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Mini oral session: Melanoma and other skin tumours

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

Date

15 Sep 2024

Session

Mini oral session: Melanoma and other skin tumours

Topics

Immunotherapy

Tumour Site

Melanoma

Presenters

Anna Di Giacomo

Citation

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Authors

E. Simonetti1, L. Calabro2, V. Vegni3, F. Santangelo4, R. Depenni5, M. Colucci1, M. Valente4, R. Grifoni6, M.F. Lofiego1, G. Amato4, H.N. Keer7, A. Oganesian7, D. Chan8, D. Giannarelli9, M. Altomonte4, M. Ceccarelli10, A. Anichini11, A. Covre1, M. Maio12, A.M. Di Giacomo12

Author affiliations

  • 1 Medical Oncology, University of Siena, 53100 - Siena/IT
  • 2 Medical Oncology, University of Ferrara, Ferrara/IT
  • 3 Radiology, NIBIT Foundation Onlus, 53100 - Siena/IT
  • 4 Medical Oncology, Center for Immuno-Oncology, University Hospital of Siena, 53100 - Siena/IT
  • 5 Medical Oncology, University of Modena, 41125 - Modena/IT
  • 6 Medical Oncology, Azienda USL Toscana Centro, Firenze/IT
  • 7 Clinical Development, TaihoPharmaceuticals Inc., Pleasanton/US
  • 8 Clinical Development, Taiho Pharmaceuticals Inc., Pleasanton/US
  • 9 Biostatistics, Fondazione Policlinico A. Gemelli, 00168 - Rome/IT
  • 10 Computational Biology, Sylvester Comprehensive Cancer Center, and Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami/US
  • 11 Experimental Oncology, Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 12 Oncology, University of Siena, Center for Immuno-Oncology, University Hospital of Siena, NIBIT Foundation Onlus, 53100 - Siena/IT

Resources

This content is available to ESMO members and event participants.

Abstract LBA47

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.

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