Josh Friedman , 2025-05-09 18:00:00
Key takeaways:
- First-line immunotherapy of microsatellite instability-high metastatic colorectal cancer improved survival compared with chemotherapy.
- Certain patients with microsatellite stable disease also benefited.
An evaluation of nearly 19,000 patients with metastatic colorectal cancer supported clinical trial data that immunotherapy significantly extended OS compared with chemotherapy for those with microsatellite instability-high disease.
Additionally, researchers found a “sliver of hope” that certain individuals with microsatellite stable (MSS) disease also could benefit from immune checkpoint inhibitors. Stephanie L. Schmit, PhD, MPH, associate staff in genomic medicine at Cleveland Clinic and associate director of population sciences at Case Comprehensive Cancer Center, told Healio. “There’s still value in investigating opportunities to find patients with microsatellite stable tumors who may be responsive,” she said. “It kicks us off on a biomarker hunt.”
Real-world setting
Approximately 25% of individuals diagnosed with colorectal cancer find out they have metastatic disease on their initial visit, according to study background.
Of those diagnosed with local disease, another 25% will have metastatic progression.
The FDA granted accelerated approval of immune checkpoint inhibitors for refractory microsatellite instability-high (MSI-H) metastatic colorectal cancer in 2017 and approved them as first-line treatment in 2020.
“About 15% of colorectal cancer cases are characterized as MSI-H,” Schmit said.
Healio previously reported on trials investigating immunotherapy in these settings.
Findings presented at ASCO Annual Meeting 2024 showed patients treated with the first-line combination of nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) had a 2-year PFS of 72% compared with 14% for those who received chemotherapy.
“Clinical trials are the gold standard,” Schmit said. “They control for various types of biases, but the inclusion criteria and exclusion criteria can be extremely strict. The patients who are included in clinical trials may not reflect the full range of patients in the population who may ultimately be receiving those therapies.
We were interested in understanding how these new therapies play out in the real-world setting.”
Schmit and colleagues used the nationwide Flatiron Health electronic health record database to investigate.
They included 18,932 patients (55.7% men; 65.2% white) diagnosed with metastatic colorectal cancer (median age at metastatic diagnosis, 64.6 years) and who had at least two documented clinical visits between Jan. 1, 2013, and June 13, 2019, with follow-up through the end of 2019.
Researchers defined immunotherapy as use of nivolumab, pembrolizumab (Keytruda, Merck), atezolizumab (Tecentriq, Genentech), ipilimumab, tremelimumab (Imjudo, AstraZeneca), durvalumab (Imfinzi, AstraZeneca) or avelumab (Bavencio, EMD Serono).
Immunotherapy usage and OS served as primary endpoints. Time to treatment discontinuation served as a secondary endpoint.
‘It’s encouraging’
In all, 3% of the study population received immune checkpoint inhibitor therapy.
Patients with MSI-H tumors had a 22 times greater likelihood of receiving immunotherapy than those with MSS disease (OR = 22.66; 95% CI, 17.3-29.73).
Those with metastatic disease at diagnosis had significantly lower odds of receiving immunotherapy than those with metastatic disease that developed post-diagnosis (OR = 0.57; 95% CI, 0.45-0.73).
Patients with MSI-H tumors who received immunotherapy as first-line treatment had significantly longer OS than those who received chemotherapy only (HR = 0.37; 95% CI, 0.25-0.56).
Those with MSS disease who received first-line immunotherapy did not have a discernable survival difference compared with those who received chemotherapy.
Among patients who received immunotherapy, those with MSI-H tumors had lower risk for death than those with MSS tumors (HR = 0.32; 95% CI, 0.22-0.47). Patients with metastatic disease at diagnosis had a higher mortality risk than those with metastatic disease that developed post-diagnosis (HR = 1.65; 95% CI, 1.19-2.29).
However, among those with MSS disease who received immunotherapy, researchers observed a mortality risk reduction for patients with high albumin levels vs. low levels (HR = 0.28; 95% CI, 0.18-0.45) and antibiotic use vs. nonuse (HR = 0.43; 95% CI, 0.27-0.67).
“About 12% of patients with MSS tumors responded to immunotherapy,” Schmit said, who described that result as a “surprising finding.”
“Around eighty-five percent of colorectal cancer is MSS,” she added. “Even 12% of that group is somewhat comparable in absolute numbers to the 15% of all colorectal cancer patients with MSI-H tumors. It’s a substantive fraction of patients.”
Researchers acknowledged study limitations, including incomplete EHR data.
“It’s encouraging to show that maybe it’s not only the 15% of patients who have MSI-H tumors [who benefit],” she said. “There also may be subsets of patients who have microsatellite stable tumors who benefit. Now the question is, who are they and how do we find them?”
‘We need to investigate further’
Schmit highlighted multiple paths researchers could explore to identify which individuals with MSS disease may benefit from immunotherapy.
Molecular and genetic features could have associations with better outcomes, as could features of the tumor microenvironment.
“Because survival in MSS disease appears to be associated with antibiotic use, are there unique microbiome features associated with the tumors that may be biomarkers of response?” Schmit asked. “Immune cells and the microbiome are two of the places where the field is starting.”
Schmit also mentioned that the “lowest hanging fruit” may involve examination of tumor-infiltrating lymphocytes (TILs).
“We’ve seen that there are some MSS tumors that have high levels of tumor-infiltrating lymphocytes, even though that’s usually a feature associated with MSI-H tumors,” Schmit said. “There is an opportunity to directly identify and measure these T-cell responses that aren’t typical in MSS tumors. If they’re there, that’s something we need to investigate further.”
For more information:
Stephanie L. Schmit, PhD, MPH, can be reached at schmits3@ccf.org.
Sources/Disclosures
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Disclosures:
Schmit reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.