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

Wayne Kuznar

Colorectal Cancer, Immunotherapy, Web Exclusives

San Francisco, CA—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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