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

In the DONIMI trial, a baseline IFN-gamma 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-gamma (IFN-gamma) 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-gamma response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-gamma high and low cohorts, we developed a baseline IFN-gamma signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-gamma scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-gamma 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-gamma score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.