REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.
“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.
In the nonrandomized phase 2 trial, patients with previously treated dMMR/MSI-H metastatic colorectal cancer were split into a 119-patient combination cohort given both nivolumab (Opdivo), which targets the receptor programmed death-1 (PD-1), and ipilimumab (Yervoy), which targets cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and a 74-patient monotherapy cohort given nivolumab alone.
Initial results for the latter cohort established a durable clinical benefit of nivolumab monotherapy, according to Dr. André. “It’s clear that there is a rationale to combine nivolumab and ipilimumab because they act synergistically to promote T-cell antitumor activity. Therefore, combination could further improve results,” he said.
With median follow-up of 13.4 months, 55% of patients had a response to the combination of nivolumab and ipilimumab, according to results reported at the symposium and simultaneously published ( J Clin Oncol. 2018 Jan 20:JCO2017769901 ). Median progression-free and overall survival were not reached.
In addition, comparison with the nivolumab monotherapy cohort, albeit in nonrandomized fashion, suggested that addition of ipilimumab netted better outcomes.
“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer,” Dr. André summarized. The results “are really very unusual in metastatic colorectal cancer, and we have a test, MSI, to select this population. It’s really a new hope for patients with metastatic colorectal cancer.”
Findings in context
“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.
“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”
Rates of treatment-related adverse events and discontinuations due to such events with the combination were generally lower than those previously seen in other cancers, according to Dr. Stadler. Nonetheless, there is some added toxicity in going from monotherapy to combination therapy.
“Further studies are clearly needed to identify those particular subgroups of patients who may benefit from combination therapies, so can we predict which MSI-H patients may progress on monotherapy, and whether we can salvage patients on monotherapy who are not responding and are having progression of disease,” she concluded. “Those are important questions that need to be addressed.”
Study details
In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).
The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.
The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)
Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.
“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
Long-term outcomes with monotherapy
In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.
Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).
Results for the entire monotherapy cohort now at a median 21 months of follow-up showed an overall response rate of 34% and a disease control rate of 62%, Dr. Overman reported. These compared with 32% and 64%, respectively, at the original 13 months of follow-up ( Lancet Oncol. 2017;18:1182-91 ).
“Deepening of response was shown with further follow-up,” he noted; in particular, the rate of complete response increased from 3% to 9%. “This is primarily related to partial responses that have converted to complete responses with additional time.” Median duration of response was not reached.
The overall response rate was 26% in the more heavily pretreated group and 52% in the less heavily pretreated group, although confidence intervals overlapped. The disease control rate was 55% and 81%, respectively.
Both progression-free and overall survival curves for the entire monotherapy cohort showed a plateau. The 12-month rates were 44% (also 44% at 18 months) and 72% (67% at 18 months), respectively.
The rate of grade 3 or 4 treatment-related adverse events was 20%. “No new signals were seen with this longer follow-up,” Dr. Overman noted.
“Nivolumab continued to provide durable clinical benefit with long-term follow-up in previously treated patients with dMMR/MSI-H metastatic colorectal cancer. “Durable clinical benefit with deepening of response was observed regardless of prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan,” he summarized. “These results support ongoing evaluation of nivolumab-based therapy in the first-line setting in patients with deficient–mismatch repair colorectal cancer.”
Findings in context
“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”
The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”
“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”
Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.
SOURCES: André T et al. GI Cancers Symposium Abstract 553 , Overman MJ et al. GI Cancer Symposium Abstract 554.
