Efficacy and Safety of Uproleselan Combined with Chemotherapy Vs. Chemotherapy Alone in Relapsed/Refractory Acute Myeloid Leukemia: Findings from an International Phase 3 Trial

Introduction: Uproleselan (GMI-1271) is an E-selectin antagonist that disrupts AML cell survival pathways, overcomes chemotherapy resistance, and potentially deepens chemotherapy response. Phase 2 data demonstrated uproleselan efficacy in patients with relapsed/refractory (R/R) and in >60 yrs newly diagnosed (ND) acute myeloid leukemia (AML) (DeAngelo et al., Blood 2022). This Phase 3 international, randomized, double-blind, placebo (PBO)-controlled trial assessed uproleselan with chemotherapy versus chemotherapy alone in R/R AML (NCT03616470). An NCTN sponsored trial (NCT03701308) in the ND population is ongoing. Methods: Eligibility included patients age 18-75 yrs, R/R patients with AML in first or second untreated relapse and fit for chemotherapy. Randomization was 1:1, stratified by age, disease status (primary refractory/early relapse ≤6 months, late relapse >6 months), and FAI or MEC chemotherapy. Uproleselan or PBO was given during induction and up to 3 consolidation cycles. The primary endpoint was overall survival. Key secondary endpoints included severe oral mucositis during induction, complete remission (CR), and remission (CR/CRh) rates. Overall, 388 patients were enrolled (N=385 dosed) in the trial at 59 sites in North America, Europe, and Australia. Due to fewer than expected death events, we report results of a time-based primary analysis (31March2024) with a median follow-up time of 37.9 months. Results: Treatment arms were well-balanced: median age, 58.0 (range 20-75); median number of prior lines of therapy, 1.0 (range 1-4); primary refractory cases, 33%; European LeukemiaNet 2017 (ELN) adverse risk, 41.5%. Median OS (mOS) was 13.0 months for uproleselan and 12.3 months for PBO (p=0.39; HR=0.89, 95% CI 0.69-1.15), with survival probabilities at 48 months for uproleselan and PBO of 34.1% and 25.5%, respectively. Rates of severe (Grade ≥3) oral mucositis during induction were equal across arms (7.2%) while CR and CR/CRh rates trended in favor of uproleselan (36.1% vs 33.5% [p=0.62] and 46.4% vs 41.2% [p=0.24]). Of patients achieving CR, a greater proportion receiving uproleselan achieved MRD negativity (67.1% vs 61.5 %). Post-treatment allogeneic stem cell transplant (allo-SCT) rates were comparable between arms (N=101, 52.1% vs N=99, 51.0%). In patients achieving allo-SCT, mOS was Not Reached (NR) on uproleselan vs 24.8 months in PBO arm (HR=0.59, 95% CI 0.38 - 0.91). Patients with primary refractory AML (N=128, 33%), a pre-specified subgroup, had mOS of 31.2 months on uproleselan (N=62) versus 10.1 months on PBO (N= 66) (HR=0.58; 95% CI 0.37-0.91). Survival in the PBO group is consistent with historical outcomes in this setting (Ferguson, 2016). Uproleselan survival benefit in primary refractory disease was agnostic to backbone chemotherapy (MEC= HR 0.68, 95% CI 0.34-1.38; FAI= HR 0.53, 95% CI 0.30-0.93). Complete response rates for primary refractory disease trended in favor of uproleselan over PBO (32.3% vs 27.3%). However, responses to uproleselan may potentially be deeper, as indicated by median duration of response (DoR) not being reached for primary refractory patients treated with uproleselan, compared to a median DoR of 12.7 months in the PBO arm (HR 0.26, 95% CI 0.09 - 0.75). Clinically meaningful activity was also seen in primary refractory patients who achieved MRD- status [uproleselan, N=22 (35.5%) vs. PBO, N=16 (24.2%)] (mOS: NR vs. 14.7 months, HR 0.07, 95% CI 0.02 - 0.35) or achieved allo-SCT [uproleselan, N=37 (59.7%) vs PBO, N=34 (51.5%)] (mOS: NR vs. 19.7 months, HR 0.34, 95% CI 0.17 - 0.69). Of patients transplanted, survival probabilities at 60 months for uproleselan and PBO were 57.5% vs 27.7%, respectively. Treatment-emergent adverse events (TEAEs), Serious Adverse Events (SAEs), grade 3 or higher TEAEs were similar across study arms in both Intent to Treat (ITT) and primary refractory populations. There was no discernible added toxicity with uproleselan treatment over chemotherapy alone. Conclusions: Although this Phase 3 trial did not meet its primary OS endpoint for the ITT population, these clinical data provide compelling evidence of uproleselan efficacy in patients with primary refractory AML without additional toxicity. In primary refractory AML, a mOS of 31.2 months highlights the potential of uproleselan to significantly improve treatment outcomes in this high unmet medical need population.