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.

Keywords: Colorectal cancer; Immune checkpoint inhibitors; Ipilimumab; Microsatellite instability‐high/mismatch repair‐deficient; Nivolumab.

Figure 1.

Any grade sTRAEs. Median (range) time to onset of sTRAEs (A), emergence of sTRAEs over time (B), and proportion of patients without resolution of sTRAEs over time (C). Blue shading indicates the first 12 weeks of therapy. ^aTime to onset includes events reported between first dose and 30 days after last dose of study therapy. ^bPatients who experienced sTRAEs without worsening from baseline grade were excluded from time to resolution analysis. Events without a stop date or with a stop date equal to the death of the patient, as well as grade 5 events, were considered unresolved. ^cSome endocrine sTRAEs were not considered resolved because of the continuing need for hormone replacement therapy. Abbreviations: NR, not reached; sTRAEs, treatment‐related adverse events.

Figure 2.

Any grade IMAEs of special interest. Time to onset median (range) (A) and time to resolution median (range) (B). ^aPatients who experienced immune‐mediated adverse events (IMAEs) without worsening from baseline grade were excluded from time to resolution analysis. Events without a stop date or with a stop date equal to the death of the patient, as well as grade 5 events, were considered unresolved. Includes events occurring within 100 days of the last dose. Abbreviations: IMAE, immune‐mediated adverse event; NR, not reached.

Figure 3.

OS and PFS in patients with or without any grade sTRAEs. OS (A) and PFS (B). Abbreviations: CI, confidence interval; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression‐free survival; sTRAE, select treatment‐related adverse event.