Abstract 1898
Background
Limitations of integrating biological knowledgebases with genomics impedes the development of predictive correlates that would help in personalization of immunotherapy. Non-small cell lung cancer (NSCLC) patients treated with atezolizumab, an antiprogrammed death-ligand 1 (PDL1) antibody, have better overall survival when compared to patients receiving docetaxel chemotherapy in Poplar (Lancet, 2016) and Oak (Lancet, 2017). We hypothesized that patterns in the mutations of immune signatures would correlate with the immunotherapeutic effect of atezolizumab in NSCLC.
Methods
Sequencing data from Poplar (n = 277 patients) and Oak (n = 725 patients) trials was analyzed for understanding genomic alterations in relation to patient outcomes. Signatures from publicly-available knowledgebases were integrated with the genomics and clinicopathological data into an algorithm for identifying patterns correlative of immunotherapeutic response.
Results
Patients benefitting from atezolizumab were more likely to have mutations in oncoimmunity-related genes which were significantly overlapping between the two trials. These overlapping genes were used to develop a de novo signature comprising of CDKN1A, ERRFI1, JAK2, NOTCH2, ACVR1B, NFKBIA, GNA13, MERTK, BTG1, CDKN1B, FOXP1, PDK1, ETV6, MLL2, SMAD3, DICER1 and BRCA2. Mutations in any of the genes within the signature identified patient subpopulations with higher immunotherapeutic response to Atezolizumab in both Oak (HR = 0.3, P = 1.8e-6 versus HR = 0.76, P = 5.5e-3 for entire cohort) and Poplar (HR = 0.18 and P = 3.6e-2 versus HR = 0.71, P = 0.023 for all patients) trials. Prediction efficiency of the signature was significantly better than established biomarkers such as PDL1 staining (Nature, 2014) in both Oak (HR: 0.58 and P = 1.8e-6) and Poplar (HR: 0.58 and P = 0.04) trials indicating that genomic correlates could add significant value to existing modalities in predicting immunotherapy response.
Conclusions
In summary, integration of biological knowledgebases with genomics suggests that a rheostat of mutational burden in non-overlapping genesets is associated with immunotherapeutic effect and identifies novel genomic correlates for response to Atezolizumab.
Clinical trial identification
NCT02008227; NCT01903993.
Editorial acknowledgement
Legal entity responsible for the study
Roche.
Funding
Roche.
Disclosure
D.R. Gandara: Research grant: Bristol-Myers Squibb, Roche-Genentech, Novartis, Merck; Consultancy: AstraZeneca, Celgene, CellMax Life, FujiFilm, Roche-Genentech, Guardant Health, Inviata, IO Biotech, Lilly, Liquid Genomics, Merck, Samsung Bioepis, Pfizer. All other authors have declared no conflicts of interest.
Resources from the same session
5218 - Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer
Presenter: Bram De Laere
Session: Poster Display session 3
Resources:
Abstract
2452 - High proportion of multiple KRAS mutations in circulating tumor DNA and tumor tissue of pancreatic ductal adenocarcinoma
Presenter: Min Kyeong Kim
Session: Poster Display session 3
Resources:
Abstract
3328 - Biological difference of tumor mutational burden (TMB) and microsatellite instability (MSI) status in patients (pts) with somatic vs. germline BRCA1/2-mutated advanced gastrointestinal (GI) cancers using cell-free DNA (cfDNA) sequencing analysis in the GOZILA study
Presenter: Yasuyuki Kawamoto
Session: Poster Display session 3
Resources:
Abstract
3022 - Cell-Free DNA to Detect Focal Versus Non-Focal MET Amplification in Metastatic Colorectal Cancer Patients: Combined Analysis from Japan and the United States
Presenter: Mishima Saori
Session: Poster Display session 3
Resources:
Abstract
2833 - Presence of circulating tumor DNA in surgically resected renal cell carcinoma is associated with advanced disease and poor patient prognosis
Presenter: Andres Correa
Session: Poster Display session 3
Resources:
Abstract
1376 - Combined genomic and epigenomic assessment of cell-free circulating tumor DNA (cfDNA) for cancer diagnosis and recurrence-risk assessment in early-stage lung cancer
Presenter: Junghee Lee
Session: Poster Display session 3
Resources:
Abstract
4050 - DEMo: a prospective evaluation of a prognostic clinico-molecular composite score in NSCLC patients treated with immunotherapy.
Presenter: Arsela Prelaj
Session: Poster Display session 3
Resources:
Abstract
4727 - Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single agent pembrolizumab (P)
Presenter: Cindy Yang
Session: Poster Display session 3
Resources:
Abstract
3662 - Dynamic changes in whole-genome cell-free DNA (cfDNA) to identify disease progression prior to imaging in advanced solid tumors
Presenter: Andrew Davis
Session: Poster Display session 3
Resources:
Abstract
3817 - Evaluation of Microsatellite Instability Testing Through cell-free DNA sequencing
Presenter: Shile Zhang
Session: Poster Display session 3
Resources:
Abstract