High concurrent interferon gamma signature expression in the primary tumor and lymph node metastasis is associated with superior outcome upon neoadjuvant ipilimumab + nivolumab in stage III melanoma

BackgroundThe interferon gamma gene signature (IFNg) has been shown to be predictive and prognostic in patients (pts) with macroscopic stage III or IV melanoma. In macroscopic stage III melanoma, IFNg from lymph node biopsies (LN-IFNg) might be used in the future for neoadjuvant treatment decisions (combination vs monotherapy). To address the question of whether the IFNg can be analyzed using primary tumor material (P-IFNg) instead of LN-IFNg or, in the case of incongruencies, has a higher predictive value when combined with LN-IFNg, we analyzed the IFNg signature in paired samples (P and LN) from stage III melanoma pts.MethodsParaffin primary tumor tissue from pts with stage III melanoma, treated in the OpACIN-neo, PRADO and DONIMI trials (neoadjuvant anti-PD1 +/- anti-CTLA4 +/- domatinostat), was retrospectively analyzed with the nanostring nCounter PanCancer immune profiling panel and compared to fresh frozen LN biopsies. The cut-off was calculated based on event-free survival (EFS) using maximally selected rank statistics.ResultsForty-four pts were included: the majority had a superficial spreading melanoma (68%), with a median Breslow thickness of 1.9mm (IQR: 1.1–2.9), ulceration of 23% and 57% had a BRAF mutation. The median time from primary tumor to trial registration was 21.8 months (IQR: 8.1-48.0). P-IFNg had a low correlation with LN-IFNg (r=0.33, p=0.03). High P-IFNg showed significantly prolonged DMFS and the same trend for EFS, RFS and OS (Table). Pts with concurrent high P- and LN-IFNg had 3 year-EFS of 95% as compared to 88% for pts with LN-IFNg high only, suggesting that addition of P-IFNg could improve selection of pts with better outcomes. Table: 1090P Low P-IFNg (n=14) High P-IFNg (n=28) Log rank p-value Low LN-IFNg (n=15) High LN-IFNg (n=27) Log rank p-value Low LN-IFNg &/or low P-IFNg (n=22) High LN-IFNg & P-IFNg (n=20) Log rank p-value 36 month(m) EFS 48% 79% 0.084 33% 88% <0.0001 45% 95% 0.0052 36m relapse free survival (RFS) 52% 84% 0.056 42% 88% 0.00058 52% 95% 0.0033 36m distant metastasis free survival (DMFS) 53% 88% 0.046 42% 95% <0.0001 54% 100% 0.00089 36m overall survival (OS) 76% 89% 0.3 59% 100% 0.00029 72% 100% 0.011 ConclusionsOur results suggest that pts with concurrently high IFNg-signature expressions (high IFNg in P and LN) have a better outcome than LN-IFNg high pts only. If confirmed, these findings could inform treatment selection and prognosis.Clinical trial identificationNCT02977052; NCT02977052; NCT04133948.Legal entity responsible for the studyNetherlands Cancer Institute.FundingBMS funded the OpACIN-neo and PRADO trials; 4SC AG funded the DONIMI trial.DisclosureP. DIMITRIADIS: Financial Interests, Personal, Royalties: Signature oncology. I. Reijers: Financial Interests, Personal, Royalties: Signature oncology. B. van de Wiel: Non-Financial Interests, Advisory Role, no activities in last two years: BMS. R.A. Scolyer: Financial Interests, Personal, Advisory Board: SkylineDx BV, IO Biotech ApS, MetaOptima Technology Inc, F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc, Bristol Myers Squibb, Myriad Genetics, GSK; Financial Interests, Personal, Full or part-time Employment: Sydney Local Health District; Financial Interests, Personal, Other, Co-Medical Director fee: Melanoma Institute Australia; Financial Interests, Personal, Officer: Bridport Pathology Pty Ltd; Financial Interests, Personal and Institutional, Coordinating PI, Investigator Grant (2022/GNT2018514): National Health and Medical Research Council of Australi. R.P.M. Saw: Financial Interests, Personal, Invited Speaker: Bristol Myers Squib, Novartis; Financial Interests, Personal, Advisory Board: MSD, Novartis, Qbiotics; Financial Interests, Personal, Advisory Board, for MelaSeq-38: Australian Clinical Labs; Financial Interests, Personal, Other, On Faculty, support of University of Sydney salary: Melanoma Institute Australia. A.J. Spillane: Financial Interests, Personal, Invited Speaker, Fee for preparation and delivery of online talk in Oct 2021: Eli Lily Australia. G. Hospers: Financial Interests, Institutional, Advisory Board: BMS, MSD; Financial Interests, Institutional, Research Grant: BMS, Seerave Foundation. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD, Merck, Merck - Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Personal, Advisory Board: Neracare, SkylineDx; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck - Pfizer. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen, Boehringer Ingelheim Ingelheim; Financial Interests, Institutional, Advisory Board: Belpharma, Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis; Financial Interests, Institutional, Local PI: BMS; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Funding: Sirius. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L, IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Advisory Board: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Immagene; Financial Interests, Personal, Stocks/Shares, intention to develop IFN signature algorithm: Signature Oncology; Financial Interests, Institutional, Coordinating PI: NanoString, BMS, Novartis, 4SC; Other, Other, pending patent: WO 2021/177822 A1. All other authors have declared no conflicts of interest.