14P - Integrated genomic analysis of whole genomes to derive a biomarker of durable response to immunotherapy in melanoma

Background

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of metastatic melanoma. However, about half of patients do not derive long term clinical benefit and biomarkers to predict initial and durable responses are lacking. Efforts are hampered by the availability of treatment-naïve samples and whole genome sequencing (WGS) data with adequate resolution of genomic events.

Methods

We analysed two cohorts of advanced melanoma treated with first-line ICI with available treatment-naïve samples: a cohort of 97 patients with WGS data in Genomics England (GEL) 100,000 genomes project and 105 patients with matched WGS and RNA from the Hartwig Medical foundation (HMF). We evaluated the association of initial and durable responses with genomic features, including TMB, neoantigen burden, copy number events, and immune infiltration.

Results

High neoantigen burden, T cell infiltration and the absence of homozygous deletion of the MTAP/CDKN2A locus most strongly associated with response in both cohorts. Combination of these features into model to predict response yielded an AUC of 0.81 in GEL and 0.7 in HMF, outperforming TMB (AUCs of 0.62 and 0.56, respectively). Patients were further classified as durable responders (DR) if there was no disease progression during the follow-up period (and >6 months of follow-up were available) or as having acquired resistance (AR) if they progressed after an initial response. Features associated with an initial response were poor predictors of DR. The best differentiator of DR and AR was the burden of nonsense-mediated decay escaping indels (AUC of 0.67 in GEL and 0.62 in HMF, vs 0.56 and 0.54 for TMB). Additional genomic features under investigation will be presented at the meeting. While initial responders had higher immune infiltrate, AR and DR tumours had comparable TME compositions. By deconvolving cell type contributions to gene expression, we found that bulk IFNg pathway expression was driven by tumour cells and was lower in DR while T cell IFNg was higher in DR patients.

Conclusions

Distinct genomic and phenotypic features predict initial and durable responses to first line ICI in melanoma, suggesting separate biomarkers might be needed to accurately stratify groups.

Legal entity responsible for the study

The authors.

Funding

Francris Crick Institute, The Royal Marsden Cancer Charity, Genomics England.

Disclosure

L.M. Pickering: Financial Interests, Personal, Invited Speaker, Recorded teaching April 2023: BMS; Financial Interests, Personal, Advisory Board, Virtual, Oct 2020: BMS; Financial Interests, Personal, Invited Speaker, In person speaker, June 2023: Eisai; Financial Interests, Personal, Invited Speaker, In person meeting, December 2022: Pfizer; Financial Interests, Personal, Invited Speaker, Virtual, Aug 20: Pfizer; Financial Interests, Personal, Invited Speaker, Group Teaching, London, Pct 2022: MSD; Financial Interests, Personal, Invited Speaker, Speaker Panel, July 2022: Ipsen; Financial Interests, Personal, Invited Speaker, Teacher / speaker March 2023: Ipsen; Financial Interests, Institutional, Funding, Uncommon theme pump priming funds: NIHR; Financial Interests, Institutional, Funding, Tracking renal cancer evolution in blood: Rosetrees Trust; Other, Personal, Other, Charitable funding to support research students and internal departmental clinical research: Kidney and melanoma cancer fund of RMH charity. S. Danson: Financial Interests, Institutional, Full or part-time Employment, National Specialty Lead for Early Phase Cancer: NIHR; Financial Interests, Institutional, Speaker, Consultant, Advisor: Oxcia, Orion; Financial Interests, Institutional, Coordinating PI, Dante lead: NIHR; Financial Interests, Institutional, Coordinating PI, Fortitude pi: Amgen; Financial Interests, Institutional, Research Grant, Ecmc lead: Cancer research UK; Non-Financial Interests, Institutional, Leadership Role, Lion steering group chair: NIHR; Non-Financial Interests, Institutional, Leadership Role, Concorde steering group member: Cancer research UK. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics, Ellipses Pharma; Financial Interests, Personal, Speaker, Consultant, Advisor: Kynos Therapeutics, Monopteros Therapeutics, Tempus; Financial Interests, Institutional, Research Grant: Ono/LifeArc, Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: BMS. J. Larkin: Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Roche, Pierre Fabre, AstraZeneca, Novartis, EUSA Pharma, MSD, Merck, GSK, Ipsen, Aptitude, Eisai, Calithera, Ultimovacs, Seagen, Goldman Sachs, Inselgruppe, Agence Unik; Financial Interests, Personal, Other, Consultancy: Incyte, iOnctura, Apple Tree, Merck, BMS, Eisai, Debiopharm; Financial Interests, Personal, Other, Honorarium: touchIME, touchEXPERTS, VJOncology, Cambridge Healthcare Research, Royal College of Physicians; Financial Interests, Institutional, Funding: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. P. Lorigan: Financial Interests, Personal, Advisory Board, ASCO/ESMO participation, travel support: MSD; Financial Interests, Personal, Invited Speaker: BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: Ultimovacs, MLA Dx; Financial Interests, Institutional, Research Grant: BMS, Pierre Fabre; Non-Financial Interests, Personal, Other, Invited Speaker: Melanoma Focus charity; Non-Financial Interests, Personal, Other, invited session chair: SMR Edinburgh 2022; Non-Financial Interests, Personal, Leadership Role, current 2023 Chairman of group: EORTC Melanoma Group; Non-Financial Interests, Personal, Other, clinical research committee: CRUK. S. Turajlic: Financial Interests, Personal, Invited Speaker: IDEA Pharma, Roche, Ventana, MSD, Merck; Financial Interests, Institutional, Funding, Uncommon theme pump priming funds: NIHR; Financial Interests, Institutional, Funding, Digital theme funding: RMH/ICR/BRC/Imperial AHSC/Faculty of Medicine; Financial Interests, Institutional, Funding, Tracking renal cancer evolution in blood: Rosetrees Trust; Financial Interests, Institutional, Funding, Clinical PhD Fellowship over 3 years: CRUK Welcome Trust; Financial Interests, Institutional, Funding, Investigating the relationship between primary melanomas and their metastases: The Robert McAlpine Foundation; Financial Interests, Institutional, Funding, Innovation Grant Award for biomarker development: The Francis Crick Institute; Financial Interests, Institutional, Funding, Developing a novel method of representative tumour in sampling in clinical setting: Ventana; Financial Interests, Institutional, Funding, Mapping clonal evolution in renal cell carcinoma: CRUK training and career development board - clinician scientist fellowship; Financial Interests, Institutional, Funding: Harry J Lloyd Charitable Trust Career Development Award; Financial Interests, Institutional, Funding, Clinical Research Fellowship in melanoma: Andy Quick Charitable fund; Financial Interests, Institutional, Funding, Mechanisms of BRAF resistance: Complete Genomics; Financial Interests, Institutional, Funding, Molecular profiling of non-cutaneous melanoma: CRUK; Financial Interests, Institutional, Funding, Target discovery in acral melanoma: Rosetrees Trust. All other authors have declared no conflicts of interest.