TY - JOUR
T1 - IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma
AU - Reijers, Irene L. M.
AU - Rao, Disha
AU - Versluis, Judith M.
AU - Menzies, Alexander M.
AU - Dimitriadis, Petros
AU - Wouters, Michel W.
AU - Spillane, Andrew J.
AU - Klop, Willem M. C.
AU - Broeks, Annegien
AU - Bosch, Linda J. W.
AU - Lopez-Yurda, Marta
AU - van Houdt, Winan J.
AU - Rawson, Robert V.
AU - Grijpink-Ongering, Lindsay G.
AU - Gonzalez, Maria
AU - Cornelissen, Sten
AU - Bouwman, Jasper
AU - Sanders, Joyce
AU - Plasmeijer, Elsemieke
AU - Elshot, Yannick S.
AU - Scolyer, Richard A.
AU - van de Wiel, Bart A.
AU - Peeper, Daniel S.
AU - van Akkooi, Alexander C. J.
AU - Long, Georgina V.
AU - Blank, Christian U.
N1 - Funding Information: Financial support for the trial was provided by 4SC AG, Planegg-Martinsried, Germany. G.V. Long, R.A. Scolyer, and A.M. Menzies are supported by National Health and Medical Research Council (NHMRC) investigator grants. G.V. Long is supported by an NHMRC investigator grant (2021/GNT2007839). G.V. Long is also supported by the University of Sydney Medical Foundation. R.A. Scolyer is supported by an NHMRC Practitioner Fellowship (APP1141295). Open Access funding provided by the Netherlands Cancer Institute. Publisher Copyright: © 2023 Reijers et al.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85150396636&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85150396636&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36920329
U2 - https://doi.org/10.1084/jem.20221952
DO - https://doi.org/10.1084/jem.20221952
M3 - Article
C2 - 36920329
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
M1 - e20221952
ER -