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
2115 - Preclinical in vivo screening to predict responder patients depend on EGFR status
Presenter: Yejin Kim
Session: Poster Display session 3
Resources:
Abstract
3349 - Interplay between miR-17-5p and MALAT-1 Shapes The Cytokine Storm in Triple Negative Breast Cancer (TNBC) Tumor Microenvironment
Presenter: Raghda Soliman
Session: Poster Display session 3
Resources:
Abstract
4014 - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer
Presenter: Wataru Goto
Session: Poster Display session 3
Resources:
Abstract
4158 - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer
Presenter: Yunjie He
Session: Poster Display session 3
Resources:
Abstract
5392 - Activated effector T cells co-expressing multiple inhibitory receptors (IRs) are enriched in the tumor immune microenvironment in high grade serous ovarian cancer (HGSOC)
Presenter: Alice Bergamini
Session: Poster Display session 3
Resources:
Abstract
2617 - Oncolytic reovirus as a new anti-tumor strategy in castration resistant prostate cancer
Presenter: Yunlim Kim
Session: Poster Display session 3
Resources:
Abstract
2995 - Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21
Presenter: Ali Memarian
Session: Poster Display session 3
Resources:
Abstract
3597 - Myeloid derived suppressor cells but not regulatory T cells are associated with adaptive immunity and clinical outcomes in anal squamous cell carcinoma
Presenter: Christophe Borg
Session: Poster Display session 3
Resources:
Abstract
3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy
Presenter: Juan Marín Jiménez
Session: Poster Display session 3
Resources:
Abstract
1995 - ¬¬Advanced melanoma patients with high CD16+ macrophages have better response and survival to anti-PD-1 based immunotherapy
Presenter: Hansol Lee
Session: Poster Display session 3
Resources:
Abstract