Abstract 797P
Background
In stage III melanoma, neoadjuvant (neoadj) IPI + NIVO induces high pathologic response rates (pRR 72-78%), which is associated with long-term RFS. Pts with a low baseline IFN-γ sign are less likely to respond (pRR 55%). Domatinostat (DOM), a class I histone deacetylase inhibitor, increased intratumoral T cell infiltration and the IFN-γ sign expression in melanoma. DONIMI tests neoadj combinations of NIVO ± IPI with DOM stratified according to the IFN-γ sign of baseline biopsies in stage IIIB-D nodal melanoma.
Methods
DONIMI randomized IFN-γ sign high pts to arm A (2 cycles NIVO) or arm B (2 cycles NIVO + DOM twice daily), and IFN-γ sign low pts to arm C (same regimen as arm B) or arm D (2 cycles NIVO + IPI + DOM once daily). Arm D expansion (D-exp) treated IFN-γ sign low pts with 2 cycles NIVO + IPI + DOM twice daily. Surgery was planned after 6 weeks. Adjuvant NIVO or dabrafenib + trametinib started at week 12 for 52 weeks. Safety/feasibility was the primary endpoint, pRR and RFS were secondary endpoints. RFS rates were calculated using a Kaplan-Meier based method. Baseline and week 3 gene expression signatures (GES) were examined using Nanostring nCounter Technologies.
Results
Between Jan 2020 - Oct 2021, 44 pts were enrolled. At data cutoff (Mar 18, 2022), median follow-up was 14.6 months. Clinical data are shown in the table. Table: 797P
| Arm A (n=10) | Arm B (n=10) | Arm C (n=10) | Arm D (n=10) | Arm D-exp (n=4) | |
| Gr 3-4 trAEs within first 12 weeks | 0 (0%) | 2 (20%)* | 4 (40%)* | 2 (20%) | 4 (100%)* |
| Surgery performed on time (week 6 ± 1 week) | 10 (100%) | 10 (100%) | 10 (100%) | 10 (100%) | 4 (100%) |
| pRR (≤50% viable tumor) | 9 (90%) | 8 (80%) | 3 (30%) | 4 (40%) | 2 (50%) |
| 12-month RFS | 100% | 100% | 90% | 63% | NA |
* These gr 3-4 teatment-related adverse events were DOM-related rash, necessitating premature stop of DOM. All IFN-γ sign low pts (Arm C + D), with persistent low IFN-γ sign at week 3 were non-responders.
Conclusions
The IFN-γ sign adequately identified pts who are likely to benefit from NIVO ± DOM alone (IFN-γ high pts) vs pts who may need an alternative scheme (IFN-γ low pts). Treatment regimen of arm D-exp was not feasible; DOM was stopped early in all arm D-exp pts. Addition of DOM did not increase the pRR in IFN-γ low pts.
Clinical trial identification
NCT04133948.
Editorial acknowledgement
None
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
4SC.
Disclosure
A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. M. Wouters: Financial Interests, Institutional, Advisory Board: Novartis. R.P.M. Saw: Financial Interests, Institutional, Advisory Board: MSD, Novartis, QBiotics; Financial Interests, Institutional, Invited Speaker: BMS, Novartis. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen, BMS; Financial Interests, Institutional, Advisory Board: Belpharma; Financial Interests, Institutional, Expert Testimony: Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis. R.A. Scolyer: Financial Interests, Institutional, Advisory Board: F. Hoffmann-La Roche , Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen, BMS, Myriad Genetics, GlaxoSmithKline. B. van de Wiel: Financial Interests, Institutional, Advisory Board: BMS. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers-Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Uniti Cars, co-founder Immagene BV; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC. All other authors have declared no conflicts of interest.