2236P - MHC-II neoantigens and copy number alterations (CNA) drive immune checkpoint inhibitor (ICI) response in metastatic melanoma (MM)

Background

ICIs have transformed the prognosis of MM, but our understanding of mechanisms of response and resistance remains incomplete. The 100,000 Genomes Project presents a melanoma cohort with whole genome sequencing (WGS) and detailed clinical annotation.

Methods

97 patients received ICIs in the 1L metastatic disease setting; ipilimumab-nivolumab (60%), anti-PD-1 monotherapy (32%), and ipilimumab (8%). Response rate was 45%. Median follow-up was 30.6 months, median time to treatment failure (TTF) 9.6 months and median overall survival (OS) not reached. From WGS, neoantigen calling, CNA and tumour purity analyses were performed, predictive variables were included in logistic regression.

Results

Incorporating MHC-II neoantigen load, CNAs and tumour purity, our multivariate model predicted response with AUC 0.86 Responders were associated with a higher number of predicted clonal neoantigens (p=0.0029), driven by MHC-II neoantigens (p=2e-04), and were more statistically significant biomarkers than TMB (p=0.016). A higher total neoantigen burden (p=0.02) and MHC-II neoantigen burden (p=0.06), but not higher TMB, were associated with superior OS. Independently, low tumour purity was associated with response (p=0.005) and superior OS (p=0.04) Non-responders harboured CNAs in key melanoma driver genes, including CDKN2A loss of function (p=0.04), and TERT gain (p=0.03) which was associated with inferior TTF (p=0.02) Genomic imprinting has established links to cancer pathogenesis, most notably at 11p15.5. In our cohort, loss of heterozygosity (LOH) at 11p.15.5 was associated with response (p=0.007), superior TTF (p=0.05), and higher MHC-II neoantigen load (p=0.04), while non-LOH loss at the same loci was associated with non-response (p=0.003), inferior TTF (p=0.007) and OS (p=0.02), highlighting that different classes of loss can lead to opposing biological sequelae. LOH with loss of the active allele and persistence of the imprinted allele will lead to non-expression of the oncogene. External validation with matched WGS and RNA will be presented at the conference.

Conclusions

In our cohort, 1L ICI response in melanoma was driven by MHC-II neoantigens, CNAs and tumour purity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The Royal Marsden Charity.

Disclosure

R. Marais: Financial Interests, Institutional, Other, Expert witness: Pfizer; Other, As a former employee, I may benefit financially from commercialised programmes: Institute of Cancer Research, London. L.M. Pickering: Financial Interests, Personal, Invited Speaker, Recorded teaching July 2020: BMS; Financial Interests, Personal, Invited Speaker, Group teaching, London, Dec 2019 : BMS; Financial Interests, Personal, Advisory Board, Virtual, Oct 2020 : BMS; Financial Interests, Personal, Invited Speaker, Virtual teaching to Eisai internal team, July 20: Eisai; Financial Interests, Personal, Advisory Board, Regional advisory board, Vienna, Nov 19: MSD; Financial Interests, Personal, Advisory Board, Regional Advisory Board, Munich, Apr 19: MSD; Financial Interests, Personal, Advisory Board, March 2019 , London: Novartis; Financial Interests, Personal, Advisory Board, Virtual, Oct 20: Pfizer; Financial Interests, Personal, Invited Speaker, Virtual, Aug 20: Pfizer; Financial Interests, Personal, Invited Speaker, Budapest, Nov 19: Pfizer; Financial Interests, Personal, Advisory Board, London, Oct 19: Pfizer; Financial Interests, Personal, Invited Speaker, Group Teaching, London, Pct 2022 : MSD; Financial Interests, Personal, Invited Speaker, Speaker Panel, July 2022 : Ipsen; Financial Interests, Institutional, Funding, Uncommon theme pump priming funds: NIHR; Financial Interests, Institutional, Funding, Tracking renal cancer evolution in blood: Rosetrees Trust; 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, Other, Consultancy: 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, Leadership Role, Lion steering group chair: NIHR; Non-Financial Interests, Leadership Role, Concorde steering group member: Cancer research UK. 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, eCancer, Inselgruppe, Agence Unik; Financial Interests, Personal, Other, Consultancy: Incyte, iOnctura, Apple Tree, Merck, BMS, Eisai, Debiopharm; Financial Interests, Personal, Other, Honorarium: touchIME, touchEXPERTS, VJOncology, RGCP, Cambridge Healthcare Research, Royal College of Physicians; Financial Interests, Institutional, Funding: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. 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. 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.