Immunotherapy Combination Shows Durable Responses in Mismatch Repair–Deficient Metastatic Colorectal Cancer

TOP - August 2018, Vol 11, No 2 - Immunotherapy
Wayne Kuznar

 

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) provides durable clinical benefit in patients with previously treated DNA mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC).

In the first report from the full cohort of patients in the CheckMate-142 clinical trial who received the combination therapy, the objective response rate (ORR) was 55% during a median of 13 months of follow-up, and the median duration of response was not reached, reported Thierry André, MD, Head, Medical Oncology, Saint-Antoine Hospital, Paris, France, at the 2018 Gastrointestinal Cancers Symposium.

“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H mCRC [metastatic CRC],” Dr André said.

Approximately 4% of patients with metastatic CRC have dMMR that leads to MSI-H. “These patients benefit less from conventional chemotherapy than patients identified as MMR-proficient or microsatellite-stable,” he added. Ni­volumab by itself has been shown to induce durable responses and promote survival in a monotherapy subset cohort from the CheckMate-142 trial.

The combination cohort consisted of 119 patients who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolu­mab 3 mg/kg every 2 weeks. The median follow-up was 13.4 months.

Three-fourths (76%) of the patients received ≥2 previous lines of therapy. The most common previous chemotherapies were fluoropyrimidine (99%), oxaliplatin (Eloxatin; 93%), and irinotecan (Onivyde; 73%). Sixty-three percent of patients continue to receive treatment; disease progression was the main reason for study discontinuation (19%) followed by medication side effects (13%).

The investigator-assessed ORR was 55%, 31% achieved stable disease, and the disease control rate was 80% for patients who received the combination therapy. By comparison, patients who received nivolu­mab monotherapy in the full study had a 31% ORR and a 69% disease control rate at 13 months of follow-­up, Dr André noted.

Three-fourths (77%) of patients who received the combination therapy had a reduction in tumor burden from baseline. The median time to response in those treated with combination therapy was 2.8 months and the responses were durable; the median duration of response was not reached and 94% of responders had ongoing responses at data cutoff. “We have only 4 patients who did not have ongoing response at data cutoff: 1 for PD, 2 died, and 1 for surgery of metastases and this patient was censored at the time of surgery,” he said.

Responses were observed irrespective of tumor PD-1 expression, BRAF or KRAS mutation status, or a history of Lynch syndrome.

The rate of progression-free survival (PFS) with combination therapy was 76% at 9 months and 71% at 12 months versus 54% and 50%, respectively, with nivolumab monotherapy. The overall survival (OS) rate was 87% at 9 months and 85% at 12 months with the combination therapy versus 78% and 73%, respectively, with nivolumab monotherapy.

Statistically significant and clinical­ly meaningful improvements were achieved in key quality-of-life measures, as assessed by the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire and the EuroQol five-dimension scale, and these improvements were maintained for extended periods. No new adverse events or treatment-related deaths were observed.

As of now, “it’s unclear if combination immunotherapy provides long-term clinical benefit over anti–PD-1 monotherapy,” because the comparison to nivolumab alone was a nonrandomized comparison, the PFS and OS data are not mature, and the follow-up thus far is short, said invited discussant Zsofia Kinga Stadler, MD, Medical Oncologist, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York City.

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Last modified: April 27, 2020