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Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

ABSTRACT: BACKGROUND:Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented. MATERIALS AND METHODS:Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs. RESULTS:Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%). CONCLUSION:The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC. IMPLICATIONS FOR PRACTICE:Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.

SUBMITTER: Morse MA

PROVIDER: S-EPMC6853093 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

Morse Michael A MA Overman Michael J MJ Hartman Leighanne L Khoukaz Taline T Brutcher Edith E Lenz Heinz-Josef HJ Atasoy Ajlan A Shangguan Tong T Zhao Huanyu H El-Rayes Bassel B

The oncologist 20190530 11

<h4>Background</h4>Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficien ...[more]

PMID: 31147488

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Project description:PurposeIn patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H).Patients and methodsNEONIPIGA (ClinicalTrials.gov identifier: NCT04006262) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate.ResultsBetween October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse.ConclusionNivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

Project description:PurposeCheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.MethodsPatients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.ResultsSeventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.ConclusionWith longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

Project description:ObjectiveThe aim of this study was to investigate the cost-effectiveness of serplulimab versus regorafenib in previously treated unresectable or metastatic microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) colorectal cancer in China.MethodsFrom the perspective of China's health-care system, a Markov model with three health states (progression free, progression, death) was developed for estimating the costs and health outcomes of serplulimab and regorafenib. Data for unanchored matching-adjusted indirect comparison (MAIC), standard parametric survival analysis, the mixed cure model, and transition probabilities calculation were obtained from clinical trials (ASTRUM-010 and CONCUR). Health-care resource utilization and costs were derived from government-published data and expert interviews. Utilities used to calculate quality-adjusted life years (QALYs) were obtained from clinical trials and literature reviews. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed as cost/QALY gained. Four scenarios were considered in scenario analysis: (a) using original survival data without conducting MAIC; (b) limiting the time horizon to the follow-up time of the clinical trial of serplulimab; (c) adopting a fourfold increase in the risk of death; and (d) applying utilities from two other sources. One-way sensitivity analysis and probabilistic sensitivity analysis were also performed to assess the uncertainty of the results.ResultsIn the base-case analysis, serplulimab provided 6.00 QALYs at a cost of $68,722, whereas regorafenib provided 0.69 QALYs at a cost of $40,106. Compared with that for treatment with regorafenib, the ICER for treatment with serplulimab was $5,386/QALY, which was significantly lower than the triple GDP per capita of China in 2021 ($30,036), which was the threshold used to define the cost-effectiveness. In the scenario analysis, the ICERs were $6,369/QALY, $20,613/QALY, $6,037/QALY, $4,783/QALY, and $6,167/QALY, respectively. In the probabilistic sensitivity analysis, the probability of serplulimab being cost-effective was 100% at the threshold of $30,036/QALY.ConclusionCompared with regorafenib, serplulimab is a cost-effective treatment for patients with previously treated unresectable or metastatic MSI-H/dMMR colorectal cancer in China.

Project description:On March 10, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The recommended approved dosage was nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks. The approval was based on data from cohort 4 of CheckMate 040, which randomized patients with advanced unresectable or metastatic HCC previously treated with or who were intolerant to sorafenib to receive one of three different dosing regimens of nivolumab in combination with ipilimumab. Investigator-assessed overall response rate (ORR) was the primary endpoint, and ORR assessed by blinded independent central review (BICR) was an exploratory endpoint. BICR-assessed ORR and duration of response (DoR) form the primary basis of the FDA's regulatory decision, and BICR-assessed ORR was comparable in all three arms at 31%-32% with 95% confidence interval [CI] 18%-47%. The DoR ranged from 17.5 to 22.2 months across the three arms, with overlapping 95% CIs. Adverse events (AEs) were generally consistent with the known AE profiles of nivolumab and ipilimumab, and no new safety events were identified. This article summarizes the FDA review of the data supporting the approval of nivolumab and ipilimumab for the treatment of HCC. IMPLICATIONS FOR PRACTICE: Nivolumab and ipilimumab combination therapy is another option for patients with advanced hepatocellular carcinoma who experience radiographic progression during or after sorafenib or sorafenib intolerance. No new toxicities were identified, but, as expected, increased toxicity was observed with the addition of ipilimumab to nivolumab as compared with nivolumab alone, which is also approved for the same indication. Whether to administer nivolumab as a single agent or in combination with ipilimumab is expected to be a joint decision between the oncologist and patient, taking into consideration the potential for a higher likelihood of response and the potentially higher rate of toxicity with the combination.

Project description:BackgroundMetastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.MethodsIn this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188.FindingsOf the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.InterpretationNivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.FundingBristol-Myers Squibb.

Project description:BackgroundIn patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).MethodsIn phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.ResultsIn phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.ConclusionsThe RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.Trial registrationNCT03271047 (09/01/2017).

Project description:ImportanceNivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC.ObjectiveTo determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC.Design, setting, and participantsThe Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021.InterventionsNivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects.Main outcomes and measuresThe primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1.ResultsOf 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab.Conclusions and relevanceIn this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC.Trial registrationClinicalTrials.gov Identifier: NCT02785952.

Dataset Information

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

Publications

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

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