: 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.

Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial / Noviello, Teresa Maria Rosaria; Di Giacomo, Anna Maria; Caruso, Francesca Pia; Covre, Alessia; Mortarini, Roberta; Scala, Giovanni; Costa, Maria Claudia; Coral, Sandra; Fridman, Wolf H; Sautès-Fridman, Catherine; Brich, Silvia; Pruneri, Giancarlo; Simonetti, Elena; Lofiego, Maria Fortunata; Tufano, Rossella; Bedognetti, Davide; Anichini, Andrea; Maio, Michele; Ceccarelli, Michele. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), p. 5914. [10.1038/s41467-023-40994-4]

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

Noviello, Teresa Maria Rosaria;Caruso, Francesca Pia;Scala, Giovanni;Costa, Maria Claudia;Tufano, Rossella;Ceccarelli, Michele
2023

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.
2023
Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial / Noviello, Teresa Maria Rosaria; Di Giacomo, Anna Maria; Caruso, Francesca Pia; Covre, Alessia; Mortarini, Roberta; Scala, Giovanni; Costa, Maria Claudia; Coral, Sandra; Fridman, Wolf H; Sautès-Fridman, Catherine; Brich, Silvia; Pruneri, Giancarlo; Simonetti, Elena; Lofiego, Maria Fortunata; Tufano, Rossella; Bedognetti, Davide; Anichini, Andrea; Maio, Michele; Ceccarelli, Michele. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), p. 5914. [10.1038/s41467-023-40994-4]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/946091
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