ESMO20 YO for YO: highlights on metastatic renal cell carcinoma-the CheckMate-9ER trial.
Ontology highlight
ABSTRACT:
SUBMITTER: Kfoury M
PROVIDER: S-EPMC7807955 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
ESMO20 YO for YO: highlights on metastatic renal cell carcinoma-the CheckMate-9ER trial.
ESMO open 20210104 1
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Project description:PurposeIn the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure-response analysis characterized the relationship of cabozantinib exposure with clinical endpoints.MethodsDose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event Cox proportional hazard (CPH) exposure-response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs.ResultsKaplan-Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure-response analysis.ConclusionTo optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.
| S-EPMC9905187 | biostudies-literature
Project description:BackgroundThe phase III CheckMate 9ER trial originally included a nivolumab plus ipilimumab plus cabozantinib triplet arm, which was discontinued early due to the evolving treatment landscape for first-line advanced renal cell carcinoma (aRCC). We report an exploratory analysis of patients randomised to the triplet regimen before enrolment discontinuation.MethodsPatients with clear-cell aRCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) Q3W for four cycles with once-daily cabozantinib (40 mg), then nivolumab (240 mg) Q2W plus once-daily cabozantinib (40 mg). CheckMate 9ER primary (progression-free survival [PFS] by blinded independent central review [BICR]) and key secondary (overall survival [OS], objective response rate [ORR] by BICR, and safety) endpoints were applied, along with investigator-assessed PFS and ORR.ResultsFifty patients were randomised to the triplet regimen. After a median follow-up of 39.1 months (range, 33.4-44.5), median PFS (95% CI) was 9.9 (5.7-16.8) months by BICR and 13.9 (7.3-24.7) months by investigator; median OS (95% CI) was 37.0 (31.8-not estimable) months. ORR (95% CI) was 44.0% (30.0-58.7; complete response, 8.0%) by BICR and 48.0% (33.7-62.6; all partial responses) by investigator. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 84.0%, most commonly alanine aminotransferase increased (20.0%), aspartate aminotransferase increased (16.0%), and hepatotoxicity (16.0%). Grade 3-4 hepatic immune-mediated AEs occurred in 40.0%. There were no grade 5 TRAEs.ConclusionsThese results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC, although monitoring of overlapping toxicities will be important in future studies of this regimen.Clinicaltrialsgov registration: NCT03141177.
| S-EPMC9750497 | biostudies-literature
Project description:BackgroundIn the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety.MethodsThis open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177.FindingsBetween Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death).InterpretationWith extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma.FundingBristol Myers Squibb and Ono Pharmaceutical.
| S-EPMC10305087 | biostudies-literature
Project description:BackgroundIn the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER.MethodsIn this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment.FindingsBetween Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001).InterpretationPROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma.FundingBristol Myers Squibb.
| S-EPMC9479564 | biostudies-literature
Project description:Purpose Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab plus ipilimumab in combination, and nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the nivolumab plus ipilimumab arms of the study are presented. Patients and Methods Patients with mRCC received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). Results All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively. Conclusion Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.
| S-EPMC7587408 | biostudies-literature