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Advances in immune therapies for the treatment of microsatellite instability‑high/deficient mismatch repair metastatic colorectal cancer (Review).

ABSTRACT: Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame‑shift mutations, resulting in the generation of frame‑shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI‑H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long‑term response to ICIs were presented.

SUBMITTER: Choucair K

PROVIDER: S-EPMC8360619 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Advances in immune therapies for the treatment of microsatellite instability‑high/deficient mismatch repair metastatic colorectal cancer (Review).

Choucair Khalil K Radford Maluki M Bansal Ajay A Park Robin R Saeed Anwaar A

International journal of oncology 20210813 3

Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame‑shift mutations, resulting in the generation of frame‑shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies ...[more]

PMID: 34396449

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).MethodsTo assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety.ResultsOf 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30-67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%.ConclusionsIn our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

Project description:BackgroundEarly 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 methodsSafety 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.ResultsAmong 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%).ConclusionThe 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 practiceNivolumab (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.

Dataset Information

Advances in immune therapies for the treatment of microsatellite instability‑high/deficient mismatch repair metastatic colorectal cancer (Review).

Publications

Advances in immune therapies for the treatment of microsatellite instability‑high/deficient mismatch repair metastatic colorectal cancer (Review).

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