Huanyu Zhao

CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

BACKGROUND The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). OBJECTIVE To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. DESIGN, SETTING, AND PARTICIPANTS Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. INTERVENTION Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. RESULTS AND LIMITATIONS The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. CONCLUSION The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. PATIENT SUMMARY We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.

Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025

BACKGROUND Response patterns to nivolumab differ from those seen with other approved targeted therapies. OBJECTIVE To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression. DESIGN, SETTING, AND PARTICIPANTS This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression. INTERVENTIONS Nivolumab 3mg/kg intravenously every 2 wk. RESULTS AND LIMITATIONS Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n=142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis. CONCLUSIONS A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784. PATIENT SUMMARY A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.

Erratum to "CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma" [Eur Urol 2017;72:962-71]

a Institute Gustave Roussy, Villejuif, France; MD Anderson Cancer Center, University of Texas, Houston, TX, USA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; Roswell Park Cancer Institute, Buffalo, NY, USA; e Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; f Stanford Cancer Institute, Stanford, CA, USA; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Vanderbilt University Medical Center, Nashville, TN, USA; i Fondazione Istituto Nazionale Tumori, Milan, Italy; j Fox Chase Cancer Center, Philadelphia, PA, USA; Hospital Universitario 12 De Octubre, Madrid, Spain; Westmead Hospital, Westmead, NSW, Australia; Aarhus University Hospital, Aarhus, Denmark; Comprehensive Cancer Center, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; o South West Wales Cancer Institute and Swansea University College of Medicine, Swansea, UK; University Hospital Essen of University of Duisburg-Essen, Essen, Germany; Chiba Cancer Center, Chiba, Japan; Bristol-Myers Squibb, Princeton, NJ, USA; Memorial Sloan Kettering Cancer Center, New York, NY, USA