The combination of immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) may soon represent a new first-line treatment option in patients with early-stage metastatic colorectal cancer (CRC) associated with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors. Two studies presented at the ESMO 2018 Congress demonstrated the efficacy of this combination in this patient population.
Metastatic CRC with MSI-H or dMMR
In the CheckMate-142 clinical trial, the combination of nivolumab plus ipilimumab improved overall survival (OS) in treatment-naïve patients with MSI-H or dMMR metastatic CRC. Approximately 4% of cases of metastatic CRC are associated with MSI-H.
CheckMate-142 previously showed that in patients with MSI-H metastatic CRC that is resistant to chemotherapy, nivolumab plus low-dose ipilimumab provided durable clinical benefit and manageable side effects, leading to the accelerated approval of the combination by the FDA in patients whose disease progresses after chemotherapy with a regimen of fluoropyrimidine, oxaliplatin, and irinotecan.
The objective response rate to the combination of nivolumab plus low-dose ipilimumab was 60% in patients with MSI-H or dMMR, and 7% of the patients had a complete response. Heinz-Josef Lenz, MD, FACP, Co-Leader, Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, presented the study results.
“The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well-tolerated as first-line treatment in patients with MSI-high metastatic colorectal cancer. The data suggest that nivolumab and ipilimumab may be a first-line treatment option for these patients,” said Dr Lenz.
In Checkmate-142, 45 treatment-naïve patients with MSI-H or dMMR metastatic CRC received nivolumab 3 mg/kg every 2 weeks, plus ipilimumab 1 mg/kg every 6 weeks until disease progression or intolerable side effects. Patients were followed for a median of 13.8 months for the primary end point of objective response rate. A total of 27 of the 45 (60%) patients continue to receive treatment with this combination.
In addition to the 3 complete responses, 24 (53%) patients had a partial response. The disease control rate was 84%. The responses were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or a diagnosis of Lynch syndrome. The median time to response to treatment was 2.6 months.
“Some 82% of responders had ongoing responses at data cutoff, and three-fourths (74%) have already had responses lasting longer than 6 months,” said Dr Lenz.
The median duration of response, median progression-free survival (PFS), and median OS have not yet been reached. The 12-month PFS rate was 77% and the OS rate was 83%.
Treatment-related grade 3 or 4 adverse events were reported in 16% of patients, and 7% of them discontinued therapy because of treatment-related adverse events.
Early-Stage dMMR Colon Cancer
A separate exploratory phase 2 clinical trial showed that preoperative combined treatment with nivolumab and ipilimumab achieved major pathologic responses in 100% of patients with early-stage dMMR colon cancers, reported Myriam Chalabi, MD, Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam.
A total of 14 patients with resectable, early-stage colon cancer have received nivolumab 3 mg/kg on days 1 and 15, and ipilimumab 1 mg/kg on day 1, before surgery. All patients underwent radical resection of 15 tumors without delays.
All 7 patients with dMMR colon cancer had major pathologic responses, with 4 of the 7 (57%) patients reaching complete responses.
In contrast, no major pathologic responses were observed in patients with MMR-proficient tumors, despite a significant, 2.4-fold mean increase (P = .018) in T-cell infiltration posttreatment. The patients with dMMR disease had a 4.8-fold increase (P = .0009) in T-cell infiltration.
“This is the first study with immune checkpoint inhibitors in early-stage colon tumors. Our data suggest that neoadjuvant immunotherapy in dMMR colon cancer warrants further research and has the potential to change the standard of care,” said Dr Chalabi. “The response we saw is much more dramatic than in metastatic disease, which we did not expect.”
Dr Chalabi added, “I think the finding will have implications for clinical practice in the future. At this stage, it’s too early to call it practice-changing, but it could be if similar results are seen in larger studies.”
Commenting on the study, Aurélien Marabelle, MD, MSc, PhD, Clinical Director, Cancer Immunotherapy Program, Gustave Roussy Cancer Centre, Villejuif, France, said, “The study positions immunotherapy at an earlier stage of the disease history for patients with localized disease, and, interestingly, in the neoadjuvant setting as opposed to the adjuvant setting that is now approved in melanoma and non–small-cell lung cancer.”