Tumor mutation burden (TMB) is unlikely indicative of checkpoint inhibitor response for patients with colorectal cancer (CRC), despite recent tissue-agnostic approvals, according to a study presented at the virtual 2021 ASCO Gastrointestinal Cancers Symposium.
“Checkpoint inhibitor therapies have shown prolonged survival in patients with microsatellite instability. [TMB] has also been associated with benefit from [checkpoint inhibitors], with pembrolizumab recently approved for solid tumors with a TMB of =10 muts/mb,” wrote Carissa Jones, PhD, Sarah Cannon Cancer Center, Nashville, Tennessee, and colleagues.
“However, the validity of a tissue-agnostic approach has been debated given the high degree of TMB variation across tumor types,” they continued.
This study aimed to examine the impact of TMB and MSI on checkpoint inhibitor response among patients with advanced gastrointestinal cancers.
Genospace, Sarah Cannon Cancer Center’s clinic-genomic analytics platform, was used to identify patients with GI cancer and comprehensive next-generation sequencing (NGS) with the institution’s network. Microsatellite status (high [MSI-H] vs stable [MSS]) was defined using NGS. TMB-high [TMB-H] status was defined as =10 muts/mb.
Kaplan-Meier estimates were used to evaluate time to treatment failure (TTF).
A total of 5788 patients were identified, of whom 3603 (48%) patients had a CRC diagnosis. Microsatellite status was evaluated in 4219 (66%) NGS reports, TMB was evaluated in 2922 (46%), and both were evaluated in 2863 (45%).
Overall, MSI-H and TMB-H co-occurred on 127 (4%) reports, MSS and TMB-H occurred on 312 (11%) reports, and MSS and TMB-low (TMB-L) occurred on 2414 (85%) reports. MSI-H and TMB-L did not occur.
TTF was significantly shorter for checkpoint inhibitor therapies (median TTF, 151 days) compared with non-checkpoint inhibitor therapies (median TTF, 238 days), irrespective of line of therapy or tumor type.
Further analyses were specified to patients with CRC due to the small sample sizes of other gastrointestinal cancers. TMB-H was independently associated with longer checkpoint inhibitor TTF vs TMB-L. Co-occurrence of MSI-H and TMB-H was also associated with longer TTF. No difference in checkpoint inhibitor TTF was noted for MSS and TMB-H, as well as MSS and TMB-L (P = .45).
TTF was longer for all patients who received non-checkpoint inhibitor therapies, irrespective of microsatellite or TMB status, than that for MSS/TMB-H and MSS/TMB-L patients who received checkpoint inhibitors.
“Despite recent tissue-agnostic approvals, TMB does not appear to be a good biomarker of [checkpoint inhibitor] response in patients with CRC. Rather, time to [checkpoint inhibitor] failure is associated with the co-occurrence of TMB-H with MSI-H,” concluded Dr Jones and colleagues.
“Continued research is needed to identify better biomarkers of response to immunotherapy in [gastrointestinal] cancers,” they added.—Janelle Bradley
Jones C, Lachs R, Sturgill E. Real-world data evaluating immunotherapy markers and checkpoint inhibitor response among GI cancers in a large community-based oncology network. Presented at: the virtual 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021. Abstract 113.