose
Arm N + P was not expanded beyond the nivolumab 2 mg/ kg (N2) dose as per prespecified criteria for dose-limiting toxicity (DLT); three patients had elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and one had fatigue
Summary
Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). In updated results from the key phase III trial comparing sunitinib with interferon alpha (N = 750), treatment-naïve patients with aRCC achieved an objective response rate (ORR) of 47% versus 12% (P < 0.001), a median progression-free survival (PFS) of 11 versus 5 months (P < 0.001), and a median overall survival (OS) of 26.4 versus 21.8 months (P = 0.051) [9]. In second-line trials of sunitinib in aRCC (post VEGF-targeted therapy), reported ORRs have ranged from 15 to 27%, and median PFS has ranged from ~ 5–18 months [14]. In the open-label COMPARZ trial, which compared the efficacy and safety of pazopanib versus sunitinib as first-line therapy in 1110 patients with clear cell aRCC, PFS was 8.4 versus 9.5 months, respectively [8]. Sunitinib and pazopanib are considered to be efficacious as first-line therapy in aRCC [17], and do not differentially impact outcomes with subsequent second-line treatment [18]
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