As a first-line regimen for patients with metastatic colorectal tumors that are microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR), the combination of nivolumab and low-dose ipilimumab yielded an objective response rate of 64%, a complete response rate of 9%, and a disease control rate of 84%, in an updated analysis of the phase II CheckMate 142 trial.¹

“[Nivolumab/ipilimumab] is showing incredible response rates and complete response rates that are never seen with chemotherapy, and the regimen is very well tolerated,” said lead author Heinz-Josef Lenz, MD, Co-Leader of the Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, who presented the CheckMate 142 data at the 2020 Gastrointestinal Cancers Symposium.

“[Nivolumab/ipilimumab] is showing incredible response rates and complete response rates that are never seen with chemotherapy, and the regimen is very well tolerated.”

— Heinz-Josef Lenz, MD

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Compared to the previous analysis,² the investigator-assessed response rates increased from 60% to 64%. The complete response rate rose to 9% and to 18% by central review.

“We also saw that 84% of patients had a reduction in tumor burden, indicating significant antitumor activity. The responses were very durable—in fact, the median duration of response has not been reached,” Dr. Lenz reported. “Nivolumab plus low-dose ipilimumab provides clinically meaningful and durable benefits and may present an option for the first-line treatment of patients with metastatic MSI-H disease.”

As Dr. Lenz pointed out, approximately 4% of metastatic colorectal cancers are MSI-H or dMMR. Various studies have found that patients with MSI-H tumors have shorter survival (approximately 14 to 19 months) than those with non–MSI-H tumors (about 17 to 25 months) when treated with first-line chemotherapy. During the discussion period, Dr. Lenz commented that MSI status is an important and interesting prognostic marker. MSI-H heralds a relatively good prognosis for stage II disease, but a poor one for stage IV colorectal cancer, he said.

Based on an earlier analysis of CheckMate 142, nivolumab received accelerated approval by the U.S. Food and Drug Administration as a single agent or in combination with ipilimumab in patients with MSI-H/dMMR metastatic colorectal cancer progressing after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In that initial analysis, the median follow-up was 13.8 months, objective response rate was 60%, complete response rate was 7%, and disease control rate was 84%; median progression-free and overall survival were not reached.

At the 2020 Gastrointestinal Cancers Symposium, Dr. Lenz presented an update on the study’s 45 patients, who have now been followed for a median of 19.9 months in this first-line trial. The primary endpoint of the study was objective response rate by investigator assessment.

Regimen and Study Results

Patients received nivolumab at 3 mg/kg every 2 weeks plus low-dose ipilimumab at 1 mg/kg every 6 weeks until disease progression or treatment discontinuation. This combination immunotherapy regimen led to “robust and durable responses,” Dr. Lenz reported.

The median overall response rate was 64% by investigator assessment and 58% by blinded central review. Complete responses were observed in 9% and 18%, and the disease control rate was 84% and 78%, respectively. Median time to response was 2.6 months by investigator assessment, and median duration of response has not been reached. Some patients remained in response past 20 months, he noted.

Median progression-free survival and overall survival were not reached. At 15 months, 75% of patients were progression-free and 84% were alive.

“Efficacy was independent of any subgroups, including assessment by performance status, primary tumor location, mutation status, or prior adjuvant or neoadjuvant therapy,” he added.

The combination was well tolerated, owing largely to the way that ipilimumab was dosed, Dr. Lenz said. Of note, CheckMate 142 used a low dose of ipilimumab (administered every 6 weeks), whereas several other trials tested a higher dose when combined with nivolumab. “The 2-week regimen is significantly more toxic,” he explained. “With nivolumab and low-dose ipilimumab given every 6 weeks, the safety profile is very similar to that of nivolumab alone…. It’s also been true for liver cancer, lung cancer, and melanoma—that the every-6-week dose remains highly efficacious without toxicity.”

Treatment-related grade 3 and 4 toxicities were reported in 20% of patients (11% reported as serious), and only two patients (4%) discontinued therapy due to a treatment-related adverse event. The most common toxicities were pruritus, hypothyroidism, arthralgia, and asthenia, but they were grade 3 or 4 for just two patients.

Additional Commentary

Dr. Lenz was asked how he would apply the results of the study “Monday morning,” for a patient with MSI-H metastatic colorectal cancer. Would he give the patient chemotherapy or a checkpoint inhibitor?

“The guidelines of the National Comprehensive Cancer Network^® (NCCN^®) recommend that you can start with the [nivolumab/ipilimumab] combination in the first line if the patient is not a candidate for chemotherapy. So the NCCN leaves the door open for the opportunity to use immunotherapy in this patient population,” he said. “Personally, I believe that patients who are MSI-H do extremely well with immunotherapy, and it’s well tolerated…. The response rates and complete response rates are so high compared to chemotherapy, and the side-effect profile is better, so if I have a choice, I start with [nivolumab/ipilimumab] in MSI-H patients.”

Others asked whether similar efficacy might be achieved with nivolumab alone—an approach that incurs less “financial toxicity.” “Comparisons of nivolumab vs nivolumab/ipilimumab have not been done in randomized trials, but in other trials, the combination is a little more active, so I always choose to use both,” he answered.

Looking to the future of combination therapy for MSI-H/dMMR colorectal tumors, Dr. Lenz said the research will build upon the established efficacy of immunotherapy in the first line. He is particularly interested in adding an agent targeting vascular endothelial growth factor in these patients.

“What we are waiting for are results of first-line treatment with immunotherapy plus chemotherapy and bevacizumab. KEYNOTE and CheckMate trials of this combination are ongoing, but with immunotherapy alone, we are seeing that progression-free and overall survivals are not reached—so it could be a while before we get readouts on these trials. We’ll find out if these combinations will further enhance the efficacy profile of immunotherapy alone.” 

DISCLOSURE: CheckMate 142 was funded by Bristol-Myers Squibb. Dr. Lenz has received honoraria from Bayer, Boehringer Ingelheim, GSK, Isofol, Merck Serono, and Roche; has served in a consulting or advisory role for Bayer, BMS, GSK, Merck Serono, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Bayer and Merck Serono.

REFERENCES

1. Lenz H-J, Lonardi S, Zagonel V, et al: Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update. 2020 Gastrointestinal Cancers Symposium. Abstract 11. Presented January 25, 2020.

2. Lenz H-J, van Cutsem E, Limon ML, et al: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer. 2018 ESMO Congress. Abstract LBA18_PR. Presented October 22, 2018.