First-Line Nivolumab/Low-Dose Ipilimumab Yield Efficacious, Long-Lasting Clinical Benefit in MSI-H/dMMR mCRC

Nivolumab (Opdivo) plus low-dose ipilimumab (Yervoy) yielded promising responses as a first-line treatment for microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to results from the phase 2 CheckMate142 trial (NCT02060188), that was published in the Journal of Clinical Oncology.

Patients treated with the combination experienced an objective response rate of 69% (95% CI, 53%-82%) and a disease control rate of 84% (95% CI, 70.5%-93.5%). The median duration of response was not reached, and 74% of patients had ongoing responses at the time of data cutoff. Additionally, after a minimum follow-up of 24.2 months, the median progression-free survival (PFS) and overall survival (OS) were not reached.

At data cutoff, 45 patients with MSI-H/dMMR mCRC who had previously received treatment for metastatic disease were enrolled on the study and treated with the combination. The median duration of follow-up was 29.0 months, and the median age was 66 years. Additionally, 51% of patients were male. A total of 38% of patients were identified as having a BRAF mutation, and 22% had a KRAS mutations. At the data cutoff, 33% patients were still receiving treatment, and 67% discontinued therapy, with a median therapy duration of 11.0 months.

Patients received a median of 34 doses of nivolumab. Patients received 3 mg/kg of nivolumab once every 2 weeks, and 1 mg/kg of ipilimumab once every 6 weeks. 

Patients who had a BRAF mutation achieved an ORR of 76% and KRAS-mutant patients had an ORR of 80%. The median time to response was 2.7 months. Of the 43 patients who were response evaluable, 84% had a reduction in tumor burden from baseline.

In the overall population, PFS rate at 12 and 18 months was 76.4% (95% CI, 60.5%-86.6%) and 73.6% (95% CI, 57.2%-84.5%) at 24 months. In the KRAS mutation subgroup, the 24-month PFS rate was 87.5% (95% CI, 38.7%-98.1%), 76.5% (95% CI, 48.8%-90.4%) in the BRAF subgroup, and 68.4% (95% CI, 35.9%-86.8%)for BRAF and KRAS wild-type.

The 12-month OS rate for the overall population was 84.1% (95% CI, 69.5%-92.1%), 81.7% (95% CI, 66.8%-90.4%) at 18 months, and 79.4% (95% CI, 64.1%-88.7%) at 24 months. Among the 19 patients who discontinued therapy and did not receive subsequent therapy, 14 had at least 1 tumor assessment during treatment-free interval. Of these 14 patients, 10 have remained progression-free.

Patients reported outcome questionaires were completed by 98% of patients at baseline and in 80% or more patients at week 115. The health-related quality of life scores remained stable over the treatment period. At week 85, the utility index score was -0.106 (95% CI, -0.198 to -0.013; P = .025), and at week 79 the visual analogue scale was 8.0 (95% CI, 1.0-14.9; P = .026).

In terms of safety, grade 3 treatment-related adverse effects (TRAEs) included colitis (4%) and 1 case (2%) each of adrenal insufficiency, asthenia, congestive cardiomyopathy, and gastroenteritis. One patient experienced grade 4 respiratory failure and hyponatremia. Serious TRAEs were reported in 16% of patients, 11% of which were grade 3 and 2% were grade 4.

Any grade TRAEs that led to discontinuation were reported in 13% of patients, which included 1 case each of grade 3 gastroenteritis and increased blood creatin, and 1 case of grade 4 respiratory failure. In total, 10 patients died, 8 of whom died from disease, and 2 due to AEs unrelated to the study.

Serious TRAEs of any grade were reported in the skin (47%), endocrine (29%), gastrointestinal (20%), hepatic (11%), pulmonary (4%), and renal (2%). Serious TRAEs resolved in most patients by data cutoff, with endocrine serious TRAEs resolving in 46% of patients and skin resolving in 62% of patients.

Reference

Lenz HJ, Van Cutsem E, Luisa Limon M, 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. J Clin Oncol. Published Online October 12, 2021. doi:10.1200/JCO.21.01015