Safety and Activity of the TIM3 Inhibitor Sabatolimab in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Lower-risk myelodysplastic syndromes (LR-MDS) are characterized by progressive cytopenias related to malignant clonal expansion. MDS progenitors exert clonal dominance but ineffective hematopoiesis; MDS progenitors may rely on TIM3 signaling to promote self-renewal. LR-MDS is also characterized by altered immunity, including diminished immune surveillance. Sabatolimab is an IgG4 antibody directed at the galectin-9 binding domain of TIM-3. Sabatolimab combined with azacitidine was studied in the phase III STIMULUS MDS2 study in higher-risk MDS, which failed to reach its primary endpoint; responses in that trial modestly favored the combination and no new safety signals were identified. In this study we evaluated sabatolimab in in a phase II study of patients with LR-MDS with cytopenias.

Methods: Patient eligibility included adults with MDS, with an IPSS-R ≤3.5 at diagnosis, who progressed on or were refractory to frontline therapy. Patients had to have a cytopenia measurable for response per IWG 2018 criteria. Patients received sabatolimab 800mg IV on day 1 of a 28-day cycle. The primary endpoint was ORR, defined as CR, PR, HI, TI, or CRh, during the first 6 months of treatment. Secondary endpoints included adverse events and 1 year overall and progression-free survival. DLTs were assessed in the first 6 patients. We followed a Simon 2-stage design, where at least 1 patient in the first 10 needed to respond in order to expand the study to a planned total of 22 patients. Sabatolimab development was halted based on the STIMULUS MDS2 results. We therefore report on the first 10 patients enrolled to the current study prior to halted enrollment.

Results: A total of 10 patients were enrolled in the first stage of this study. Most were male (9/10); 8 identified as white and 2 as Asian race. The median age was 72 (range 54-88). Most patients had high transfusion burden MDS (HTB; n=8) with only 2 low transfusion burden (LTB). The median number of cycles received on study was 4.5 (range 3-20). One patient continues on therapy; only one of 10 developed progressive disease during study treatment; this patient experienced increased bone marrow blasts from <5% at baseline to 8% (MDS-IB1) at the end of cycle 6.

The most frequent ≥grade 3 all-cause adverse events reported on study included anemia (n=5), neutropenia (n=5), myocardial infarction (n=1; deemed unrelated), central line infection (n=1), pneumonia (n=1), thrombocytopenia (n=1), rash (n=1), and hypoxia (n=1). No DLTs were reported and no patients stopped study treatment due to an AE.

The ORR of the study was 3 of 10 patients. The best response on treatment included one patient who achieved transfusion independence, and one patient who achieved HI-E (minor HI-E per IWG 2018). A third patient achieved HI-N (ANC 0.53 increased to 2.66 during study).

The patient with transfusion independence had an improvement in hemoglobin (hgb) starting during cycle 4 of treatment. This patient had known heart disease and experienced an NSTEMI and atrial fibrillation during treatment, felt unrelated to sabatolimab; in that setting they had worsened counts and treatment delay, but they were able to resume therapy on recovery and again achieved TI with a 2g/dL improvement in hgb. Median follow-up was 16 months. The median overall survival of the cohort was not reached; estimated 12 month OS was 64%. A total of 2 patients proceeded to transplant. Based on the response rate, this study met the pre-defined criteria and could have continued to full accrual. Further analysis of serum cytokines and immune cell subsets during treatment is ongoing.

Conclusions: Sabatolimab, an IgG4 antibody directed at TIM-3 and administered every 4 weeks, can be given to patients with LR-MDS without excess toxicity. Sabatolimab produced hematological responses in this cohort, including two patients with erythroid responses and one with neutrophil recovery. This study suggests clinical activity in blocking the TIM3 axis in lower-risk MDS and supports further evaluation of this target.

Brunner:Keros Therapeutics: Consultancy; i-Mab Biopharma: Consultancy; Novartis: Consultancy, Research Funding; Lava Therapeutics: Consultancy; Rigel Pharmaceuticals: Consultancy; Servier: Consultancy; AstraZeneca: Research Funding; Geron: Consultancy; Takeda Oncology: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy. Narayan:Novartis: Other: Research funding to the institution; Sanofi: Other: Spouse employment. Lee:Morphosys: Membership on an entity's Board of Directors or advisory committees. Hobbs:Pfizer: Honoraria; Pharmaessentia: Honoraria; GSK: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Sobi: Honoraria; Cogent: Honoraria; Regeneron: Other: spouse employment. Neuberg:Madrigal Pharmaceutical: Current equity holder in publicly-traded company. Fathi:Ispen: Consultancy; PureTech: Consultancy; Rigel: Consultancy; Mablytics: Consultancy; Ipsen: Consultancy; EnClear: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Takeda: Consultancy; Autolus: Consultancy; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; AstraZeneca: Honoraria; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Orum: Consultancy; Genentech: Honoraria; ImmunoGen: Consultancy; Forma: Consultancy; Menarini Group: Consultancy; Remix: Consultancy; Agios: Ended employment in the past 24 months; MorphoSys: Consultancy; Astellas: Consultancy; Servier: Consultancy, Research Funding; Kite: Consultancy; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria.

Sabatolimab is an anti TIM3 antibody that is not clinically approved for the treatment of MDS