Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and correlation with integrated, multiomic analysis in the NIBIT-M4 trial
Noviello, T.; Di Giacomo, A. M.; Caruso, F. P.; Covre, A.; Scala, G.; Costa, M. C.; Coral, S.; Fridman, W. H.; Sautes-Fridman, C.; Mortarini, R.; Brich, S.; Pruneri, G.; Simonetti, E.; Logiego, M. F.; Bedognetti, D.; Anichini, A.; Maio, M.; Ceccarelli, M.; EPigenetic Immune-oncology Consortium AIRC (EPICA) investigators,
Show abstract
Association of DNA hypomethylating agents (DHA) with immune-checkpoint inhibitors (ICI) is a promising strategy to improve efficacy of ICI-based therapy. Here we report the five-year clinical outcome and an integrated multi-omics analysis of pre- and on-treatment lesions from advanced melanoma patients enrolled in the phase Ib NIBIT-M4 study, a dose-escalation trial of the DHA agent guadecitabine combined with ipilimumab. With a minimum follow-up of 45 months the median OS was 25.6 months; the 5-year OS rate was 28.9% and the median DoR was 20.6 months. Specific genomic features and extent of T and B cellmediated immunity discriminated lesions of responding compared to non-responding patients. Enrichment for proliferation and EMT-related gene programs, and immune escape mechanisms characterized lesions from non-responding patients. Integration of a genetic immunoediting index (GIE) with an adaptive immunity signature (ICR) stratified patients/lesions into four distinct subsets and discriminated 5-year OS and PFS. These results suggest that coupling of immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.
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