MIS Biomarker May Effectively Anticipate Outcome of Immune Checkpoint Inhibitors for Colorectal Cancer

It is estimated that 5% of patients with metastatic colorectal cancer (MCRC) have microsatellite instability (MSI) and/or deficiency in the mismatch repair pathway (DMMR), according to authors of a recently published study in JAMA Network Open. MCRCs with MSI are often presented with high tumor mutational burden (TMB), which creates an enhanced response to immune checkpoint inhibitors (ICIs).

Investigators recently discovered that MCRC patients with high microsatellite instability (MSI-H)—assessed by next-generation sequencing (NGS)—and/or DMMR appeared to have more favorable outcomes with first-line ICIs than chemotherapy. However, MSI appeared to anticipate ICI outcomes better than DMMR.

“Herein we have extended the study of MMR or MSI in MCRC and report, to our knowledge, the first comparison of outcomes between patients with MSI-H MCRC receiving first-line therapy with ICIs vs chemotherapy in standard practice settings,” wrote study authors. “Our findings support MSI assessed by NGS as a biomarker of outcomes of first-line ICIs in patients with MCRC.”

MSI is caused by a sequence variation of an MMR gene that results in lost protein expression—immunohistochemistry (IHC) is a method that can detect MMR deficiency. Like NGS and polymerase chain reaction (PCR), IHC detects MSI, but studies are limited on their ability to be a biomarker of ICI response.

In this trial, investigators evaluated MSI determined by NGS as a biomarker for ICI treatment outcomes for patients with MCRC with MSI-H tumors receiving first-line ICIs vs chemotherapy. The primary endpoints were time to next treatment (TTNT), PFS, and OS. Investigators identified 138 patients with MSI-H MCRC to received first-line ICIs or chemotherapy. In a second cohort, 182 patients received ICIs in any line of therapy (LOT) for biomarker examination.

“We asked a question not about optimal detection method but rather about best performing biomarker in anticipating outcomes,” study authors wrote in the article.

The results showed that MMR and MSI could similarly anticipate ICI outcomes. However, when comparing NGS-derived MSI assessments with IHC, NGS was found to be a superior method. This could be because NGS addresses multiple MMR biomarkers. Additionally, first-line ICIs led to a PFS of 24.87 months compared to 5.65 months in the control group, while the median OS for ICI patients was 24 months.

There are a few limitations in the study. First, the patient population is rare, therefore the relative sample size is small, which may limit biomarker comparisons. The data also did not include presence or absence of liver metastases.

In the prior trial KEYNOTE-177, investigators had compared first-line ICI therapy pembrolizumab (Keytruda; Merck) with chemotherapy in a randomized cohort of MSI-H and/or DMMR MCRC patients, which also determined that ICIs are a first-line treatment option for this patient population.

“Detection of MSI by NGS may be favored for evaluating patients with MCRC for ICI-based treatments when the biomarkers are discordant,” study authors wrote.

Reference

Quintanilha J, Graf R, Fisher V, et al. Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden. JAMA Netw Open. 2023;6(1):e2252244. doi:10.1001/jamanetworkopen.2022.52244