LBA47 - Nivolumab plus ipilimumab and ASTX727 or nivolumab plus ipilimumab in PD-1 resistant metastatic melanoma: Primary analysis of the randomized phase II NIBIT-ML1 study

Background

We had shown that the hypomethylating agent (HMA) guadecitabine (guad), a prodrug of decitabine (D), followed by ipilimumab (I) is safe, with promising clinical and immune-modulating activity in metastatic melanoma (MM) patients (pts) (Di Giacomo, CCR 2019; Noviello, Nature Comm 2023). To further explore the activity of HMA combined with ICI, the NIBIT-ML1 trial investigated the efficacy of guad plus I+nivolumab (I+N) in PD-1/PDL-1 resistant MM or NSCLC pts. We report results from the Run-in and Stage I phase of the MM Cohort.

Methods

The NIBIT-ML1, a randomized, non-comparative, multicenter, phase II study (Simon two stage optimal design), in unresectable Stage III/IV MM (Cohort A) or NSCLC (Cohort B) pts with confirmed progression to anti-PD-1/PDL-1, was conceived and led by the NIBIT Foundation; a SDMC reviewed safety data. An amendment replaced guad with ASTX727, an oral fixed-dose combination of D (20mg) with cedazuridine (10mg). After a safety Run-in and PK study (6 pts), pts were randomized (1:1) to ASTX727 plus I+N or to I+N. With 1 or 2 OR in the Stage I, study would be dropped for futility. Primary objective is immune(i)-ORR; secondary are safety, and DCR.

Results

Run-in: 6 Stage IV MM pts [4 male; median age 71y, 5/1 ECOG 0-1] received guad (2 pts) or ASTX727 (4 pts) plus I+N. No DLT occurred. Any grade (G) treatment-related (TR) AEs occurred in 100% pts, 50% were G3/4. Three PR, 2 SD, 1 PD were observed. D exposures (mean AUC) dosed as 20mg ASTX727 and as 80mg guad (∼45 mg/m2) were similar in PK analyses. Stage I: 36 Stage III (3)/IV (33) MM pts [22 male; median age 62y, 33/3 ECOG 0-1], received ASTX727 plus I+N (ARM A) or I+N (ARM B). ORR was 39% (1 CR, 6 PR) and 17% (3 PR) in ARM A and B, respectively; DCR was 56% in ARM A and 33% in ARM B. Both ARM met the Stage I Simon design. With no overlapping toxicities, 1 DLT occurred in ARM A (G5 macrophage activation syndrome). Any G TRAEs occurred in 94% pts in Arm A, and in 100% pts in ARM B. G3/4 TRAEs were 72% and 50% in ARM A and B, and G3/4 irAEs were 39% in ARM A and 44% in ARM B. Integrated multi-omics analyses are ongoing.

Conclusions

Treatment with ASTX727 plus I+N is feasible, safe, with meaningful clinical activity in PD-1 refractory MM pts.

Clinical trial identification

NCT04250246; EudraCT 2019 - 002986-36.

Editorial acknowledgement

Legal entity responsible for the study

NIBIT Foundation ONLUS.

Funding

Fondazione AIRC under 5 per Mille 2018 - ID 21073 program and unrestricted grant from Bristol Myers Squibb and Astex Pharmaceutical Inc. to the NIBIT Foundation Onlus.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Incyte, Pierre Fabre, GSK, Bristol Myers Squibb, Merck Sharp Dohme, Sun Pharma, Immunocore, Sanofi; Financial Interests, Personal, Training: Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, Sanofi. L. Calabro: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Roche, Merck Sharp Dohme; Financial Interests, Personal, Training: Bristol Myers Squibb, AstraZeneca, Sanofi. R. Depenni: Financial Interests, Personal, Other: Novartis, MSD, BMS, Roche, Pierre Fabre, Merck, Sanofi, Sun Pharma. M. Valente: Financial Interests, Personal, Advisory Role: Novartis. H.N. Keer: Financial Interests, Personal, Member: Astex Pharmaceuticals Inc.. A. Oganesian: Financial Interests, Personal, Member: Astex Pharmaceuticals Inc.. D. Chan: Financial Interests, Personal, Member: Astex Pharmaceuticals Inc.. M. Ceccarelli: Financial Interests, Personal, Speaker, Consultant, Advisor: Moderna Therapeutics; Other, Personal, Stocks/Shares: Immunomica Srl.. A. Covre: Financial Interests, Personal, Ownership Interest: Epigen Therapeutics, Srl. M. Maio: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GSK, Sciclone, Sanofi, Alfasigma, Merck Serono; Financial Interests, Personal, Ownership Interest: Epigen Therapeutics, Srl.. All other authors have declared no conflicts of interest.