Nivolumab plus low-dose ipilimumab demonstrates ‘robust’ benefit for certain patients with metastatic colorectal cancer

MUNICH — The combination of nivolumab and low-dose ipilimumab may become a new first-line treatment option for patients with microsatellite instability-high metastatic colorectal cancer, according to results from the phase 2 CheckMate-142 trial presented at European Society for Medical Oncology Congress.

“Despite advances in treatment for metastatic colorectal cancer, patients with microsatellite instability-high disease continue to have poor prognosis,” Heinz-Josef Lenz, MD, FACP, associate director for clinical research and co-leader of the gastrointestinal cancers program at USC Norris Comprehensive Cancer Center, said during his presentation. “[This combination] provided robust and durable clinical benefit as first-line treatment for this population of patients.”

The combination of the anti-PD-1 antibody nivolumab (Opdivo, Bristol-Myers Squibb) and low-dose ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 monoclonal antibody, provided durable benefit to patients with microsatellite instability-high metastatic colorectal cancer who previously received chemotherapy. Researchers reported a 55% objective response rate, a 69% disease control rate and a 12-month OS rate of 85%, according to an earlier analysis of results from CheckMate-142, which included 82 patients who had undergone prior treatment with fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy. The combination’s safety profile also appeared manageable.

Based on these results, the FDA granted accelerated approval to nivolumab as a single agent or in combination with ipilimumab for patients with microsatellite instability-high metastatic colorectal cancer who progressed after chemotherapy.

At ESMO, Lenz presented efficacy and safety results from a cohort of 45 patients (median age, 66 years; 51% male) with metastatic, microsatellite instability-high colorectal cancer who received the combination as first-line therapy. More than half of patients had an ECOG performance status of 0.

All patients received nivolumab dosed at 3 mg/kg every 2 weeks, plus low-dose ipilimumab at 1 mg/kg every 6 weeks.

Treatment continued until disease progression or unacceptable toxicity.

Investigator-assessed ORR served as the primary endpoint. Secondary endpoints included ORR per blinded independent central review, PFS, OS, disease control rate, duration of response and safety.

Median follow-up was 13.8 months (range, 9-19).

“Responses were observed regardless of tumor PD-L1 expression, BRAF mutation or KRAS mutation status, or diagnosis of Lynch syndrome,” Lenz said.

Seven percent of patients achieved complete response.

Researchers reported ORRs of 60% (95% CI, 44.3-74.3) in the entire cohort and 71% among those with BRAF mutations. Median time to response was 2.6 months (range, 1.2-13.8) and median duration of response had not been reached (range, 11.5-not estimable).

Investigators reported disease control rates of 84% (95% CI, 70.5-93.5) among the entire cohort and 88% among those with BRAF mutations.

Median PFS and OS had not been reached; however, at 12 months, 83% of patients remained alive and 77% remained progression free.

Sixteen percent of patients experienced grade 3 or grade 4 treatment-related adverse events, and 7% discontinued treatment due to any-grade treatment-related adverse events.

Any-grade immune-mediated treatment-related adverse events that affected patients’ hepatic (13%), gastrointestinal (11%), pulmonary (2%) or renal (2%) systems resolved in all patients.

One-third (33%) of patients experienced treatment-related adverse events that affected their skin, and 45% of those resolved. In addition, 24% of patients experienced treatment-related adverse events that affected their endocrine systems, and 60% of those resolved.

“The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well tolerated as first-line treatment [for] patients with microsatellite instability-high metastatic colorectal cancer,” Lenz said. “The data suggest that nivolumab and ipilimumab may be a first-line treatment option for these patients.”

The CheckMate-142 results show nivolumab plus low-dose ipilimumab is effective for most patients with microsatellite instability-high metastatic colorectal cancer, according to Thierry André, MD, head of medical oncology at Hôpital Saint-Antoine in Paris.

“Patients improve dramatically and some return to work,” André, who was not involved with the study, said in a press release. “It means health care systems can be confident that resources are being targeted effectively. This is in contrast to other metastatic cancers — such as melanoma, lung cancer or kidney cancer — where it is more difficult to select patients who benefit from immunotherapy.”

The phase 2 results may prompt Bristol-Myers Squibb to seek FDA approval for this combination for first-line treatment of microsatellite instability-high metastatic colorectal cancer, André said.

The ongoing phase 3 KEYNOTE-177 trial is comparing the anti-PD-1 agent pembrolizumab (Keytruda, Merck) with chemotherapy with or without targeted therapy, and initial results are expected in 2019.

“Another question is whether the combination of nivolumab and ipilimumab is superior to nivolumab alone for the first-line treatment of patients with microsatellite instability-high metastatic colorectal cancer,” André said. “Previous results from CheckMate-142 suggest — with indirect comparisons — improved efficacy with nivolumab plus low-dose ipilimumab relative to nivolumab alone in previously treated patients with microsatellite instability-high metastatic colorectal cancer.” – by Jennifer Southall

Reference:

Lenz H-JJ, et al. Abstract LBA18_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosures: Bristol-Myers Squibb provided funding for this study. Lenz reports honoraria from, consultant/advisory roles with, or travel, accommodations or expenses from Bayer, Boehringer Ingelheim, Merck Serono, Pfizer and Roche. Please see the abstract for all other authors’ relevant financial disclosures.