Abstract
Background – Immune checkpoint inhibitors (ICI) are approved in advanced colorectal cancer (CRC) patients with the microsatellite instability-High (MSI-H) biomarker. MSI-H CRC patients represent a minority of advanced CRC disease. Though the majority of CRC patients are MSS, they lack a predictive biomarker for ICI response, an urgent unmet clinical need. The immune profile score (IPS), a DNA and RNA-based molecular signature, was validated as a prognostic biomarker in >1,500 advanced solid pan-cancer patients. We conducted an exploratory study evaluating IPS as a biomarker of ICI benefit in a real-world cohort of MSS CRC patients treated with ICI.

Methods – We used the Tempus Database to identify advanced MSS CRC patients who received an ICI alone or ICI-containing regimen in the third line and beyond. Using pre-ICI tissue samples, IPS was calculated using the Tempus xT (DNA) and xR (RNA) assays. Patients were stratified as IPS-High vs. IPS-Low. The prognostic value of IPS for real-world overall survival (rwOS) was assessed using Cox proportional hazards models. To evaluate the relative stratification of IPS (high vs. low) for ICI regimens compared to non-ICI regimens, we compared IPS association with time-to-next-treatment (TTNT) on prior chemotherapy regimens to rwOS on ICI therapy, anchoring on prior regimen start.

Results – Of 46 evaluable patients, 24 (52%) received ICI monotherapy and 22 (48%) received ICI-based combinations. Six patients (13%) were classified as IPS-High. A clinically meaningful improvement in real-world survival was observed in the IPS-High group vs. IPS- Low group (median >24 months (IPS-High) vs. 7.3 months (IPS-Low)). This effect size was comparable to our prior validation of IPS stratification across advanced solid cancers (HR= 0.22, 95% CI [0.04-1.16]). Additionally, we compared IPS risk stratification on ICI therapy (rwOS HR = 0.21 [0.03-1.70] to the prior non-ICI regimen (TTNT HR=1.07 [0.54-2.13]). The difference in stratification between the non-ICI prior treatment cohort versus the ICI cohort was clinically meaningful.

Conclusions – Our analysis suggests that the multi-omic IPS biomarker may stratify rwOS in advanced MSS CRC patients who received ICI therapy. The comparison of IPS-High to IPS-Low on ICI versus prior non-ICI provides additional insight about the utility of IPS as an ICI specific biomarker beyond its established prognostic validity. This hypothesis-generating data address an unmet need for patients whom an ICI therapy and predictive biomarkers are urgently needed.

Ethics Approval – This study was conducted on de-identified health information subject to an IRB exempt determination (Advarra Pro00072742) and did not involve human subjects research.

VIEW THE PUBLICATION