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3236 Molecular Measurable Residual Disease (MRD) Clearance (≤1%) Is Associated with Improved Clinical Outcomes in Patients with Higher-Risk Myelodysplastic Neoplasms (HR-MDS): An Exploratory Analysis of Stimulus-MDS1 in Patients Receiving Sabatolimab or Placebo + Hypomethylating Agent (HMA)

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, AML, MDS, Biological therapies, adult, Translational Research, Clinical Research, Combination therapy, Chronic Myeloid Malignancies, drug development, Diseases, Therapies, Immunotherapy, Myeloid Malignancies, Monoclonal Antibody Therapy, Study Population, Human, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Amer M. Zeidan, MBBS, MHS1, Pierre Fenaux, MD, PhD2, Xia Han, MSc3*, David A. James, MSc3*, Kamel Malek, MD MPH4*, Pedro Marques Ramos, PhD4*, Yasushi Miyazaki, MD PhD5 and Uwe Platzbecker, MD6

1Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT
2Department of Hematology, Université de Paris, Saint-Louis Hospital, Paris, France
3Novartis Pharmaceuticals Corporation, East Hanover, NJ
4Novartis Pharma AG, Basel, Switzerland
5Nagasaki University, Nagasaki, Japan
6Department of Hematology, University Hospital of Leipzig, Leipzig, Germany

Background: Sabatolimab (MBG453) is a novel immunotherapy targeting TIM-3, an immuno-myeloid regulator expressed on both immune and leukemic stem cells. In the randomized, double-blind, placebo-controlled, Phase (Ph) II STIMULUS-MDS1 study (NCT03946670) in patients (pts) with HR-MDS, although improvements in complete remission (CR) and progression-free survival (PFS) were not statistically significant, sabatolimab + HMA was associated with longer duration of response (DoR), and the data suggest a delayed-onset benefit in the sabatolimab arm, as well as a potential treatment effect in pts with lower disease burden (Zeidan AM, et al. ASH 2022). The clinical significance of MRD in HR-MDS is not well established. We report an exploratory analysis of mutational clearance and MRD by next-generation sequencing (NGS) to evaluate the association with clinical outcomes.

Methods: Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. ASH 2022). Peripheral blood (PBMC) and/or BM mononuclear cell (BMMC) samples were collected and NGS performed on genomic DNA extracted from baseline (BL) and on-treatment samples using a 38-gene NGS-error-corrected panel with sensitivity of 2% and 0.2% variant allelic frequency (VAF), respectively. Concordance and correlation between PBMC and BMMC were assessed. The prognostic value of clonal clearance at different VAF cut-offs (0.2%, 0.5% or 1%) was assessed. MRD-x status was defined as any mutation call above VAF cut-off x, excluding mutations in DNMT3A, TET2 and ASXL1 (DTA). Association between MRD status and clinical outcomes was analyzed regardless of treatment to increase sample and used best overall response, 6-month landmark analysis, and a time-dependent Cox model to rule out immortal bias.

Results: NGS was run on 332 BMMC samples from 112 pts and 439 PBMC samples from 123 pts (127 pts randomized). 112 pts had ≥1 qualifying BL mutation (NGS cohort) and 106 pts (sabatolimab + HMA, N=56; placebo + HMA, N=50) had ≥1 at follow-up (MRD cohort). BL characteristics were balanced between NGS/MRD cohorts and between treatments in the MRD cohort.

Overall agreement in mutation calling at variant level between BMMC and PBMC was >97% (8312/8566 total mutation calls), with >88% positive (817/926) and >98% negative agreement (7495/7640). Across reported mutated variants (N=817), there was good correlation (pearson cor=0.88) in VAF between BMMC and PBMC. When considering all paired samples, concordance of best MRD status using PBMC or BMMC results at the pt level (N=95) was: MRD-0.2, 97%; MRD-0.5, 89%; MRD-1, 90%. Given good PBMC and BMMC agreement, results were combined (higher VAF used if both) for outcomes analysis.

In the MRD cohort, 11% (N=12), 18% (N=19) and 27% (N=29) of pts achieved MRD-0.2, MRD-0.5 and MRD-1 negativity, respectively. Most pts with MRD-0.2, -0.5 and -1 clearance had documented response of CR/marrow CR [mCR] (>80%) or CR/partial remission [PR]/hematologic improvement [HI] (>75%). Best overall response of MRD-1 negativity achieved anytime on treatment was associated with improved PFS and overall survival (OS) in the overall population and for responding pts (CR/mCR or CR/PR/HI). Similar results were obtained in a landmark analysis at 6 months (Fig 1). This was supported by a time-dependent Cox-model indicating that MRD-x negativity was associated with a lower hazard ratio for PFS and OS vs MRD-x positivity (Fig 2).

A consistently higher proportion of pts in the sabatolimab (N=56) vs placebo (N=50) arms had on-treatment mutation clearance at different cut-offs: MRD-0.2, 16.1% vs 6.0%; MRD-0.5, 25.0% vs 10.0%; MRD-1, 35.7% vs 18.0%, respectively.

Conclusions: We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA. These findings will be further explored in the ongoing Ph III STIMULUS-MDS2 study (NCT04266301).

Disclosures: Zeidan: Schrödinger: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Syros: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Shattuck Labs: Research Funding; Agios: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; Lox Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria. Fenaux: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; French MDS Group: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Han: Novartis: Current Employment. James: Novartis: Current Employment. Malek: Novartis: Current Employment. Marques Ramos: Novartis: Current Employment. Miyazaki: Novartis: Honoraria; Celgene: Honoraria; Dainippon-Sumitomo: Honoraria; Nipponshinnyaku: Honoraria; Chugai: Honoraria; Otsuka: Honoraria; Astellas: Honoraria; Kyowa-Kirin: Honoraria. Platzbecker: Geron: Consultancy, Research Funding; Janssen Biotech: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Fibrogen: Research Funding; Roche: Research Funding; BeiGene: Research Funding; BMS: Research Funding.

*signifies non-member of ASH