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. 2023 Feb 7;3:14. doi: 10.1038/s43856-023-00243-7

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Real-world treatment and molecular profiling data from formalin fixed paraffin embedded (FFPE) tumor tissue from patients enrolled in the StrataTrial (NCT03061305) are collected in the Strata Clinical Molecular Database (SCMD). Molecular data from both DNA (yellow) and RNA (blue) include both comprehensive genomic profiling (CGP) with both DNA and RNA components, and in-parallel quantitative transcriptional profiling (qTP) comprised of RNA from analytically and clinically validated tests. To develop an integrative predictor of PD-(L)1 therapy benefit, we identified a cohort of 648 patients (from 26 tumor types) with available molecular information who were treated with a pembrolizumab (pembro; PD-1) containing systemic therapy line of treatment. Lasso-penalized Cox proportional hazards modeling with five-cross validation was used to develop the IRS model for predicting real world progression free survival (rwPFS; by time to next therapy), which includes tumor mutation burden (TMB; from CGP) and expression of PD-1, PD-L1, ADAM12 and TOP2A (from qTP). The locked IRS model and threshold to assign patients to IRS-Low [L] or IRS-High [H; increased benefit] was then applied to an independent validation cohort of 248 patients (from 24 tumor types) treated with non-pembrolizumab PD-[L]1systemic monotherapy. Pie charts for the development and validation cohorts show tumor type distributions for the 11 most common tumor types and other tumor types. b IRS stratifies pembrolizumab rwPFS in the development cohort. Pembrolizumab rwPFS in the development cohort stratified by IRS groups is shown by Kaplan Meier analysis with the adjusted hazard ratio (HR) and p value (adjusted by variables shown in (c) for IRS-H vs. IRS-L. The number (n) of patients, events, and median rwPFS (with 95% confidence intervals [CI]) for each group are shown. c IRS is robust to potential confounders in the development cohort. Forest plot of variables included in the adjusted Cox proportional hazards model used to evaluate the ability of IRS to stratify pembrolizumab rwPFS. Adjusted hazard ratios with 95% CIs are shown for each variable with statistically significant variables bolded. n = 648 patients (from 26 tumor types).