Two Genes Predict Resistance to ICIs in dMMR/ MSI-H GI Cancers

Investigators have identified 2 genes that help to determine primary resistance to immunotherapy among patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) gastrointestinal cancers, according to findings published in the Journal for ImmunoTherapy of Cancer.¹

The immuno-oncology therapy predictor (IOpred) combined mutations in both AKT1 and CDH1 to identify patients with primary resistance to immune checkpoint inhibitors (ICIs). Both mutations were independent predictors of poor progression-free survival (PFS) from immunotherapy treatment.

“In view of the predictive role of IOpred for primary resistance to ICIs, IOpred might guide clinical decision-making that the dMMR/MSI-H patients with IOpred mutation should not be recommended for ICI therapy,” wrote the study authors, led by Zhenghan Wang, MD, and coinvestigators from the Peking University Cancer Hospital and Institute in Beijing, China.

Investigators are seeking to determine why only certain patients with dMMR/ MSI-H gastrointestinal (GI) cancers will respond to treatment with ICIs and to identify biomarkers that may help to determine which patients will respond to therapy.

Wang et al conducted a next-generation sequencing (NGS) analysis on 65 patients with dMMR/MSI-H GI cancers who had received ICI treatment at the Peking University Cancer Hospital and Institute for a biomarker discovery cohort. The patients’ dMMR/MSI-H status was confirmed by both NGS and immunohistochemistry/polymerase chain reaction testing.

Forty-four patients were sensitive to ICI treatment and 21 were resistant. In the ICI-sensitive group, the median age was 53 years (range, 22-76), 25 patients were male, 42 had an ECOG performance status of 0 or 1. Thirty-six patients had intestinal cancer and 8 had gastric cancer. Ten patients had Lynch syndrome, 1 had HER2-positive disease, 5 had positive PD-L1 expression, 2 had high differentiation, and all had metastatic disease.

Among the ICI-resistant group, the median age was 49 years (range, 26-82), 13 patients were male, 20 had an ECOG performance status of 0 or 1. Fourteen patients had intestinal cancer and 7 had gastric cancer. Four patients had Lynch syndrome, 3 had PD-L1 positive expression, 1 had high differentiation, and all had metastatic disease.

Overall, patients had an objective response rate to ICI treatment of 53.9%, which consisted of 6 complete responses and 29 partial responses. The median progression-free survival (PFS) was 10.4 months, and the median overall survival (OS) was 20.2 months.

The investigators found that mutations in AKT1, CUL3, and CDH1 were significantly correlated with PFS. However, only AKT1 and CDH1 mutations were enriched in the ICI-resistant population vs the ICI-sensitive group. These 2 mutations were identified in more than 5% of the overall population.

Patients who had an AKT1 mutation (n = 6) showed significantly worse outcomes than patients with AKT1 wild-type disease in terms of both PFS (median, 2.4 months vs not reached [NR]; HR, 7.80; 95% CI, 2.90-20.95; P <.001) and OS (median, 8.2 months vs NR; HR, 6.21; 95% CI, 1.89-20.44; P < .001). A similar result was seen for patients with CDH1 mutations (n = 7) compared with CDH1 wildtype for PFS only (median, 1.5 months vs NR; HR, 5.37; 95% CI, 2.10-13.76; P < .001). No significant differences in values for tumor mutational burden, indel burden, copy number alteration load, or mutant-allele tumor heterogeneity were observed between the 2 subgroups.

Combined, patients with mutant AKT1 or CDH1 tumors (IOpred) had worse survival rates than those with wild-type disease in terms of both PFS (median, 2.1 months vs NR; HR, 8.36; 95% CI, 3.58-19.55; P < .001) and OS (median, 16.9 months vs NR; HR, 5.17; 95% CI, 1.77-15.12; P < .001), regardless of cancer type.

IOpred was found to be an independent predictor of PFS in this patient population by both univariate and multivariate Cox regression analyses. The positive predictive value was 91.7% for the overall group.

The investigators then tried to validate the utility of IOpred in a cohort of 22 patients with dMMR/MSI-H GI cancers. In this group, 5 patients had IOpred mutations, meaning AKT1 and/or CDH1 mutations, and 17 had IOpred wild type. In the mutated group, the median age was 53 years (range, 44-75), 4 were male, 3 had an ECOG performance status of 1. Two had intestinal cancer and 3 had gastric cancer, and all had metastatic cancer. In the wild-type group, the median age was 48 years (range, 31-75), 10 patients were male, 10 had an ECOG performance status of 1. Fourteen had intestinal cancer and 3 had gastric cancer, 1 had Lynch syndrome, 3 had positive PD-L1 expression, 1 had high differentiation, and all patients had metastatic disease.

Patients with IOpred-mutated disease compared with those with IOpred wild-type disease had worse PFS (median, 1.6 months vs 21.7 months; HR, 4.68; 95% CI, 1.47-14.97; P=.004) and OS (median, 2.8 months vs 20.0 months; HR, 15.98; 95% CI, 2.98-85.64; P<.001). Four of the 5 patients with IOpred mutations were resistant to ICI treatment compared with 6 of the 17 patients with IOpred wild type.

“Collectively, these results validated that IOpred was a convenient and powerful predictor of primary resistance to ICIs,” the study authors concluded.

Because only 2 genes were required to be tested to determine primary resistance, the investigators suggested that IOpred could be turned into a clinical assay.

“IOpred can be easily translated into an easy-to-use clinical assay due to only detection of 2 decisive common genes and could be recommended for routine clinical care in dMMR/MSI GI cancer,” Wang et al wrote.

Reference:

Wang Z, Zhang Q, Qi C, et al. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer. 2022;10(6):e004703. doi:10.1136/jitc-2022-004703