The phase II NIBIT-ML1 study of nivolumab plus ipilimumab and ASTX727 or nivolumab plus ipilimumab in PD-1 resistant metastatic melanoma: Tumor methylation landscape and correlation with clinical outcomes.

Abstract

LBA2512 Background: In the NIBIT Foundation-sponsored phase Ib NIBIT-M4 study, we firstly showed that the hypomethylating agent (HMA) guadecitabine (guade), a prodrug of decitabine (D), followed by ipilimumab (I) was safe with promising clinical and immunologic activity in cutaneous metastatic melanoma (MM) patients (pts) (Di Giacomo, Clin Cancer Res 2019; Noviello, Nat Commun 2023 ). Thus, we further explored the activity of HMA combined with checkpoint inhibitors in the NIBIT-ML1 trial in which we investigated the efficacy of guade plus I+nivolumab (I+N) in PD-1/PDL-1-resistant MM and NSCLC pts. The primary analysis and the correlation between tumor methylome and immune contextures with the MM Cohort clinical outcome will be presented. Methods: The NIBIT Foundation NIBIT-ML1 is a multicenter, run-in, phase II randomized, non-comparative study (Simon two stages optimal design), in unresectable Stage III/IV MM (Cohort A) and NSCLC (Cohort B) pts progressing to PD-1/PDL-1 as last treatment. A Monitoring Committee reviewed safety data throughout the study. A trial amendment replaced guade with ASTX727, an oral fixed-dose combination of D with cedazuridine. Following a safety run-in of 6 pts, 36 eligible MM pts were randomized (1:1) to ASTX727 plus I+N or to I+N. Primary objective was immune(i)-ORR, according to a centralized radiologic assessment, defined as the proportion of pts with an iBOR of confirmed iCR/iPR. Secondary were: safety, DCR and PFS. Tumor methylation and immune contextures of serial tumor biopsies at baseline (W0) and on-treatment (W12 and/or W19) were investigated by EPIC Array and RNAseq. Results: Run-in phase: 6 Stage IV MM pts received guade (2 pts) or ASTX727 (4 pts) plus I+N. No DLT occurred. Three PR, 2 SD, and 1 PD were observed. Stage I: 36 Stage III (3)/IV (33) MM pts, received ASTX727 plus I+N (ARM A) or I+N (ARM B). ORR was 33% (2 CR, 4 PR) and 17% (3 PR) in ARM A and B; DCR was 56% in ARM A and 39% in ARM B. Both ARMs met the Stage I Simon design. The 1-year PFS rate was 43% and 11% for ARM A and B. With no overlapping toxicities, 1 DLT (G5 macrophage activation syndrome) was reported in ARM A. G3/4 TRAEs were 72% and 50% in ARM A and B, respectively, and G3/4 irAEs were 39% in ARM A and 44% in ARM B. A time-dependent reduction in tumor methylation levels in run-in and ARM A pts was observed, with more hypomethylated probes in on-treatment vs baseline tumors. Integrative methylation and transcriptomic analyses showed a promotion of immune regulatory genes, T and B cell activation in on-treatment tumors of ARM A pts. Enrichment of immune pathways was found in the Run-in and in ARM A responder pts. Conclusions: Treatment with ASTX727 plus I+N is feasible and has meaningful clinical and immunologic activity in PD-1 refractory MM pts. Clinical trial information: NCT04250246 .