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SAN FRANCISCO -- More than half of patients with previously treated metastatic colorectal cancer and DNA mismatch repair deficiency (dMMR) had objective responses to the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy), results of a cohort study showed.

Overall, 65 of 119 patients responded to the combination. The disease control rate (response plus stable disease) was 80%, as reported here at the Gastrointestinal Cancers Symposium.

"Nivolumab plus ipilimumab provided durable clinical benefit in previously treated patients with DNA mismatch repair-deficient, microsatellite instability-high [MSI-H] metastatic colorectal cancer," said Thierry Andre, MD, of Hopital Saint Antoine and Sorbonne University in Paris. "Median progression-free and overall survival were not reached with a median follow-up of 13 months; 85% of patients remained alive at 1 year.

"Meaningful improvements in quality of life were observed, and the safety of nivolumab and ipilimumab was manageable, with a low rate of discontinuation due to treatment-emergent adverse events."

The were published simultaneously in the .

Acknowledging the high response rate and durability of responses with the combination, the invited discussant, Zsofia Kinga Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York City, nonetheless said the combination's superiority over single-agent nivolumab cannot be assumed: "It's unclear whether combination immunotherapy provides long-term clinical benefit over anti-PD1 monotherapy. The answer to this will require randomized comparisons of monotherapy versus combination therapy.

"As expected, based on studies of other malignancies, combination therapy with an anti-PD1 and CTLA-4 inhibitor had additional toxicity. Further studies are needed to identify particular subgroups of patients who may benefit from combination therapy."

Andre reported findings from a study that addressed a small but poor-prognosis subgroup of patients with metastatic colorectal cancer. About 4% of patients have a deficiency in the DNA mismatch repair system, leading to MSI. Multiple studies showed that this subgroup of patients derive less benefit from conventional chemotherapy as compared with patients who have MMR proficient or microsatellite stable disease, Andre noted.

Previously showed that nivolumab monotherapy led to objective responses in a third of patients with dMMR/MSI metastatic colorectal cancer. The responses were durable in many instances. The combination study was conducted in parallel to the monotherapy trial as components of .

Eligible patients had metastatic colorectal cancer associated with dMMR/MSI-H and exposure to at least one prior line of therapy. In the combination arm, patients received a dose of nivolumab, followed by ipilimumab once every 3 weeks for four doses, and then nivolumab every 2 weeks until disease progression or development of unacceptable toxicity. The primary endpoint was investigator-determined overall response rate.

The 119 patients had a median age of 58; men accounted for 59% of the study population, and all the patients had ECOG 0-1 performance status. Tumor PD-L1 expression was ≥1% in 22% of patients, <1% in 55%, and unknown in 24%. The group included 35 patients (29%) with a clinical history of Lynch syndrome. About a third of patients had received two prior therapies, and 40% had three or more.

The results showed partial responses in 51.3% of patients and complete responses in 3.7%. An additional 31 patients had stable disease during treatment, resulting in a disease control rate of 80%.

"Combination therapy provided a numerically higher objective response rate, including complete responses, and disease control rate, relative to monotherapy during a similar follow-up period," said Andre.

Almost 80% of patients treated with the combination had some reduction in tumor burden, he added.

Neither objective response rate nor disease control rate differed substantially by PD-L1 expression status, BRAF/KRAS mutation status, or history of Lynch syndrome.

The combination cohort had a median progression-free survival of 76% at 9 months and 71% at 12 months. The overall survival rates at the same time points were 87% and 85%, respectively, with both surpassing the rates observed in the monotherapy groups, Andre reported.

The combination was associated with "statistically significant and clinically meaningful" improvement in quality-of-life measures, and the improvements were maintained for extended treatment periods.

A third of patients had grade 3/4 treatment-emergent adverse events (TRAEs), including serious adverse events in 20% of patients, and leading to treatment discontinuation in 10%. The most commonly reported grade 3/4 TRAE was elevated liver enzymes (AST/ALT) in 7-8% of patients; grade 3/4 diarrhea, fatigue, pruritus, and rash each occurred in 2% of patients.

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