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Abstract
Background Both TMB-H and dMMR/MSI-H have been proposed as predictive biomarkers and received tissue-agnostic approval for CPIs, but there has been no head-to-head comparison between TMB-H and MSI-H as predictive biomarkers for CPIs. MSI-H demonstrated its promising predictive value in multiple independent cohorts with different CPI agents. In contrast, TMB-H has been suggested as a CPI predictive biomarker mainly based on the exploratory study from KEYNOTE-158, which showed response benefit without further meaningful clinical endpoints, raising concern for the validity of TMB-H as a predictive biomarker for CPIs. Also, data for TMB-H in GI cancer is limited.
Methods We reviewed Moffitt Cancer Center databases for patients with histologically confirmed advanced/metastatic GI cancer, harboring either MSS with TMB-H (≥ 10 mut/Mb by tissue and/or blood) or dMMR/MSI-H (by IHC, PCR or NGS) who received CPI between June 2016 and April 2023 with measurable disease by RECIST1.1. We compared CPIs’ efficacy profiles including ORR, DCR, DoR, PFS, and OS between MSS-TMB-H (N=56) versus MSI-H (N=50) in GI tumors.
Results 106 patients with 50(47.2%) colorectal, 38(35.8%) esophagogastric, 11(10.4%) pancreaticobiliary and 7(6.6%) other GI tumors were included. MSS-TMB-H group had more later-line CPI recipients and esophagogastric cancer, but otherwise there was no significant difference in key prognostic variables including age, ECOG-PS, brain metastasis, and CPI type (table 1). At a median follow-up of 9.4 months, CPI-recipients with MSI-H GI tumors showed significantly superior ORR (58.0% vs 32.1%, p=0.0132), DCR (84.0% vs 50.0%, p=0.0005), PFS (22.5mo vs 4.8mo, p=0.0007), OS (Not reached vs 12.6mo, p=0.0004), and statistically non-significant trend towards improved DoR (Not reached vs 10.6mo, p=0.1669) compared to MSS-TMB-H (figures 1 and 2). Multivariable analysis with adjusting key prognostic variables including lines of treatment showed that MSI-H was an independent favorable factor compared to MSS-TMB-H for PFS (HR=0.50, CI 0.26–0.95, p=0.033) and OS (HR=0.34, CI 0.14–0.78, p=0.011). In the following subgroup analyses, MSS-TMB-20+ (≥20 mut/Mb) showed statistically non-significant trend towards improved ORR, DCR, and PFS compared to MSS-TMB-10s (20>TMB ≥10) (figures 1 and 3). Overall, MSI-H group showed favorable ORR, DCR, and PFS compared to MSS-TMB-H, regardless of cut-off (10+ or 20+).
Conclusions Regardless of TMB cutoff 10 or 20, MSS-TMB-H does not appear to be a promising predictive biomarker for CPIs compared to MSI-H in GI tumors. Our finding raises the necessity to reconsider TMB-H as a predictive biomarker for CPIs in GI tumors, but further verification is warranted in a larger population.
Acknowledgements There are no funding sources
Ethics Approval This study was approved by the corresponding Ethical and Independent Institutional Review Board (IRB) from our (Moffitt Cancer Center) institution
Patient characteristics (N=106)
Overall Response Rate and Disease Control Rate to Check-Point Inhibitors in GI Tumors by Groups. (A) ORR was significantly higher in MSI-H vs MSS-TMB-H (58.0% vs 32.1%, P=0.0132). (B) ORR was significantly higher in MSI-H vs MSS-TMB-10s (58% vs 25%, P=0.0017). ORR was numerically higher in MSS-TMB-20+ vs MSS-TMB-10s (41.7% vs 25.0%, P=0.0932) and MSI-H vs MSS-TMB-20+ (58.0% vs 41.7%, P=0.0939). (C) DCR was significantly higher in MSI-H vs MSS-TMB-H (84% vs 50%, P=0.0005). (D) DCR was significantly higher in MSI-H vs MSS-TMB-10s (84.0% vs 46.9%, P=0.0002) and MSI-H vs MSS-TMB-20 (84.0% vs 54.2%, P=0.0030). There was no significant DCR difference between MSS-TMB-10s vs MSS-TMB-20+ (46.9% vs 54.2%, P=0.2946). * P-Value<0.05. TMB-H: TMB≥10mut/Mb, TMB-10s: 20>TMB≥10, TMB-20+: TMB≥20. MSI-H: either dMMR by IHC or MSI-H by NGS or PCR
Kaplan-Meier Graphs and Forest Plots for Multivariate Cox Regression for PFS and OS between MSS-TMB-H and MSI-H in GI tumors treated with CPIs. (A) Median PFS was significantly longer in MSI-H vs MSS-TMB-H by log-rank test (22.5mo vs 4.8mo, P=0.00073). (B) In multivariate PFS analyses, MSI-H was an independent favorable factor compared to MSS-TMB-H (HR=0.50, Cl 0.26–0.95, p=0.033). (C) Median OS was significantly longer in MSI-H vs MSS-TMB-H by log-rank test (Not Reached vs 12.6mo, P=0.00036). (D) In multivariate OS analyses, MSI-H was an independent favorable factor compared to MSS-TMB-H (HR=0.34, Cl 0.14–0.78, p=0.011).
Kaplan-Meier Graphs for PFS between MSS-TMB-10s, MSS-TMB-20+, and MSI-H in GI tumors treated with CPIs. PFS was significantly longer in MSI-H compared to MSS-TMB-10s (22.5mo vs 4.3mo, P=0.0005) and MSS-TMB20+ (22.5mo vs 8.2mo, P=0.02). There was no significant PFS difference between MSS-TMB-10s vs MSS-TMB-20+ (p=0.42).
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