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SAN FRANCISCO — An immunotherapy combination for advanced, highly mutated colorectal cancer (CRC) significantly slowed disease progression versus a single drug, according to a randomized study.

Median progression-free survival (PFS) had yet to be reached with nivolumab (Opdivo) plus ipilimumab (Yervoy) after 47 months of follow-up as compared with a median of 39.3 months with nivolumab, which translated into a 38% risk reduction. Subgroup analyses revealed a consistent benefit of the combination versus monotherapy in the population of patients with centrally confirmed microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors.

More grade 3/4 treatment-related adverse events (AEs) occurred with the combination, but these did not reduce quality of life (QoL), reported Thierry Andre, MD, of Sorbonne University and Saint Antoine Hospital in Paris, in presenting the data at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

“These results, combined with the previously reported superiority, with nivolumab plus ipilimumab versus chemotherapy in the first-line setting established nivolumab-ipilimumab as a new standard of care for patients with MSI-H/dMMR metastatic colorectal cancer,” said Andre.

Findings from the CheckMate 8HW study were published simultaneously in The Lancet.

The phase III trial showed a clear benefit with the combination, achieved with a fairly low rate of AEs, particularly grade 3/4 and serious AEs, said ASCO-invited discussant Wells Messersmith, MD, of the University of Colorado Cancer Center in Aurora. The same was true of immune-related AEs, as a total of 28 additional grade 3/4 events occurred in the combination arm.

“Now some of these can be difficult to manage, and if you’re the patient, they can feel quite severe,” said Messersmith, who evaluated the findings within the context of a hypothetical patient with an MSI-H/dMMR tumor. “But we usually are able to manage these, and the improvement in quality-of-life scores was also quite encouraging.”

Several issues related to the combination therapy remain unresolved, he added. Elucidation of the disease biology might provide insights into the management of patients with microsatellite-stable tumors, which are more prone to liver metastases. The optimal duration of treatment with each drug has yet to be determined as well. Finally, are two drugs always necessary, or can treatment begin with one drug and escalate to two at a later date?

MSI-H/dMMR tumors account for 4-7% of CRCs and are associated with poor outcomes when treated with chemotherapy plus targeted agents, Andre noted in discussing the background of the study. Single-agent pembrolizumab (Keytruda) improved PFS in MSI-H/dMMR CRC in the first-line setting, but 29% of patients had primary progressive disease. PFS at 2 and 5 years was 48% and 34%, respectively, leaving a substantial unmet need.

Indirect comparisons involving data from the phase II CheckMate 142 trial suggested nivolumab plus ipilimumab provided better outcomes than did single-agent nivolumab. The phase III CheckMate 8HW trial continued evaluation of nivolumab/ipilimumab in patients who were immunotherapy-naive with advanced MSI-H/dMMR CRC, comparing the combination with either nivolumab alone or chemotherapy with or without targeted drugs.

The trial had two primary endpoints: PFS by blinded independent review for the combination versus physician’s choice of chemotherapy in the first-line setting (previously reported), and PFS by blinded independent review for nivolumab/ipilimumab versus nivolumab across all lines of treatment. Andre reported findings from the comparison of the combination versus single-agent nivolumab.

The two arms had a combined total of 707 patients who had a median age of 62-63. The combination arm had a higher proportion of women compared with the nivolumab arm (54% vs 46%). A quarter of the patients had received two or more prior lines of therapy.

Median duration of therapy was 20.5 months for the combination and 16.4 months with single-agent nivolumab. Median number of treatment cycles with nivolumab was 23 in the combination arm and 21 in the nivolumab arm. More than 80% of patients in the combination arm received the planned four cycles of ipilimumab.

After a median follow-up of 47 months, the combination demonstrated a statistically significant and clinically meaningful benefit in the 582 patients with centrally confirmed MSI-H/dMMR status (HR 0.62, 95% CI 0.48-0.81, P=0.0003). In the combination arm, the lower limit of the 95% confidence intervals for PFS was 53.8 months while the median value for the nivolumab arm was 39.3 months (95% CI 22.1 to not estimable). The combination also prevailed in an analysis of all randomized patients (median PFS 54.1 vs 18.4 months), said Andre. The PFS benefit with the combination was consistent across all prespecified subgroups.

The objective response rate was 71% with the combination and 58% with nivolumab (P=0.0011). Median duration of response had yet to be reached in either treatment arm.

All-grade, treatment-related AEs occurred in 81% of the combination-arm patients and 71% among patients randomized to single-agent nivolumab. Grade 3/4 treatment-related AEs occurred in 22% versus 14% of patients, and serious treatment-related AEs in 18% versus 8%. The most frequent treatment-related AEs (all grades) were the same in both treatment arms: pruritus, diarrhea, hypothyroidism, asthenia, and fatigue. Immune-mediated AEs also occurred more often with the combination, but toxicity was consistent with known effects of the drugs.

QoL, as assessed by a global health quality instrument, improved over time and did not differ significantly between treatment groups.