Nivolumab Plus Ipilimumab Displays Durable Benefit in MSI-H/dMMR mCRC

Nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) continued to demonstrate sustained clinical benefit as second- and first-line therapy, respectively, in patients with microsatellite instability–high (MSI-H) and mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to findings from the five year-follow-up analysis of the phase 3 CheckMate 142 trial (NCT02060188) that were presented at the 2022 ASCO Annual Meeting.

The results, which had updated since the 2021 publication in the Journal of Clinical Oncology, reflected a median progression-free survival (PFS) of 13.8 months (95% CI, 4.7-38.2) in cohort 1 that was not reached in cohorts 2 (95% CI, 32.8-not evaluable [NE]) and 3 (95% CI, 28.8-NE). The 2-year PFS rate was 36% in cohort 1, 54% in cohort 2, and 51% in cohort 3. The 3-year PFS rates were 34%, 52%, and not available, respectively.

The median overall survival (OS) was 44.2 months (95% CI, 20.9-75.1) in cohort 1 and was not reached in cohorts 2 and 3. The 2-year OS rate was 49% in cohort 1, 71% in cohort 2, and 72% in cohort 3. The 3-year OS rates were 46%, 68%, and not available, respectively.

“These updated data further support current treatment recommendations for second-line nivolumab with or without ipilimumab and frontline nivolumab plus ipilimumab for patients with MSI-H/dMMR mCRC,” the study authors wrote in the poster.

CheckMate 142 is an ongoing, multicohort, nonrandomized phase 2 study evaluating the efficacy and safety of nivolumab-based therapy in patients with mCRC.

The study enrolled patients with histologically confirmed metastatic or recurrent, MSI-H/dMMR CRC per local laboratory assessment.

The study consisted of 3 cohorts, which evaluated 3 mg/kg of nivolumab every 2 weeks as second-line therapy (n = 74); 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, after which nivolumab was administered every 2 weeks as second-line therapy (n = 119); and 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks as frontline therapy (n = 45).

The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1 criteria. Other key end points included disease control rate (DCR), duration of response (DOR), PFS, OS, and safety.

At the data cutoff of September 22, 2021, the median follow-up time was 70.0 months, (range, 66.2-88.7), 64.0 months (range, 60.0-75.8), and 52.4 months (range, 47.6-57.1) in cohorts 1, 2, and 3, respectively. The median duration of study therapy was 15.2 months (range, 0.0-85.6+), 24.9 months (range, 0.0-70.9), and 19.1 months (range, 0.0-56.1+), respectively.

At data cutoff, 93% (n = 69), 91% (n = 108), and 98% (n = 44) of patients in cohorts 1, 2, and 3, respectively, had discontinued treatment. The most common reasons for treatment discontinuation were disease progression and maximum clinical benefit.

The ORRs were 39% (95% CI, 28%-51%) in cohort 1, 65% (95% CI, 55%-73%) in cohort 2, and 71% (95% CI, 56%-84%) in cohort 3. Notably, the benefit was consistent across subgroups including age (<65 vs ≥65), sex (male vs female), mutation status (BRAF/KRAS wild-type vs BRAF mutant vs KRAS mutant), and ECOG performance status (0 vs ≥1) and was comparable to that of the overall population.

The DCR was 69% (95% CI, 57%-79%) in cohort 1, 81% (95% CI, 72%-87%) in cohort 2, and 84% (95% CI, 71%-94%) in cohort 3.

Responses were durable across cohorts, with a median duration of response that was not reached at data cutoff. The 5-year DOR rates were 77% (95% CI, 55%-89%), 73% (95% CI, 60%-82%), and not applicable in cohorts 1, 2, and 3, respectively.

At this analysis, 41%, 68%, and 73% of patients were alive in cohorts 1, 2, and 3, respectively. Among these patients, 60%, 75%, and 88% were treatment-free. The median treatment-free intervals were 37.6 months (range, 8.5-66.3), 27.8 months (range, 3.7-74.9), and 23.7 months (range, 1.6-49.6), respectively.

Subsequent therapy of any kind was received by 47% of patients in cohort 1, 30% in cohort 2, and 31% in cohort 3; 38%, 21%, and 16% of patients received subsequent systemic therapy, respectively. Subsequent immunotherapy including ipilimumab, nivolumab, pembrolizumab (Keytruda), and investigational immunotherapy was received by 15%, 6%, and 2% of patients, respectively.

In terms of safety, no new signals were identified with extended follow-up with the regimen in the first- or second-line setting.

Treatment-related adverse effects (TRAEs) occurring in at least 20% of patients included diarrhea, fatigue, pruritus, and arthralgia. Most TRAEs with potential immunologic origin including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin toxicities were grade 1 or 2.

The confirmatory, randomized phase 3 CheckMate 8HW trial (NCT04008030) comparing nivolumab plus ipilimumab vs nivolumab or chemotherapy is underway.

Reference

Overman MJ, Lenz HJ, Andre T, et al. Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Five-year follow-up from CheckMate 142. J Clin Oncol. 2022;40(suppl 16):3510. doi:10.1200/JCO.2022.40.16_suppl.3510