Sabatolimab achieved durable responses in patients with high-risk MDS and AML

Sabatolimab plus hypomethylating agents (HMA) showed durable responses in a phase 1b study in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) with poor-outcome cytogenetic risk profiles. Treatment was well tolerated.

Novel therapies with durable efficacy and favourable safety profiles represent an unmet medical need in high-risk and very high-risk MDS (HR/VeryHR MDS) and AML. TIM-3 is an inhibitory receptor expressed on immune and leukaemic cells but not on normal haematopoetic stem cells. Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3. Prof. Andrew Wei (Alfred Hospital and Monash University, Australia) presented updated results of a multi-arm, open-label, phase 1b study (NCT03066648) [1].

The study enrolled patients with HR/VeryHR MDS or newly diagnosed AML unfit for chemotherapy and without prior treatment with HMA. The participants received 28-day treatment cycles with sabatolimab 240 mg or 400 mg (every 2 weeks), or 800 mg (every 4 weeks) plus either 20 mg/m² decitabine on days 1–5 or 75 mg/m² azacitidine on days 1–7. Primary endpoints were maximum tolerated dose, recommended dose, safety, and tolerability. Secondary endpoints included preliminary efficacy evaluation.

At data cut-off (22 September 2020), 53 HR/VeryHR MDS patients (sabatolimab + decitabine n=19; sabatolimab + azacitidine n=34) and 48 AML patients were included (sabatolimab + decitabine n=22; sabatolimab + azacitidine n=26). Of all patients, 36 had interrupted sabatolimab treatment, 1 received a reduced dose, 2 had dose-interruption plus -reduction, 5 discontinued treatment, and 3 had dose-interruption plus discontinuation; 4 discontinuations were due to adverse events (1 related to study treatment), and 4 due to death. Most adverse events were consistent with HMA treatment alone.

Sabatolimab plus HMA demonstrated promising response rates with emerging durability: objective response rate (ORR) in patients with HR/VeryHR MDS was 58%, with a median duration of response (DOR) of 16.1 months (95% CI 6.7–not evaluable [NE]) and an estimated 12-month progression-free survival (PFS) rate of 50.1% (95% CI 27.3–69.2). In patients achieving complete response (CR), the median DOR was 21.5 months (95% CI 12.1–NE), while median DOR was 7.3 months (95% CI 3.0–NE) in patients achieving bone marrow CR only. In the AML cohort, ORR was 42.5%, median DOR was 12.6 months (95% CI 5.2–NE) and the estimated 12-month PFS rate was 27.4% (95% CI 14.5–42.0). Median DOR was 23.0 months (95% CI 1.3–NE) in patients with CR and 5.2 months (95% CI 2.4–NE) in patients with bone marrow CR. Biomarker assessment showed that interleukin (IL)-1β was significantly reduced in responding patients.

Evaluation of poor-risk subgroups showed that sabatolimab treatment achieved durable responses. Results for HR/VeryHR MDS subgroups were:

• 
  
  • TP53: ORR 71.4%, median DOR 14.7 months (n=14);
  • TP53/RUNX1/ASXL1: ORR 67.7%, median DOR 16.1 months (n=31);
  • cytogenetic poor risk: ORR 60%, median DOR 12.1 months (n=5); and
  • cytogenetic very poor risk: ORR 65%, median DOR 7.9 months (n=20).

Results for AML subgroups were:

• 
  
  • TP53: ORR 40.0%, median DOR 4.2 months (n=5); and
  • TP53/RUNX1/ASXL1: ORR 53.8%, median DOR 12.6 months (n=13).

Prof. Wei summarised, “Sabatolimab plus HMA is well tolerated and demonstrated durable clinical benefit in patients with HR/VHR MDS and AML. Further phase 2/3 studies are underway as part of the STIMULUS immune-myeloid clinical trial programme.”

1. 
   
   1. Wei A, et al. Sabatolimab plus hypomethylating agents (HMAS) in patients (pts) with high-/very high-risk myelodysplastic syndrome (HR/VHR-MDS) and acute myeloid leukemia (AML): subgroup analysis of a phase 1 study. S168, EHA 2021 Virtual Congress, 9–17 June.

 

Copyright ©2021 Medicom Medical Publishers



Posted on 5 August 2021