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

Response patterns to nivolumab differ from those seen with other approved targeted therapies. 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. 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. Nivolumab 3mg/kg intravenously every 2 wk. 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. 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. 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.

Escudier B ，Motzer RJ ，Sharma P ，Wagstaff J ，Plimack ER ，Hammers HJ ，Donskov F ，Gurney H ，Sosman JA ，Zalewski PG ，Harmenberg U ，McDermott DF ，Choueiri TK ，Richardet M ，Tomita Y ，Ravaud A ，Doan J ，Zhao H ，Hardy H ，George S ... -  《-》

Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial.

George S ，Motzer RJ ，Hammers HJ ，Redman BG ，Kuzel TM ，Tykodi SS ，Plimack ER ，Jiang J ，Waxman IM ，Rini BI ... -  《-》

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials.

Long GV ，Weber JS ，Larkin J ，Atkinson V ，Grob JJ ，Schadendorf D ，Dummer R ，Robert C ，Márquez-Rodas I ，McNeil C ，Schmidt H ，Briscoe K ，Baurain JF ，Hodi FS ，Wolchok JD ... -  《-》

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

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). To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. 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. 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. 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.

Escudier B ，Sharma P ，McDermott DF ，George S ，Hammers HJ ，Srinivas S ，Tykodi SS ，Sosman JA ，Procopio G ，Plimack ER ，Castellano D ，Gurney H ，Donskov F ，Peltola K ，Wagstaff J ，Gauler TC ，Ueda T ，Zhao H ，Waxman IM ，Motzer RJ ，CheckMate 025 investigators ... -  《-》

Safety and Efficacy of Nivolumab in Patients With Advanced Non-small-cell Lung Cancer Treated Beyond Progression.

Treatment with immune checkpoint inhibitors beyond progression is associated with improved survival in patients with melanoma and clear-cell renal carcinoma. Whether this association exists for patients with non-small-cell lung cancer (NSCLC) is currently still unclear. We performed a multi-institutional retrospective study based on landmark and multivariable analyses to evaluate the safety and efficacy of treatment with nivolumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression in patients with advanced NSCLC. Criteria for receiving nivolumab beyond progression were investigator-assessed clinical benefit, stable performance status, tolerance of treatment, and no need of immediate intervention to prevent serious complication of progression. Of 176 patients progressed to nivolumab according to RECIST v1.1, 60 (34.1%) were treated beyond progression (TBP) and 116 (65.9%) were not-TBP (NTBP). The median overall survival was significantly longer in the TBP group compared with the NTBP group (17.8 vs. 3.7 months; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.21-0.46; P < .0001). In a landmark analysis of evaluable patients beginning 6 weeks from first progression, the median overall survival for patients TBP was 10.7 months and for those NTBP, 3.4 months (HR, 0.48; 95% CI, 0.30-0.77; P = .002). Discontinuation of nivolumab at first progression was associated with shorter survival in multivariable analysis (HR, 2.98; 95% CI, 1.95-4.54; P < .001). No safety concerns emerged in patients who were in the TBP group. A subset of patients with NSCLC and progressive disease may continue to benefit from nivolumab beyond progression. Discontinuation of immunotherapy based only on RECIST v1.1 may be premature.

Ricciuti B ，Genova C ，Bassanelli M ，De Giglio A ，Brambilla M ，Metro G ，Baglivo S ，Dal Bello MG ，Ceribelli A ，Grossi F ，Chiari R ... -  《-》