Dataset Information

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

ABSTRACT: Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

SUBMITTER: Liu D

PROVIDER: S-EPMC6898788 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Liu David D Schilling Bastian B Liu Derek D Sucker Antje A Livingstone Elisabeth E Jerby-Arnon Livnat L Zimmer Lisa L Gutzmer Ralf R Satzger Imke I Loquai Carmen C Grabbe Stephan S Vokes Natalie N Margolis Claire A CA Conway Jake J He Meng Xiao MX Elmarakeby Haitham H Dietlein Felix F Miao Diana D Tracy Adam A Gogas Helen H Goldinger Simone M SM Utikal Jochen J Blank Christian U CU Rauschenberg Ricarda R von Bubnoff Dagmar D Krackhardt Angela A Weide Benjamin B Haferkamp Sebastian S Kiecker Felix F Izar Ben B Garraway Levi L Regev Aviv A Flaherty Keith K Paschen Annette A Van Allen Eliezer M EM Schadendorf Dirk D

Nature medicine 20191202 12

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transc ...[more]

PMID: 31792460

Similar Datasets

Project description:BackgroundImmune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test.ResultsOur cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 vs 25 months, p=0.368) and PFS (3.1 vs 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians.ConclusionsOur real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.

Dataset Information

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Publications

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets