Nivolumab plus low-dose ipilimumab provided durable clinical benefit over 4 years of follow-up in the CheckMate 142 study, characterised by high response rates, low rates of disease progression, and long-term survival benefit. The safety profile was manageable, and no new safety signals were seen with longer follow-up. Findings from the longest duration of follow-up reported for combination of two immune checkpoint inhibitors (ICIs) in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) confirm long-term clinical benefit of nivolumab plus low-dose ipilimumab and support the use of this combination as a standard of care for these patients. The latest findings are published by Prof. Thierry André of the Sorbonne Université and Department of Medical Oncology, Hôpital Saint Antoine, APHP in Paris, France and colleagues on 25 June 2022 in the Annals of Oncology.
The authors wrote in the study background that approximately 5% of patients with mCRC have MSI-H/dMMR disease and suffer poor outcomes with chemotherapy of median overall survival (OS) shorter than 16 months in the second-line setting. ICI–based monotherapy and combination therapy regimens have demonstrated clinical benefit in patients with MSI-H/dMMR mCRC in non-randomised studies.
CheckMate 142 is an ongoing phase II, multicohort, non-randomised study of nivolumab-based therapies in previously treated or untreated patients with MSI-H/dMMR or microsatellite stable/MMR-proficient mCRC. In patients with MSI-H/dMMR mCRC who had one or more prior treatments, treatment with nivolumab and low-dose ipilimumab demonstrated durable clinical benefit in terms of objective response rate (ORR) 55%, median duration of response (DoR) not reached, and 12-month OS rate 85% and manageable safety after a median follow-up of 13.4 months.
Based on the CheckMate 142 results, nivolumab received approval in combination with ipilimumab in the European Union, and either as monotherapy or in combination with ipilimumab in Japan and the United States for treatment of patients with MSI-H/dMMR mCRC that progressed following treatment with chemotherapy. Continued clinical benefit with deepening of response was observed at 25.4 months of median follow-up and no new safety signals were identified. Findings from 13.4- and 25.4-month median follow-up were previously published in the Journal of Clinical Oncology.
In the latest report published in the Annals of Oncology, the authors report an analysis of the 4-year efficacy, safety, patient-reported outcomes (PROs), and characterisation of patients based on best overall response from the nivolumab plus low-dose ipilimumab cohort of CheckMate 142 in previously treated patients with MSI-H/dMMR mCRC. Patients received nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) every 3 weeks (4 doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed ORR per RECIST v1.1.
A total of 119 patients were treated; 76% had at least 2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7). Median duration of therapy was 24.9 months (95% confidence interval [CI] 15.8-33.2). Investigator-assessed ORR increased from 55% (95% CI 45-64) at 13.4 months to 65% (95% CI 55-73) at 50.9 months with a disease control rate of 81% (95% CI 72-87). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease.
The ORR benefit was observed in all evaluated subgroups, including BRAF or KRAS mutation status, and was consistent with that in the overall population. Median time to response was 2.8 months (range 1.1-37.1), and median DoR was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 patients (48%) had ongoing responses. Median progression-free survival was not reached (95% CI 38.4 months-not estimable), and median OS was not reached (95% CI not estimable).
The safety profile was manageable with no new safety signals. Grade 3/4 treatment-related adverse events (TRAEs) were observed in 32% of patients with 13% of patients who had any-grade TRAEs leading to discontinuation. The majority of select TRAEs were reported early, and their frequency decreased over time. No treatment-related deaths were observed at any follow-up.
Significant and clinically meaningful improvements in health-related quality of life were largely maintained with continuous treatment. In exploratory analyses, significant and clinically meaningful improvements were reported in PRO measures, some as early as week 13, and were largely maintained with long-term follow-up.
The authors concluded that their results show the long-term benefit of nivolumab plus low-dose ipilimumab in previously treated MSI-H/dMMR mCRC. The authors commented that absence of a comparator due to the non-randomised design is a limitation of this study. A confirmatory randomised phase III study of nivolumab monotherapy, nivolumab plus low-dose ipilimumab, or chemotherapy (CheckMate 8HW) is underway in patients with recurrent or metastatic MSI-H/dMMR CRC irrespective of prior treatment history.
The CheckMate 142 study was supported by Bristol Myers Squibb, Princeton, NJ, USA.
André T, Lonardi S, Wong KYM, et al. Nivolumab + low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year followup from CheckMate 142. Annals of Oncology; Published online 25 June 2022. DOI: https://doi.org/10.1016/j.annonc.2022.06.008