Dataset Information

High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naive Patients with Diverse Cancers.

ABSTRACT: Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here, we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both as a tiered variable (low ≤5 mutations/Mb, intermediate >5 and <20, high ≥20 and <50, and very high ≥50) and as a continuous variable. Interestingly, we observed a parabolic correlation between TMB and overall survival, in which intermediate-range TMB correlated with decreased survival, whereas low and very high TMB correlated with improved outcomes (median survival: 238, 174, 195, and 350 weeks for low, intermediate, high, and very high TMB, respectively; multivariate P < 0.01). This corresponded to an HR of 1.29 (95% confidence interval, 1.07-1.54; P < 0.01) for intermediate-range TMB on multivariable survival analysis correcting for known confounders, including primary tumor of origin. These results demonstrate that TMB may have utility as a prognostic biomarker in immunotherapy-naïve patients, with a protective effect at higher TMBs, and that studies of survival in immunotherapy-treated patients may need to stratify or randomize by TMB in a nonlinear fashion to account for this confounding.

SUBMITTER: Riviere P

PROVIDER: S-EPMC7541603 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers.

Riviere Paul P Goodman Aaron M AM Okamura Ryosuke R Barkauskas Donald A DA Whitchurch Theresa J TJ Lee Suzanna S Khalid Noor N Collier Rachel R Mareboina Manvita M Frampton Garrett M GM Fabrizio David D Sharabi Andrew B AB Kato Shumei S Kurzrock Razelle R

Molecular cancer therapeutics 20200803 10

Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here, we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both as a tiered variable (low ≤5 mutations/Mb, intermediate >5 and <20, high ≥20 and <50, and very high ...[more]

PMID: 32747422

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Project description:ImportanceThere are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers.ObjectiveTo clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay.Design, setting, and participantsA prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022.ExposureTreatment with US Food and Drug Administration (FDA)-approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI.Main outcomes and measuresThe primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP).ResultsIn the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non-small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02).Conclusions and relevanceIn this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.

Project description:Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (≥65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.

Dataset Information

High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naive Patients with Diverse Cancers.

Publications

High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers.

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