Combining ESA and Luspatercept in Non-RS MDS Patients Having Failed ESA - Results of the Phase 1-2 Part a of the GFM Combola Study

Context

The therapeutic landscape of lower risk MDS has recently changed with the approval of Luspatercept to treat anemia in transfusion-dependent patients with ring sideroblast (RS)-positive LR-MDS who are refractory/intolerant to ESAs, following the phase 3 MEDALIST study. More recently, the COMMANDS study has challenged the place of ESA as a first-line treatment for low-risk MDS with or without RS ,showing a superiority of luspatecept over ESA, at least in RS-MDS. To better understand the role of luspatercept in non-RS MDS, we carried out a study evaluating the combination of luspatecept and ESA to assess the safety of the combination and to determine the best doses for the combination in a LR non-RS MDS population having failed ESA, before comparing luspatercept to this combo in a randomized trial (COMBOLA-Part B).

Patients & Methods

A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted by the GFM in patients with LR-MDS (IPSS low risk and Int-1) without RS or del(5q) and ineligible or having failed to achieve a response (or subsequently relapsed) after ESA without disease progression, and with hemoglobin < 9 g/dl. The primary objective of this dose-finding part of the trial was to determine the optimal dose in terms of both toxicity and efficacy for luspatercept + ESA, for selection in the randomized part B of the trial. Luspatercept was administered subcutaneously every 21 days at dose concentrations ranging from 0.8 to 1.75 mg/kg. Based on a TITE-BOIN-ET design, Epoetin alfa was administered weekly at dose concentrations ranging from 30 000UI to 60 000 UI. Four dose levels were tested: Dose level 1 (n=3): Luspatercept 0.8 mg/kg/21d and EPO alpha 30.000 UI/w; Dose level 2 (n=3): Luspatercept 1.33 mg/kg/21d and EPO alpha 30.000 UI/w; Dose Level 3 (n=3) : Luspatercept 1.75 mg/kg/21d and EPO alpha 30.000 UI/W; Dose Level 4 (n=15): Luspatercept 1.75 mg/kg/21d and EPO alpha60.000 UI/w. The assessment window for efficacy was d-21 days, and for toxicity d-42.

Results

Thirty-five patients were screened and 24 patients from 10 French centers were included between May 2022 and November 2023. Median age at inclusion was 77.7 y [71.4;84.1] and male/female ratio was 18/6. According to 2016-WHO, 18 had refractory cytopenia with multilineage dysplasia, 2 refractory cytopenia with unilineage dysplasia, and 4 had MDS-EB1. According to historical IPSS, 2 and 22 patients had low and intermediate-1 risk, respectively. According to IPSS-R, 5, 15 and 4 patients had low, intermediate risk and high risk respectively. All patients had resistance to ESA and 7 had also received Revlimid (n=3), IDH inhibitors (n=2), Thalidomide (n=1), AZA (n=1). Six (25%) had low transfusion burden, 16 (67%) had high transfusion burden (according to IWG 2018 criteria) and 2 were non-transfusion dependent.

D-42 Tolerance and D21-efficacy have been assessed after treatment initiation for all patients. At these timepoints, No DLT was observed, and efficacy was only reported in one patient treated at the dose level 4 (Luspatercept 1.75 mg/kg/21d and EPO 60 000 UI/w)). At week 25, 7 (29 %) patients had achieved an erythroid response , 2/3 at dose level 2, and 5/15 at dose level 4. Moreover, 2 patients achieved platelet response and 1 neutrophil response. According to transfusion burden, ½, 2/6 and 4/16 achieved Erythroid response in the non-transfusion dependent, Low TD and High TD cohorts, respectively. Among the 7 patients who achieved an erythroid response, 3 were still responders at the time of the present analysis and the median duration of response was 9.2 (95%CI 0.85-NA) months. During the first 6 months, 45 adverse events were observed including 16 serious adverse events (all grade >2) including 3 infections, 2 cardiac events, 2 GI disorders, 1 worsening of general condition and 8 others. Overall, 6 (25 %) patients had an AML evolution (n=2) or died in the 6 months after treatment initiation leading to a 6-month PFS of 74.8% [59.2-94.5] and a 6-month OS of 78.9% [64.1-97.2], with no differences across the different cohorts.

Conclusions: In this difficult to treat population, one third achieved erythroid response with the combination of Luspatercept and ESA. Based on the results of this Phase 1 study, the dosing schedule Luspatercept 1.75 mg/kg/21d and EPO 60 000 UI/w, that balanced clinical efficacy and safety profile was selected as the RP2D. This regimen is being compared to Luspatercept 1.75 mg/kg/21d in the ongoing randomized Phase 2 study.