AI Summary
This article discusses a study that aimed to identify predictive biomarkers associated with patient response to combination immunotherapy in patients with microsatellite stable (MSS) or mismatch repair-proficient (pMMR) metastatic colorectal cancer (CRC). The study used whole-exome sequencing, RNA sequencing, and immunohistochemistry to analyze tumors from patients who received different combination immunotherapy regimens. The results showed that certain molecular pathways and tumor microenvironment factors were associated with response to specific regimens. Consensus molecular subtype 4 and the presence of specific immune cell types were associated with response to the REGONIVO regimen, while mutations in the POLE gene were associated with response to the TASNIVO regimen. These findings could help develop biomarkers to predict treatment efficacy and guide future immunotherapy combinations for patients with MSS/pMMR CRC.
Background
Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations.
Methods
Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies.
Results
The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial.
Conclusions
We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.