Dataset Information

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

ABSTRACT: PURPOSE:We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods:In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ?1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. RESULTS:The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths. CONCLUSION:Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

SUBMITTER: Kim JH

PROVIDER: S-EPMC7577804 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

Kim Jwa Hoon JH Kim Sun Young SY Baek Ji Yeon JY Cha Yong Jun YJ Ahn Joong Bae JB Kim Han Sang HS Lee Keun-Wook KW Kim Ji-Won JW Kim Tae-You TY Chang Won Jin WJ Park Joon Oh JO Kim Jihun J Kim Jeong Eun JE Hong Yong Sang YS Kim Yeul Hong YH Kim Tae Won TW

Cancer research and treatment 20200424 4

<h4>Purpose</h4>We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.<h4>Materials and methods</h4>In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H ...[more]

PMID: 32340084

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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: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.

Project description:BackgroundMonoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously.MethodsThis open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival.ResultsOne hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0-52.8), and the disease control rate was 66.0% (95% CI 56.0-75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5-97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7-82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1-2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events.ConclusionsThis is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. Trial registration ClinicalTrials.gov, NCT03667170. Registered 10 September 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03667170 .

Project description:PurposeKEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).MethodsThis phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.ResultsA total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.ConclusionPembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Dataset Information

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

Publications

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

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