Graphical Abstract
melanoma, P., Johnson & Johnson outside the submitted work.
MELANOMA, ONCOLOGY, TUMOR GROWTH, SKIN TOXICITY, STAGE III MELANOMA
I.L.M. Reijers and D. Rao authors contributed equally to this paper.Disclosures: I.L.M. Reijers reported financial interest in Signature Oncology, and will receive some possible revenues if the IFN-γ signature is being developed as clinical companion diagnostic. A.M. Menzies reported personal fees from BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics outside the submitted work. P. Dimitriadis reported financial interest in Signature Oncology, and will receive some possible revenues if the IFN-γ signature is being developed as clinical companion diagnostic. W.J. van Houdt reported personal fees from Amgen, Sanofi, Belpharma, MSD, and Novartis outside the submitted work. Y.S. Elshot reported personal fees from Bristol-Meyers Squibb, AbbVie, MSD, and Johnson & Johnson outside the submitted work. R.A. Scolyer reported grants from National Health and Medical Research Council of Australia during the conduct of the study; personal fees from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline outside the submitted work. A.C.J. van Akkooi reported grants from Amgen and Merck-Pfizer, and personal fees from Bristol-Myers Squibb, Novartis, MSD-Merck, Pierre Fabre, Sanofi, Provectus, 4SC, and Sirius Medical outside the submitted work. G.V. Long reported personal fees from Agenus Inc, Amgen Inc, Novartis, OncoSec, PHMR, Pierre Fabre, Provectus, Qbiotics, Regeneron Pharma, Boehringher Ingelheim, BMS, Evaxion, Hexal AG, Highlight, Innovent Biologics, and MSD outside the submitted work. C.U. Blank reported grants from BMS, Novartis, NanoString, and 4SC; personal fees from BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; and is a co-founder of and has stock ownership in Immagene BV and Signature Oncology outside the submitted work; in addition, C.U. Blank had patents (incl. submitted): WO 2021/177822 A1, N2027907, P091040NL2 pending. No other disclosures were reported.In the DONIMI trial, a baseline IFN-γ signature enables prospective selection of patients who can benefit from anti-PD-1 monotherapy. In contrast to results of our murine melanoma model, domatinostat (a class I HDAC inhibitor) does not add benefit to neoadjuvant anti-PD-1 ± anti-CTLA-4 in patients.Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.
