Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial

Teresa Maria Rosaria Noviello, Anna Maria Giacomo, Francesca Pia Caruso, Alessia Covre, Roberta Mortarini, Giovanni Scala, Maria Claudia Costa, Sandra Coral, Wolf H. Fridman, Catherine Sautès-Fridman, Silvia Brich, Giancarlo Pruneri, Elena Simonetti, Maria Fortunata Lofiego, Rossella Tufano, Davide Bedognetti, Andrea Anichini, Michele Maio () and Michele Ceccarelli
Additional contact information
Teresa Maria Rosaria Noviello: University of Miami
Anna Maria Giacomo: University of Siena
Francesca Pia Caruso: BIOGEM Institute of Molecular Biology and Genetics
Alessia Covre: University of Siena
Roberta Mortarini: Fondazione IRCCS Istituto Nazionale dei Tumori
Giovanni Scala: University of Naples “Federico II”
Maria Claudia Costa: BIOGEM Institute of Molecular Biology and Genetics
Sandra Coral: University of Siena
Wolf H. Fridman: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape
Catherine Sautès-Fridman: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape
Silvia Brich: Fondazione IRCCS Istituto Nazionale dei Tumori
Giancarlo Pruneri: Fondazione IRCCS Istituto Nazionale dei Tumori
Elena Simonetti: University Hospital of Siena
Maria Fortunata Lofiego: University of Siena
Rossella Tufano: BIOGEM Institute of Molecular Biology and Genetics
Davide Bedognetti: Research Branch, Sidra Medicine
Andrea Anichini: Fondazione IRCCS Istituto Nazionale dei Tumori
Michele Maio: University of Siena
Michele Ceccarelli: University of Miami

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

Date: 2023
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DOI: 10.1038/s41467-023-40994-4

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