DNA hypomethylating agents (DHA) combined with immune checkpoint inhibitors (ICI) are a promising strategy to improve the immunomodulatory and antitumor activity of ICI-based treatment. Providing initial support to this notion, guadecitabine plus ipilimumab in the phase Ib NIBIT-M4 trial, proved to be feasible, safe, and tolerable, with clinical and biological activity in metastatic melanoma patients (pts) (Di Giacomo AM, CCR 2019).
Pts enrolled in the NIBIT-M4 trial were assessed for long-term clinical outcomes. Molecular profiles of serial tumor biopsies performed at week 0, 4, and 12, including RNA, Whole Exome and Genome-wide methylation sequencing, were analyzed in an integrative manner and correlated with clinical data; pts were classified as Responder (R) or Non-responder (NR) based on disease control.
Among the 19 pts enrolled (minimum follow-up 45 months), the 5-y OS rate was 29%; median duration of response was 20.6 months (95% CI,12.4-28.8). Analysis of longitudinal biopsies from 14 pts showed that primary/acquired resistance is underpinned by multi-level molecular mechanisms. Indeed, NR pts had higher mutation frequency in NRAS and harbored somatic alterations in genes involved in the Epithelial to Mesenchymal Transition (EMT) and chromatin organization pathways compared to R pts. Moreover, NR pts had a heterogeneous expression phenotype, characterized by activated patterns of proliferation/differentiation/EMT and by deactivation of INF-ɣ/HLA-II/immune-related genes. Conversely, R pts displayed dynamic patterns of activated immune signatures and favorable tumor-infiltrating microenvironment with T/NK cell clonal activation progressively increasing with therapy. We also developed a DNA-RNA immune stratification, simultaneously taking into account both the composition of the tumor microenvironment and the presence of reactive T-cells measured as the ratio between observed and predicted tumor neoantigens.
Our comprehensive longitudinal multi-omics analyses of tumors from the NIBIT-M4 study identify a landscape of biomarkers predictive of response that may guide patient stratification and selection in ICI plus DHA therapies.
EudraCT 2015-001329-17, NCT02608437.
NIBIT Foundation Onlus.
Fondazione AIRC under 5 per Mille 2018 – ID 21073 program (principal investigator M. Maio).
A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi. M. Maio: Financial Interests, Personal, Advisory Board: MSD, BMS, AstraZeneca, Incyte, Amgen, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Roche, Eli Lilly; Financial Interests, Personal, Ownership Interest: Epigen Therapeutics, Theravance. All other authors have declared no conflicts of interest.