OS Data Could Dictate Next Directions for Uproleselan in R/R AML

Although the addition of uproleselan to chemotherapy did not lead to a statistically significant improvement in overall survival (OS) compared with chemotherapy alone in patients with relapsed/refractory acute myeloid leukemia (AML), a clinically meaningful OS improvement was observed with the use of the E-selectin antagonist in combination with chemotherapy in patients with primary refractory AML, according to data from a phase 3 trial (NCT03616470).¹

GlycoMimetics, the developer of uproleselan, previously reported that the phase 3 study missed its primary end point of OS.²

Findings showed that at a median follow-up of over 3 years in the intention-to-treat (ITT) population (n = 388), uprloeselan plus chemotherapy (n = 194 ) elicited a median OS of 13.0 months compared with 12.3 months for chemotherapy plus placebo (HR, 0.89; 95% CI, 0.69-1.15). However, patients with primary refractory disease treated in the uproleselan arm (n = 62) achieved a median OS of 31.2 months vs 10.1 months for those given chemotherapy alone (n = 66; HR, 0.58; 95% CI, 0.37-0.91). In this patient population, the OS benefit was observed irrespective of chemotherapy backbone.¹

“There is a wealth of data across large subsets of this pivotal phase 3 study that help us understand how prespecified stratification factors such as backbone chemotherapy, disease status, and age impacted survival outcomes for patients,” said Daniel DeAngelo, MD, PhD, professor of medicine, Harvard Medical School, chief, Division of Leukemia, Dana-Farber Cancer Institute, and principal investigator of the pivotal phase 3 study. “In the primary refractory setting, uproleselan’s improvement of median OS and greater duration of remission were particularly compelling, as there is a significant unmet need for new treatment options in this setting that can extend and improve the lives of patients. These results demonstrate uproleselan has the potential to address this unmet need in primary refractory AML.”

Additional OS Data

Further findings from the subgroup analysis for OS showed that patients who experienced early relapse prior to enrollment achieved a median OS of 3.7 months in the uproleselan arm (n = 28) compared with 6.4 months for those in the placebo arm (n = 22; HR, 1.50; 95% CI, 0.69-3.27). In patients who had a late relapse prior to enrollment, the median OS was 15.4 months for uproleselan (n = 104) vs 18.2 months for placebo (n = 106; HR 1.10; 95% CI, 0.77-1.57).

Regarding chemotherapy backbone used during the study in the ITT population, patients treated with uproleselan plus fludarabine, cytarabine and idarubicin (FAI; n = 98) experienced a median OS of 30.2 months vs 12.8 months for patients given placebo plus FAI (n = 96; HR 0.73; 95% CI, 0.50-1.06). Those administered uproleselan plus mitoxantrone, etoposide and cytarabine (MEC; n = 96) had a median OS of 8.7 months compared with 12.3 months for those given placebo plus MEC (n = 98; HR 1.06; 95% CI, 0.75-1.51).

Finally, for patients who underwent hematopoietic stem cell transplantation (HSCT) after study treatment, the median OS was not reached for patients in the uproleselan arm (n = 101). In the placebo arm, the median OS for patients who received FAI (n = 53) and MEC (n = 46) was 26.3 months and 24.4 months, respectively.

“As we have analyzed data from this large, well-balanced, and well-executed study alongside medical, statistical, and regulatory experts, it has become clear that uproleselan may offer clinically meaningful patient benefit in multiple settings, including primary refractory AML,” Harout Semerjian, chief executive officer of GlycoMimetics, added in a news release. “We are committed to addressing unmet needs of [patients with] AML and plan to engage with regulators and the National Cancer Institute to discuss potential paths forward for uproleselan.”

Phase 3 Trial Design, Methods, and Additional Data

The randomized, double-blind, placebo-controlled trial enrolled patients between 18 and 75 years of age with relapsed/refractory AML who underwent no more than 1 prior stem cell transplant; had not received the chemotherapy regimen planned for use during induction during the study; and were considered eligible to receive one of the chemotherapy regimens.³

The study excluded patients with acute promyelocytic leukemia, acute leukemia of ambiguous lineage, chronic myeloid leukemia with myeloid blast crisis, or secondary refractory AML; those with active signs or symptoms of central nervous system involvement by malignancy; and those who underwent stem cell transplant within 4 months of first study treatment.³

Investigators randomly assigned 388 patients in a 1:1 fashion to receive uproleselan or placebo in combination with FAI or MEC. Uproleselan and placebo were administered for 8 days during cycle 1 of induction therapy, then for up to 3 cycles during consolidation.¹

Notably, the primary end point of OS was not censored for HSCT. Secondary end points included incidence of severe oral mucositis, complete remission (CR) rate, and CR with partial hematologic recovery (CRh) rate.

Additional data showed that the rate of induction-emergent severe oral mucositis was 7.2% in both arms. CR at the end of induction rate as assessed by an independent end point review committee was 36.1% in the uproleselan arm vs 33.5% in the placebo arm. At the end of induction, the CR/CRh rate was 46.4% for the uproleselan regimen vs 41.2% of for the placebo regimen.

Furthermore, 52.1% of patients in the uproleselan arm underwent HSCT following treatment compared with 51.0% of patients in the placebo arm. Forty percent of non-responders in the uproleselan arm (n = 80) received subsequent AML therapy vs 46.2% of non-responders in the placebo arm (n = 78).

Safety findings were consistent with the known profiles of the backbone chemotherapy regimens. Serious treatment-emergent adverse effects (TEAEs) were reported in 35.9% of patients in the uproleselan arm vs 34.2% of patients in the placebo arm. The rates of grade 3 or higher TEAEs were 85.9% and 87.6%, respectively.

References

1. GlycoMimetics announces comprehensive results from pivotal phase 3 study of uproleselan in relapsed/refractory (R/R) acute myeloid leukemia (AML). News release. GlycoMimetics, Inc. June 4, 2024. Accessed June 4, 2024. https://ir.glycomimetics.com/news-releases/news-release-details/glycomimetics-announces-comprehensive-results-pivotal-phase-3
2. GlycoMimetics announces results of pivotal phase 3 study of uproleselan in relapsed/refractory (R/R) acute myeloid leukemia (AML). News Release. GlycoMimetics, Inc. May 6, 2024. Accessed June 4, 2024. https://ir.glycomimetics.com/news-releases/news-release-details/glycomimetics-announces-results-pivotal-phase-3-study
3. Study to determine the efficacy of uproleselan (GMI-1271) in combination with chemotherapy to treat relapsed/refractory acute myeloid leukemia. ClinicalTrials.gov. Updated July 25, 2023. Accessed June 4, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03616470