Immunotherapy combination shows longer progression-free survival than chemotherapy alone for patients with a rare type of metastatic colorectal cancer

Abstract

Results from a new study published in the November 27, 2024, issue of The New England Journal of Medicine (NEJM; doi:10.1056/NEJMoa2402141) showed that a combination of two immunotherapy drugs led to longer progression-free survival (PFS) than chemotherapy alone in patients with a rare type of metastatic colorectal cancer (CRC) called mismatch repair–deficient (dMMR) adenocarcinoma. Experts consider these results practice changing.

“We’ve had very few innovations in colorectal cancer up until the immunotherapy era starting around 2014, so this is huge in this rare subtype,” says Benjamin L. Schlechter, MD, a Dana Farber Cancer Institute oncologist who specializes in gastrointestinal cancers and was not involved with the study. “It really hammers home the point that for the vast majority of these patients, first-line immunotherapy is superior to first-line chemotherapy.”

The phase 3, multinational, open-label randomized trial is known as CheckMate 8HW. It was conducted at 128 hospitals and cancer centers across 23 countries. Researchers compared the effectiveness of the immunotherapy drugs nivolumab and ipilimumab to that of chemotherapy in patients with microsatellite instability–high (MSI-H) or dMMR metastatic CRC.

MSI-H and dMMR refer to the same rare type of CRC. This subtype represents between 4% and 7% of CRCs. Unlike other CRCs, the MSI-H and dMMR subtypes have deficiencies in their DNA repair proteins that make them more susceptible to treatment with immunotherapy.

“These cancers don’t normally repair their DNA, and that happens in a few different ways,” Dr Schlechter says. “You can be born with a mutation in DNA repair that’s called Lynch syndrome, and that’s a significant proportion of these patients. Or, the cancer, through other mechanisms, can damage those same DNA repair genes. These cancers are very genetically distinct from normal tissue, which is not the case with the average colorectal cancer.”

The study authors note that patients with MSI-H or dMMR metastatic CRC have poor outcomes with standard chemotherapy with or without targeted therapy. In previous nonrandomized studies, nivolumab plus ipilimumab showed a benefit in treating the disease.

CRC survivor and patient advocate Allison Rosen, who did not have this type of cancer, is enthusiastic about the results. “The more options that rare colorectal cancers have, the better,” she says. “The treatment options haven’t changed for a long period of time, so anytime I see new research that gives any mutation a new line of therapy, it’s exciting.”

In the trial, patients with unresectable or metastatic CRC with an MSI-H or dMMR status received nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapy (mFOLFOX-6 or FOLFIRI) in a 2:2:1 ratio with or without targeted therapies (bevacizumab or cetuximab).

Researchers enrolled 808 patients who either had or previously had not had systemic treatment for metastatic CRC. In the entire study population, 666 patients had centrally confirmed MSI-H or dMMR tumors.

The study had two primary endpoints. The first endpoint was PFS with nivolumab plus ipilimumab versus chemotherapy as first-line therapy. The second endpoint was PFS with nivolumab plus ipilimumab versus nivolumab alone in patients regardless of previous systemic treatment for metastatic CRC.

The NEJM article describes an interim analysis of results for the first primary endpoint concerning patients in the first line. At a median follow-up of 31.5 months, PFS was significantly better with nivolumab plus ipilimumab than chemotherapy. The 2-year PFS rate was 72% (95% confidence interval, 64%–79%) with nivolumab plus ipilimumab but 14% (95% confidence interval, 6%–25%) with chemotherapy. Median PFS was not reached in the nivolumab-plus-ipilimumab arm, whereas it was 5.9 months with chemotherapy.

The immunotherapy combination resulted in fewer grade 3 or 4 treatment-related adverse events than chemotherapy (23% vs. 48%). However, two patients died in the group treated with nivolumab and ipilimumab, whereas no deaths were reported in the chemotherapy group. One death was cardiac-related, and the other death was caused by lung inflammation.

At the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January 2025, lead study author Thierry André, MD, professor of medical oncology at the Sorbonne Université in Paris, France, presented additional data from a new interim analysis of the study. Findings showed a high 3-year PFS rate of 69% in the nivolumab-plus-ipilimumab arm but a rate of only 11% in the chemotherapy arm.

Dr André also presented findings on the second primary endpoint comparing the nivolumab-plus-ipilimumab combination to nivolumab alone across different lines of therapy.

These results were published in The Lancet (doi:10.1016/S0140-6736(24)02848-4). The combination showed superior PFS in comparison with nivolumab monotherapy. Median PFS was not reached in the combination arm, whereas it was reached at 39.3 months for the patients receiving nivolumab alone. Grade 3 or 4 treatment-related adverse events occurred in 22% of the patients in the combination arm and in 14% of the patients who were on monotherapy. In prespecified subgroup analyses, PFS favored nivolumab plus ipilimumab over nivolumab monotherapy.

“The high overall response rate and particularly high complete response rate, with the long duration of response in this study, suggests cure may be achieved in a percentage of these patients,” Dr André says.

Dr Schlechter notes that the NEJM article confirms information previously presented at the annual ASCO and the ASCO gastrointestinal meeting but provides more information on the risks and benefits of nivolumab plus ipilimumab.

“This is a really important finding for the rare MSI-H or dMMR colorectal cancers, but it doesn’t tell us much about the other colorectal cancers,” he says.

Dr Schlechter points out that another challenge in treating these rare CRCs with immunotherapy is that a very small group of patients perform worse in the beginning (e.g., tumor swelling), although the tumors eventually shrink. This phenomenon is called pseudoprogression.

“Some of those cases are rare but are real progression, and patients get very sick very fast,” Dr Schlechter says. “Those patients are better off with chemotherapy, and we still need to figure out which ones and why.”

Despite the two deaths with nivolumab and ipilimumab (one due to myocarditis and another due to pneumonitis) and the one death in the nivolumab arm (due to pneumonitis), the authors conclude that the immunotherapy combination leads to both a better quality of life and fewer toxic side effects overall. They plan to publish another article on their quality-of-life findings.

“It’s another world for the patient because immunotherapy by the combination is around one hour of injection at day one every three weeks for four cycles, and for nivolumab alone, it’s one hour of injection every four weeks for a maximum treatment duration of two years,” Dr André says. “But with chemotherapy, it’s every 15 days with a pump that lasts two days, and it never really ends because you have first-line, second-line, third-line therapy compared to immunotherapy, where if you have good results, you can be free of therapy for a long time or even be cured.”

Dr Schlechter agrees, noting that chemotherapy side effects, such as fatigue and diarrhea, worsen over time, whereas immunotherapy side effects are autoimmune-related and occur more randomly and less persistently.

The Lancet article’s authors suggest that because nivolumab plus ipilimumab showed superior results across all treatment lines in comparison with nivolumab alone, the former should be considered the potential new standard of care.