ASCO 2025 | NIBIT-ML1: ASTX727, ipilimumab and nivolumab in metastatic melanoma

The NIBIT-ML1 trial is a phase 2 randomized non-comparative trial designed to assess the efficacy of the combination of ipilimumab and nivolumab, so an anti-PD-1 and anti-CTLA-4, combined with a hypomethylating agent ASTX727or immunotherapy, so the double combination of PD-1 nivolumab alone in patients resistant to anti-PD-1 with metastatic melanoma. In the study, we have treated 42 patients. The first six patients in a running safety phase that clearly demonstrated the safety and feasibility of this treatment. And in the randomized phase, we have enrolled 36 patients. The primary endpoint of the study was the objective response rate. and the study met its primary endpoint with 33% of objective responses, so six objective responses in the triple combination arm as compared with the double combination in which we observed 17%, so three objective responses. Moreover, also the duration of response and the PFS as a secondary endpoint are very interesting because in the triple combination, the duration of response is more than seven months as compared with 3.5 months in the double combination. The PFS rate at one year demonstrated that 43% of patients in the triple combination arm were alive without progression as compared with 11% in the double combination arm. And so this clearly supports the, from a clinical viewpoint, the evidence that this triple combination could be more effective in overcoming resistance to anti-PD1. In addition, this year we also presented the initial results from the translational endpoint. First of all, we have demonstrated that the tumor demethylation based on the action of the hypomethylating agent is higher in the patients, of course, treated with a triple combination and correlated with the clinical responses. In addition, we have also performed integrative methylation and expression analysis that clearly demonstrated that in patients treated with a triple combination, we are able to induce a higher expression of immune-related genes, so to modulate the immune system. And of course, also this integrative analysis, so the methylation and the expression of these immune genes was higher and reached in patients who received the triple combination as compared with patients who received immunotherapy alone. So also the omic results support the triple combination to be more effective in overcoming resistance of a PD-1 and melanoma patients.

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