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First-Line Immunotherapy Shows Benefit in Metastatic Colorectal Cancer Subset


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In previously untreated patients with metastatic colorectal cancer and tumors demonstrating microsatellite instability–high (MSI-high) or mismatch repair deficiency (dMMR), immunotherapy with nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) produced a durable clinical benefit in the CheckMate-142 trial.1

“Nivolumab and low-dose ipilimumab demonstrated a robust and thorough clinical benefit in the first-line treatment of MSI-high metastatic colorectal cancer, with a response rate of 60% and a complete response rate of 7%. We have not even reached the median duration of response,” said Heinz-Josef Lenz, MD, FACP, of the University of Southern California Keck School of Medicine in Los Angeles, at the European Society for Medical Oncology (ESMO) 2018 Congress.1

MSI-high/dMMR tumors account for about 5% of metastatic colorectal cancer cases. Despite advances in treatment, these patients have a median progression-free survival of about 7 months and overall survival of 15 to 22 months, Dr. Lenz said. Nivolumab and low-dose ipilimumab, a regimen that is already approved for second-line therapy based on CheckMate-142, may present a new option as first-line treatment for patients with MSI-high metastatic colorectal cancer, he suggested.

Checkmate-142 Details

The phase II Checkmate-142 trial is evaluating whether the combined use of inhibitors of cytotoxic T-lymphocyte–associated protein 4 and programmed cell death protein 1 can promote an antitumor immune response and improve outcomes in patients with metastatic colorectal cancer. In a previous cohort of this multipart clinical trial, nivolumab (3 mg/kg) was given with low-dose ipilimumab (1 mg/kg) once every 3 weeks for four doses followed by nivolumab (3 mg/kg) every 2 weeks, as second-line therapy, producing responses in 55% of patients, with 85% of patients alive at 1 year. Grade 3 or 4 treatment-related adverse events were seen in 32% of patients on the combination, with 31% discontinuing treatment due to toxicity.

At the ESMO meeting, Dr. Lenz presented data for this chemotherapy-free combination in 45 previously untreated patients. These 45 patients received nivolumab at 3 mg every 2 weeks and ipilimumab at 1 mg every 6 weeks. The primary endpoint was investigator-assessed overall response rate. Median follow-up was 13.8 months.

The median number of doses was 24 for nivolumab and 8 for ipilimumab, for a total of 48 weeks of treatment with both drugs. At the time of the presentation, 60% of patients were continuing on treatment. Only 7% discontinued treatment because of toxicity.

Robust Responses, Encouraging Survival

The overall response rate was 60%, with 7% of patients achieving a complete response and 84% of patients achieving disease control lasting at least 12 weeks. Responses were independent of programmed cell death ligand 1 expression and the presence of KRAS and BRAF mutations or Lynch syndrome, Dr. Lenz reported.

“The high efficacy is really nicely documented in the waterfall plot, with 84% of patients having some reduction of their tumor burden,” he said.

The median time to response was 2.6 months and responses were durable, with the median duration not yet reached. “We know that 82% of the responders have ongoing responses and 74 % of the responders had responses lasting longer than 6 months,” he said. “The majority achieved a response in the first 3 months, but interestingly, there were other late responders.”


Nivolumab and low-dose ipilimumab demonstrated a robust and thorough clinical benefit in the first-line treatment of MSI-high metastatic colorectal cancer, with a response rate of 60% and a complete response rate of 7%.
— Heinz-Josef Lenz, MD, FACP

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One such patient was a 77-year-old with BRAF-mutant disease who discontinued treatment because of immune-related arthritis after achieving a partial response. The patient is still stable. Another is a 42-year-old with KRAS-mutant disease whose partial response was not documented until week 48. “We still have no understanding of the clinical pathologic criteria for earlier or later responses,” he said. Some patients underwent curative resection or thermal ablation, with several pathologic complete responses observed, he added.

After almost 14 months of follow-up, median progression-free survival was not reached; at 12 months, 77% of patients were free of disease progression. Median overall survival was also not reached; 83% of patients were alive at 12 months. “This indicates that there will be very promising long-term overall survival benefits with nivolumab and low-dose ipilimumab,” he said.

IMMUNOTHERAPY IN COLORECTAL CANCER

  • CheckMate-142 evaluated nivolumab plus low-dose ipilimumab as first-line treatment of metastatic colorectal cancer with MSI-H/dMMR tumors. Benefit in the second line, also in the ongoing CheckMate-142 trial, led to approval of this regimen.
  • The combination produced responses in 60% (7% complete responses), with some occurring very late in the 1-year treatment course.
  • After almost 14 months’ follow-up, median progression-free survival and overall survival were not reached.
  • The combination was essentially as well tolerated as single-agent nivolumab.

Treatment-related adverse events of any grade occurred in 78%, with 16% being grade 3 or 4. The most common toxicities were those involving the skin (33%) or endocrine (24%), hepatic (13%), gastrointestinal (11%), pulmonary (2%), and renal (2%) systems.

“The toxicities were well tolerated, and most types of toxicity resolved in 100% of patients. Skin toxicity resolved in 45%, and endocrine toxicities, in 60%. The 16% grade 3 or 4 adverse event rate is lower than was seen with nivolumab monotherapy, and the rate of treatment discontinuation (7%) is the same,” he noted. 

DISCLOSURE: The study was sponsored by Bristol-Myers Squibb. Dr. Lenz has received honoraria and fees for consulting or advising from Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Genentech, and Merck Serono; research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Incyte Corporation, Merck Serono, National Institutes of Health, National Cancer Institute, Roche, SWOG Cancer Research Network, and Taiho Pharmaceuticals; and travel reimbursements from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Caris Life Sciences, and Merck Serono.

REFERENCE

1. 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.


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