In an updated analysis of the phase II CheckMate 142 trial with median follow-up of 20.9 months, nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).
EXPERT OPINION OF PROF. DR. HANS PRENEN, ONCOLOGIST, UNIVERSITY HOSPITAL ANTWERP
“In first line MSI-H/MMRd metastatic colon cancer, the combination of nivolumab plus ipilimumab demonstrated a durable clinical benefit.”
Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) treated with first-line, standard-of-care chemotherapy have poor outcomes and may benefit from programmed death-1 (PD-1) checkpoint blockade. A combination of PD-1 and cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitors, which promote antitumour immune response by distinct but complementary mechanisms, may further enhance efficacy relative to monotherapy. A previous report from the phase II CheckMate 142 study after 13.4 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.
CheckMate 142 is an ongoing, multi-cohort, non-randomised phase II trial in patients with histologically confirmed metastatic MSI-H/dMMR CRC. Enrolment into the first-line cohort occurred at 18 sites in six countries. Eligible patients were at least 18 years of age with an Eastern Cooperative Oncology Group performance status of 0 or 1 and had not received prior treatments for metastatic disease. Patients received nivolumab 3 mg/kg once every 2 weeks and low-dose ipilimumab 1 mg/kg once every 6 weeks as 30-minute intravenous infusions until disease progression, discontinuation because of toxicity, death, withdrawal of consent, or study end. Dose interruptions of < 6 weeks were permitted to manage treatment-related adverse events (TRAEs).
At data cut-off (October 2019), 45 patients with MSI-H/dMMR mCRC who had not received prior therapy for metastatic disease were treated. Median age of treated patients was 66 years and 51% were male. BRAF and KRAS mutations were identified in 38% and 22% of patients, respectively. Median follow-up was 29.0 months. Objective response rate (ORR) and disease control rate (DCR) were 69% and 84%, respectively, with 13% complete response rate. Median duration of response was not reached. At data cut-off, 23 of 31 (74%) responders had ongoing responses, 71% of responders had a response lasting at least 12 months and 90% were alive. Among 43 response-evaluable patients, 84% had a reduction in tumour burden from baseline. A majority of these patients experienced a deepening of response with longer follow-up. With a minimum follow-up of 24.2 months, median progression-free survival and median overall survival were not reached (24-month rates, 73.6% and 79.4%, respectively). Clinical benefit was observed regardless of baseline demographic and tumour characteristics, including BRAF or KRAS mutation status. Patients with a BRAF or KRAS mutation had an ORR of 76% and 80%, respectively. 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. Any-grade treatment-related adverse events (TRAEs) were reported in 80% of patients, the most common being pruritus (36%), arthralgia (20%), and hypothyroidism (18%). Any-grade TRAEs leading to discontinuation were reported by 13% of patients, including one case (2%) each of grade 2 arthritis, congestive cardiomyopathy, and encephalitis; one case (2%) each of grade 3 gastroenteritis and increased blood creatinine; and one case (2%) of grade 4 respiratory failure. Of the 10 patient deaths, eight were because of disease and two were because of AEs unrelated to study treatment. Any-grade serious TRAEs occurred in 47% (skin), 29% (endocrine), 20% (gastrointestinal), 11% (hepatic), 4% (pulmonary), and 2% (renal) of patients.
In this first report of a dual immune-oncology combination as first-line therapy for MSI-H/dMMR mCRC, nivolumab plus low-dose ipilimumab demonstrated a robust clinical benefit characterised by an ORR of 69% (CR rate,13%), DCR of 84%, and durable responses after a median 29.0 months of follow-up. In addition, ORR benefit was observed in all evaluated subgroups, including BRAF or KRAS mutation status. Based on these promising data, randomised studies are warranted.
Lenz HJ, et al. 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. J Clin Oncol. 2022;40:161-70.