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Nivolumab Alone or With Ipilimumab Provides Durable Benefit in MSI-H/dMMR mCRC

Wayne Kuznar
Published: Tuesday, Jan 23, 2018

Michael J. Overman, MD
Michael J. Overman, MD
Data from the CheckMate-142 study support the use of nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) for the treatment of patients with previously treated DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), according to 2 analyses presented at the 2018 Gastrointestinal Cancers Symposium.

An update of patients receiving nivolumab monotherapy in CheckMate-142 showed that nivolumab continued to provide clinically meaningful and durable responses in the 74 patients treated, with a deepening of responses with longer follow-up.1 Five additional patients achieved a complete response (CR) between median follow-up at 13 months and 21 months. Median overall survival (OS) was not yet reached at the 21-month follow-up.

Separately, the combination of nivolumab and ipilimumab provided durable clinical benefit over a median follow-up of 13 months, with a high objective response rate (ORR) of 55% and a median duration of response that was not reached.2

Michael J. Overman, MD, assistant professor, Department of Gastrointestinal Medical Oncology at MD Anderson Cancer Center in Houston updated the results of nivolumab monotherapy, 3 mg/kg every 2 weeks, in 74 patients with dMMR/MSI-H mCRC. As previously published, with a median of 13 months of follow-up, the ORR was 32% per blinded independent central review, and 73% of patients were alive at 1 year.3

The updated analysis followed patients to 21 months and in an exploratory analysis, assessed for efficacy by prior chemotherapy. Group A consisted of 53 patients who received ≥3 prior chemotherapies, including a fluoropyrimidine, oxaliplatin, and irinotecan. Group B comprised 21 patients who did not receive prior treatment with all 3 of these chemotherapies.

Baseline characteristics were well matched in groups A and B; 38% in each group had a clinical history of Lynch syndrome and about 40% in each group were BRAF/KRAS wild-type. Fifty-five percent of all patients were in disease stage I-III at diagnosis: 58% in group A and 48% in group B.

Fifty-four percent of the overall patient population received ≥3 prior lines of therapy: 70% in group A and 14% in group B. Overall, 61% of patients discontinued nivolumab treatment at the time of the updated analysis: 58% in group A and 67% in group B. The most common reason for discontinuation was disease progression (42% overall; 43% in group A and 38% in group B).

In all 74 patients, the ORR at 21 months was 34%, and the best overall response was a CR in 9% (n = 7), a partial response (PR) in 24% (n = 18), stable disease (SD) in 31% (n = 23), and progressive disease (PD) in 30% (n = 22), for a disease control rate (DCR) of 62%. The median duration of response was not reached and the median duration of SD was 8.3 months.

Group B had a higher ORR compared with group A (52% vs 26%), and also higher rates of CR (14% vs 8%), PR (38% vs 19%), and SD (33% vs 30%), but a shorter median duration of SD (5.3 vs 8.5 months). “The median time to response was approximately 2.8 months across all groups,” said Overman. Sixty percent of patients overall had a reduction in tumor burden from baseline.

“Deepening of response was shown with further follow-up…primarily related to PRs that converted to CRs with additional time,” said Overman. Among all patients, the CR rate improved from 3% (n = 2) at 13 months to 9% (n = 7) at 21 months. The DCR was durable: 47% at 13 months and 46% at 21 months. Eighty percent of responses are ongoing, said Overman, and 64% had responses lasting ≥12 months.

The median progression-free survival (PFS) for the entire cohort was 6.6 months; median PFS was 4.2 months in group A and not reached in group B. “The median PFS of 6.6 months does not well represent the benefit from this therapy,” he said. “What’s better representation is that at 12 months, we see a PFS rate of 44%, which at 18 months is exactly the same, at 44%. These are similar across…[groups] A and B.”

The OS rate was 72% at 12 months and 67% at 18 months. The 12-month OS rates were 68% and 81% in groups A and B, respectively, and the 18-month OS rates were 66% and 70%, respectively. The 21 patients with a best overall response of PD who had a reduction in or stabilization of target lesions were more likely to survive at least 12 months.

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