41P - Contrasting drivers of response to immunotherapy across solid tumour types: results from analysis of >2500 cases

Background

Multiple genomic and transcriptomic biomarkers have been associated with response to immune checkpoint inhibitor (CPI) therapy. Our previously published meta-analysis of biomarkers included over 1000 patients across multiple cancer types, which demonstrated clonal TMB and CXCL9 expression as the strongest pan-cancer biomarkers of CPI response. However, over half of the variance in response to CPI treatment remains unexplained, for example 52% of patients who respond to CPI treatment were low-TMB and showed no evidence of an oncogenic viral infection.

Methods

To address the missing understanding in CPI response mechanisms, we have recently extended our dataset to 16 immunotherapy treated cohorts, across 10 solid tumour types, encompassing >2500 treated patients. Matched tumour/normal whole exome sequencing (WES) data and tumour transcriptomic data (RNAseq) was available. All data was accessed in raw sequencing read format and reprocessed through a standardized bioinformatics pipeline. Using pubmed key word search we completed a systematic literature review of ∼1,000 papers, which identified >200 unique biomarkers that could be quantified in exome or RNA-seq data. Data will be presented on these biomarkers to understand the full landscape of biomarkers responses to CPI therapy.

Results

Biomarkers with strongest effect size pan-cancer, and per cancer type will be presented, highlighting divergent mechanisms of CPI response across histology types. We will present data on emerging checkpoint targets in late-stage trials (e.g. LAG3, TIGIT, VISTA) across cancer types, to assess the potential of these new candidates to overcome resistance to current anti-PD-1 or anti-CTLA-4 treatment. We will additionally assess expression of tumor-associated antigen targets in solid tumour CAR T cell and vaccine trials (e.g. MAGE, NY-ESO-1, MUC1), to understand their role in CPI response. Lastly, we will discuss how these biomarkers can be combined into a multimodal test to accurately predict CPI response.

Conclusions

Results from this work have strongly highlighted the varying determinants of immunotherapy response across solid tumour types, offering unique insight into both tumour intrinsic and extrinsic drivers of immunogenicity.

Legal entity responsible for the study

The authors.

Funding

The Medical Research Council.

Disclosure

C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1 and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Kynos Therapeutics, Monopteros Therapeutics, Tempus; Financial Interests, Personal, Invited Speaker, Invited speaker: Ellipses Pharma; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: BMS. All other authors have declared no conflicts of interest.