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.

Biomarkers of immunotherapy in non‑small cell lung cancer (Review)

“…The CheckMate142 study confirmed that mCRC with MSI-H/dMMR treated with nivolumab and pembrolizumab had an increased immune response compared with nivolumab monotherapy (79). Moreover, nivolumab has been approved for mCRC with MSI-H/dMMR following unsuccessful standard chemotherapy (80). Thus, MSI-H/dMMR has emerged as another immunotherapy-related biomarker for screening the subpopulation of patients that are likely to benefit from immunotherapy.…”

Comprehensive review of targeted therapy for colorectal cancer

“…382 Further studies argued that a combination of nivolumab and the CTLA-4 inhibitor ipilimumab surpassed single-agent immune checkpoint blocking with an acceptable rate of adverse events. [398][399][400] Combined therapy with nivolumab and ipilimumab helped patients with dMMR or MSI-H CRC who had previously received chemotherapy to reach a PFS of 71% and an OS of 85% at 1 year; 80% of them maintained disease control over 12 weeks. For firstline use of this doublet regimen, a new study assessed its efficacy and safety for patients with dMMR or MSI-H CRC.…”

Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials

“…In the nivolumab-only cohort, 31% of patients had an objective response and 12-month OS was 73% [ 74 ]. Among 119 patients, 25% had an endocrine, 23% had a gastrointestinal, 19% had hepatic, 5% had pulmonary, 5% had renal and 29% experienced skin irAEs; the majority (57%) were grade 1/2 [ 75 ]. The result of this study indicated nivolumab plus ipilimumab as a new treatment option for patients with MSI-high CRC.…”