2018 GI CANCERS SYMPOSIUM: Nivolumab Plus Ipilimumab Yields Survival Benefit in Metastatic Colorectal Cancer


Key Points

  • Nivolumab was evaluated as monotherapy or in combination with ipilimumab in previously treated patients with dMMR/MSI-H tumors.
  • Single-agent nivolumab produced a 34% response rate (9% complete responses).
  • Response rates for nivolumab/ipilimumab were 55% (3.4% complete responses).
  • The study is not formally comparing the two arms, but outcomes are numerically higher with the combination.

Nivolumab (Opdivo) plus ipilimumab (Yervoy) led to a 1-year overall survival rate of 85% in previously treated metastatic colorectal cancer patients with DNA mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) tumors. These data were presented in the first report on the full cohort of CheckMate-142 at the 2018 Gastrointestinal Cancers Symposium (Abstract 553). Median overall survival and progression-free survival have not yet been reached at a median follow-up time of 13.4 months, reported Thierry André, MD, of the Saint-Antoine Hospital, in France, who presented data on the combination.

Durable clinical benefit was also achieved with single-agent nivolumab, based on longer follow-up of that cohort. Michael J. Overman, MD, of The University of Texas MD Anderson Cancer Center, Houston, reported data on single-agent cohort of CheckMate-142 at the Symposium (Abstract 554).

CheckMate-142 in dMMR/MSI-H Patients

CheckMate-142 is a nonrandomized phase II study designed to determine, within the dMMR/MSI-H population, whether nivolumab alone or in combination with another checkpoint inhibitor has activity against colorectal cancer that has metastasized or recurred following at least one prior treatment. The study enrolled 119 patients, who received nivolumab as a single agent (3 mg/kg every 2 weeks) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks.

CheckMate-142 is the largest single study of combination immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer. Data for the combination and for the single-agent arm were presented at the meeting, but the two arms were not directly compared.

Nivolumab and ipilimumab act synergistically to promote T-cell antitumor activity, providing the rationale for trying to improve upon nivolumab’s single-agent activity. Based on initial data from CheckMate-142, the U.S. Food and Drug Administration granted accelerated approval to nivolumab for dMMR/MSI-H patients with disease progressing after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Combination Achieves Survival Benefits

Dr. André presented findings for the combination treatment arm after a median follow-up of 13.4 months. The objective response rate was 55%, with 3.4% being complete responses, and the disease control rate was 80%. Some degree of tumor reduction was achieved by 78% of patients.

Responses were observed regardless of tumor programmed cell death ligand 1 (PD-L1) expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. The median time to response was 2.8 months (range = 1–14 months), and the median duration of response has not yet been reached.  

Among patients who responded to the combination, 94% were still responding at the time of data cutoff. At the time of this report, 63% of the nivolumab/ipilimumab cohort remained on treatment.

Combined treatment with nivolumab/ipilimumab also provided benefits in progression-free survival and overall survival, with rates at 1 year of 71% and 85%, respectively. Statistically significant and clinically meaningful improvements in quality-of-life measures were also reported.

No new safety signals emerged with the addition of ipilimumab to nivolumab, and rates of all-grade adverse events were similar to those seen with the single agent: 73% vs 70%, respectively. A modest increase in the rate of grade 3/4 treatment-related adverse events was seen: 32% vs 20%, respectively. Treatment-related adverse events leading to drug discontinuation occurred in 13% and 7%, respectively. The most common toxicities with the combination were diarrhea (22%), fatigue (18%), pruritus (17%), and pyrexia (15%).

Monotherapy Data Update

Nivolumab monotherapy also showed improved activity in an update on the 74 patients in the monotherapy arm of CheckMate-142, including 53 who received 3 or more prior chemotherapies (including a fluoropyrimidine, oxaliplatin, and irinotecan) and 21 who had not received all three drugs.

In the previously reported initial analysis, performed after 13 months of median follow-up, the objective response rate per blinded independent central review was 32%, with 73% of patients alive at 1 year. Now after 21 months, the response rate was 34%, with 9% being complete responses, and the disease control rate was 62%.

The median duration of response was still not reached in the overall cohort or in the two subgroups (by prior treatment). Among responders, 80% had ongoing responses at the time of data cutoff, and 64% had responses lasting at least 1 year.

Dr. Overman noted that the complete response rate deepened with longer follow-up. Whereas only 3% of patients had attained a complete response to nivolumab monotherapy by 13 months, this rose to 9% after a median of 21 months of follow-up. Similar trends in complete response were seen in both subgroups.

Median progression-free survival for the overall cohort was 6.6 months. Median overall survival has not been reached. A small difference in 18-month survival was found for patients who had received fluoropyrimidine, oxaliplatin, and irinotecan (66%) vs those who had not (70%).

No new safety signals emerged with long-term follow-up. Grade 3/4 treatment-related adverse events, the most common being increased lipase (8%), were reported in 20% of patients.

Disclosure: Dr. Overman holds a consulting or advisory role at Bristol-Myers Squibb, Merrimack, and Roche/Genentech.  

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.