Durable and deep tumour responses were observed in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with first-line nivolumab plus low-dose ipilimumab, regardless of baseline demographic and tumour characteristics, including BRAF or KRAS mutation status. Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were not reached, with a minimum follow-up of 24.2 months. This combination therapy was well tolerated at a median follow-up of 29.0 months. The findings from the CheckMate 142 study are published by Prof. Heinz-Josef Lenz of the USC Norris Comprehensive Cancer Center in Los Angeles, CA, USA and colleagues on 12 October 2021 in the Journal of Clinical Oncology.
CheckMate 142 is a phase II, multicohort, non-randomised study of nivolumab-based therapies in patients with previously treated and untreated MSI-H and non–MSI-H mCRC. In patients with MSI-H/dMMR mCRC who had one or more prior treatments (second-line or greater), nivolumab monotherapy and nivolumab plus low-dose ipilimumab followed by nivolumab monotherapy demonstrated promising clinical activity as reflected by high and durable responses after a median follow-up of 12.0 and 13.4 months, respectively. Nivolumab monotherapy was well tolerated, and nivolumab plus low-dose ipilimumab had a manageable safety profile.
Based on these results, nivolumab received accelerated US Food and Drug Administration approval as a single agent or in combination with ipilimumab for patients with MSI-H/dMMR mCRC that progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
An indirect comparison of CheckMate 142 cohorts suggested that nivolumab plus low-dose ipilimumab demonstrated improved clinical benefit relative to nivolumab monotherapy, with a favourable benefit-risk profile, in second-line or greater MSI-H/dMMR mCRC.
The study team now reports the results of nivolumab plus low-dose ipilimumab as first-line therapy for patients with MSI-H/dMMR mCRC. This is the first report of a dual immune checkpoint inhibitors combination treatment in first-line MSI-H/dMMR mCRC.
Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary endpoint was objective response rate (ORR) per investigator assessment (RECIST v1.1).
Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. The ORR was 69% (95% confidence interval [CI] 53 to 82) and disease control rate was 84% (95% CI 70.5 to 93.5) with 13% complete response rate. Median DoR was not reached; 74% of responders had ongoing responses at data cut-off.
Median PFS and median OS were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumour characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free.
Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events.
The authors commented that the limitations of their study include its non-randomised design, the absence of a standard-of-care or anti–PD1 monoclonal antibody monotherapy comparator arm, and its small sample size.
The authors concluded that nivolumab plus low-dose ipilimumab demonstrated robust, deep, and durable clinical benefit as a first-line treatment for patients with MSI-H/dMMR mCRC. This combination represents a first-line treatment option for MSI-H/dMMR mCRC with potential for improved efficacy relative to anti-PD1 monotherapy and conventional chemotherapy with or without targeted therapy. A confirmatory randomised phase III study, CheckMate 8HW, is underway.
The findings were presented in part at the ASCO 2020 Annual Meeting and the ASCO 2021 Gastrointestinal Cancers Symposium.
The study was supported by Bristol Myers Squibb.
Lenz H-J, Van Cutsem E, Limon ML, et al. First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. JCO; Published online 12 October 2021. DOI: 10.1200/JCO.21.01015