Frontline ICI Therapy Confers OS Benefit in MSI-H Metastatic CRC

Compared with patients treated with chemotherapy alone, a significantly longer OS benefit was observed in those who received first-line ICI therapy, but a statistically significant benefit was not observed among patients who received ICIs in later therapy lines.

Immune checkpoint inhibitor (ICI)-based treatment exhibited a survival benefit in patients with microsatellite instable (MSI-H) metastatic colorectal cancer (CRC), according to a population-based cohort study published in JAMA Open Network.

Findings from the study revealed that among 566 patients treated with ICIs for metastatic CRC between January 1, 2013, and June 31, 2019, 234 had MSI-H tumors and 235 had microsatellite stable (MSS) tumors.

In the overall treatment population (n = 18,932), the median overall survival (OS) was 21.0 months (95% CI, 20.5-21.4), and the median time to treatment discontinuation (TTD) was 5.3 months (95% CI, 5.2-5.3). Additionally, associations between receipt of immunotherapy and outcomes were statistically significantly different among those with MSI-H or MSS tumors (OS: P = .002; TTD: P = .03).

Compared with patients treated with chemotherapy alone, a significantly longer OS benefit was observed in those who received first-line ICI therapy (HR, 0.60; 95% CI, 0.44-0.82; P = .002). A statistically significant benefit was not observed among patients who received ICIs in later therapy lines. Additionally, among patients stratified by mismatch repair (MMR) status, patients with MSI-H tumors experienced significantly longer OS outcomes with first-line ICI therapy vs chemotherapy (HR, 0.37; 95% CI, 0.25-0.56; P <.001), but a similar association was not found in those with MSS tumors (HR, 1.30; 95% CI, 0.78-2.15; P = .32). Furthermore, the line of immunotherapy did not significantly impact TTD in the MSI-H cohort.

“In this cohort study of 18,932 patients with [metastatic CRC], the results supported findings from clinical trials about the benefits of ICIs as first-line treatment [for] patients with MSI-H mCRC,” primary investigator Shahla Bari, MBBS, assistant professor of Medicine and medical oncologist at Duke Cancer Institute, wrote in a publication with coinvestigators. “In addition, we provided important insights about characteristics of patients that may influence clinical outcomes in patients with [metastatic CRC] treated with immunotherapy, especially for patients with MSS tumors that have generally been unresponsive to ICIs in clinical trials. Further research is needed to better understand the potential interaction between ICIs and patient/tumor characteristics and identify additional factors that may modulate the effect of ICIs on clinical outcomes.”

Utilizing the Flatiron Health electronic health record (EHR)-derived database, investigators selected 23,963 patients with metastatic CRC for evaluation in the population-based study. Those selected were diagnosed and had at least 2 documented clinical visits from January 1, 2013, to June 31, 2019, with follow-up extending up to December 31, 2019. A total of 18,932 received treatment and met the eligibility criteria for study inclusion.

Baseline demographic, clinical, and tumor characteristics were collected via EHR, survey, and self-report, with information recorded directly into the EHR or practice management system, which was also imported into the EHR. Date of death at month- and year-granularity was identified using structured and unstructured EHR-derived data, including physician notes, condolence letters, external death data sources, and the US Social Security Death Index, as well as a commercial death database.

Among patients on trial who did or did not receive immunotherapy, most patients were males (50.2% vs 55.8%), White (69.3% vs 65.0%), and insured at diagnosis (53.0% vs 54.4%). Most patients in respective groups were treated at community practices (94.3% vs 94.2%), had stage IV disease at initial diagnosis (44.3% vs 61.0%), or had primary tumors in the colon (81.1% vs 73.9%). Most patients received treatment before FDA approval of ICIs for the treatment of refractory MSI-H metastatic CRC (61.1% vs 66.1%).

Regarding MMR mutational status in the immunotherapy and chemotherapy-only groups, 41.3% vs 2.7% had MSI-H tumors, 41.5% vs 58.2% had MSS tumors, and 17.1% vs 39.1% had unknown MMR status (P <.001). Furthermore, in respective groups, 50.5% vs 43.8% had BRAF wild-type disease, 17.5% vs 5.0% had BRAF-positive disease, and 32.0% vs 51.2% had unknown BRAF mutational status (P <.001).

The coprimary study end points were the receipt of ICI-base therapy and OS. The secondary end point was TTD.

Reference

Bari S, Matejcic M, Kim RD, et al. Practice patterns and survival outcomes of immunotherapy for metastatic colorectal cancer. JAMA Netw Open. 2025;8(3):e251186. doi:10.1001/jamanetworkopen.2025.1186