Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

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Abstract

Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden ≥10 mut/Mb (TMB ≥ 10) have more favorable outcomes on immune checkpoint inhibitor (ICPI) monotherapy compared with chemotherapy in subgroup analyses of randomized controlled trials. We sought to evaluate the robustness of these associations in real-world settings where patients and practices are more diverse. A total of 362 2 L and 692 1 L patients, respectively received ICPI (n = 99, 33) or chemotherapy (n = 263, 659) across approximately 280 U.S. academic or community-based cancer clinics March 2014–July 2021. Deidentified data were captured into a real-world clinico-genomic database. All patients underwent Foundation Medicine testing. Time to next treatment (TTNT) and overall survival (OS) comparing ICPI versus chemotherapy were adjusted for treatment assignment imbalances using propensity scores. 2L: TMB ≥ 10 had more favorable TTNT [median 24 vs. 4.1 months; HR: 0.19; 95% confidence interval (CI): 0.09–0.44; P = 0.0001] and OS (median 43.1 vs. 6.2 months; HR: 0.24; 95% CI: 0.011–0.54; P = 0.0005), TMB < 10 did not (P > 0.05). 1L: TMB ≥ 10 had more favorable TTNT (not reached vs. median 4.1 months; HR: 0.13; 95% CI: 0.03–0.48; P = 0.0024) and OS (not reached vs. median 17.1 months; HR: 0.30; 95% CI: 0.08–1.14; P = 0.078), TMB < 10 had less favorable TTNT (median 2.8 vs. 6.5 months; HR: 2.36; 95% CI: 1.25–4.45; P = 0.008) and OS (median 4.5 vs. 13.1 months; HR: 1.82, 95% CI: 0.87–3.81; P = 0.11). TMB ≥ 10 robustly identifies patients with mEG with more favorable outcomes on 2 L ICPI monotherapy versus chemotherapy. 1 L data are more limited, but effects are consistent with 2L. Significance: Using real-world data, we sought to evaluate robustness of these clinical associations using the same assay platform and biomarker cut-off point used in both clinical trials and pan-tumor CDx approvals for later treatment lines. TMB ≥ 10 robustly identified patients with mEG with more favorable outcomes on ICPI monotherapy versus chemotherapy and suggests this subset of patients could be targeted for further trial development.

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Graf, R. P., Fisher, V., Creeden, J., Schrock, A. B., Ross, J. S., Nimeiri, H., … Klempner, S. J. (2022). Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer. Cancer Research Communications, 2(9), 1037–1048. https://doi.org/10.1158/2767-9764.CRC-22-0161

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