IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

Reijers ILM, Rao D, Versluis JM, Menzies AM, Dimitriadis P, Wouters MW, Spillane AJ, Klop WMC, Broeks A, Bosch LJW, Lopez-Yurda M, van Houdt WJ, Rawson RV, Grijpink-Ongering LG, Gonzalez M, Cornelissen S, Bouwman J, Sanders J, Plasmeijer E, Elshot YS, Scolyer RA, van de Wiel BA, Peeper DS, van Akkooi ACJ, Long GV, Blank CU. J Exp Med. 2023 May 1;220(5):e20221952. doi: 10.1084/jem.20221952. Epub 2023 Mar 15. PMID: 36920329; PMCID: PMC10037109.


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.