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

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.

Combination Induces High PFS Rates

No new safety signals were reported with longer-term follow-up. The results support ongoing evaluation of nivolumab-based therapy in the first-line setting in patients with dMMR mCRC, concluded Overman.Results from the nivolumab plus ipilimumab combination therapy cohort from CheckMate-142 were reported by Thierry André, MD, medical director, Gastroenterology Oncology Unit, Hôpital Saint Antoine, Paris, France. This cohort consisted of 119 patients who were treated with nivolumab, 3 mg/kg plus ipilimumab, 1 mg/kg, every 3 weeks for 4 doses followed by nivolumab every 2 weeks. Their median follow-up was 13.4 months. André compared the results from this cohort with those of the nivolumab monotherapy from CheckMate-142 after the same duration of median follow-up.

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

Of the 119 treated patients, 76% had ≥2 prior lines of therapy. The most common prior chemotherapies were fluoropyrimidine (99%), oxaliplatin (93%), and irinotecan (73%). Sixty-three percent continue on treatment; disease progression was the main reason for discontinuation (19%) followed by toxicity related to a study drug (13%).

The investigator-assessed ORR was 55%, with 31% with SD, with combination therapy, and the DCR was 80%. By comparison, patients treated with nivolumab monotherapy had a 31% ORR and a 69% DCR at 13 months of follow-up. Three-fourths (78%) had a reduction in tumor burden from baseline with combination therapy.

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 deaths, and 1 for surgery of metastases and this patient was censored at the time of surgery,” said André.

When analyzed according to patient subsets, “responses were observed irrespective of tumor PD-1 expression, BRAF or KRAS mutational status, or clinical history of Lynch syndrome,” he said.

The 9- and 12-month rates of PFS with combination immune checkpoint inhibitor therapy were 76% and 71%, respectively. In the nivolumab monotherapy cohort, these rates were 54% and 50%. OS at 9 and 12 months was 87% and 85%, respectively, in patients treated with the combination, which was also superior relative to nivolumab monotherapy (78% and 73%, respectively).

Quality of life (QOL) was assessed by the EORTC QLQ-C30 global health status/QoL and the EQ-5D visual analog scale. Statistically significant and clinically meaningful improvements were achieved in key QOL measures, and improvements were maintained for extended periods. No new safety signals or treatment-related deaths were observed.

Invited discussant Zsofia K. Stadler, MD, associate attending physician at Memorial Sloan Kettering Cancer Center in New York City reminded attendees that André presented a nonrandomized comparison, “thus not intended for comparison of monotherapy to combination therapy…or to show superiority.” Similarly, the stratification by lines of previous therapy presented by Overman was an unplanned retrospective analysis, she said.

Based on previously reported results for the 74-patient nivolumab monotherapy group from CheckMate-142, the FDA approved single-agent nivolumab in August 2017 for the treatment of adult and pediatric patients with MSI-H/dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

References

1. Overman MJ, Bergamo F, McDermott R, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 554.
2. André T, Lonardi S, Yeung Mark Wong K, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 553.
3. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182-1191.