Long-term benefit of nivolumab plus low-dose ipilimumab in previously treated patients with MSI-H/dMMR metastatic colorectal cancer

In an updated analysis of the phase II CheckMate 142 trial with median follow-up of 50.9 months, the combination of nivolumab and low-dose ipilimumab yielded an objective response rate of 65% and a complete response rate of 13% in a cohort of patients with metastatic colorectal tumours that are microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR). In addition, the regimen proved to be well tolerated without any new safety signals.

In metastatic colorectal cancer (mCRC), approximately 4% of patients have a microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) phenotype, which is associated with poor outcomes. Previous reports from the phase II CheckMate 142 study after 13.4 and 25.4 months of follow-up demonstrated that nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) provided a robust and durable clinical benefit with a manageable safety profile in previously treated patients with MSI-H/dMMR mCRC. At WCGIC 2021, Prof. André presented efficacy and safety outcomes with four years of follow-up.

CheckMate 142 study design

CheckMate 142 is an ongoing, multi-cohort, non-randomised phase II study including 119 patients with histologically confirmed metastatic or recurrent MSI-H/dMMR CRC. All patients previously received at least one line of prior therapy. Patients received NIVO (3 mg/kg) plus low-dose (1 mg/kg) IPI once every three weeks (Q3W) for four doses followed by nivolumab (3 mg/kg) Q2W until disease progression. The primary endpoint of the study was objective response rate (ORR) per investigator assessment. At the data cut-off in October 2020, the median duration of follow-up was 50.9 months with a median duration of therapy of 24.9 months. The median age of the 119 treated patients was 58 years, 59% were male, and three quarters of patients (76%) received at least two prior lines of therapy. Overall, 55% had an ECOG performance status (PS) of 1, 25% had a BRAF mutation, 37% had a KRAS mutation, and 26% were BRAF/KRAS wild type.

Robust and durable response rates

The investigator-assessed ORR increased from 55% at 13.4 months to 65% at 50.9 months. In addition, also the rate of complete responses (CR) increased over time from 3% to 13%. Partial responses (PR) were observed in 52% of patients, 21% had stable disease (SD) and 12% had progressive disease (PD) as best response. Of the fourteen patients with a best overall response of PD, six were identified as MSS per central testing and another six were confirmed as MSI-high. The ORR benefit was observed across evaluated subgroups (by age, sex, ECOG PS, tumour cell PD-L1 expression and mutation status) and proved to be consistent with what was seen in the overall population. Most patients (79%) had a reduction in tumour burden from baseline. The median duration of response was not reached with responses lasting for at least 12, 24 and 36 months being observed in 90%, 64% and 52% of patients, respectively. Also the median progression-free (PFS) and overall survival (OS) were not reached, with 48-months PFS- and OS-rates were 53% and 70.5%, respectively. 

The safety profile was manageable and no new safety signals were identified with long-term follow-up. Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 10% (grade 3-4) and 13% (any grade) of patients had TRAEs leading to discontinuation. The majority of select TRAEs were grade 1 or 2 and no grade 5 events were reported.

Conclusion

NIVO plus low-dose IPI continued to provide durable clinical benefit over 50.9 months of follow-up. This extended follow-up demonstrated an increasing ORR with deepened responses, and a long-term survival benefit. The safety profile of NIVO plus low-dose IPI was manageable, with low discontinuation rate due to TRAEs. As such, these results from CheckMate 142 demonstrate the long-term benefit of NIVO plus low-dose IPI in previously treated patients with MSI-H/ dMMR mCRC.

Reference

André T, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 4-year follow-up from CheckMate 142. Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract SO-27.