Pancreatic cancer anatomy concept: © Лилия Захарчук – stock.adobe.com
New data from a prespecified subgroup analysis of the phase 2 Actuate-1801 part 3B trial (NCT03678883) highlight the potential of elraglusib (9-ING-41), an investigational glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in combination with gemcitabine/nab-paclitaxel (GnP) for first-line metastatic pancreatic adenocarcinoma (mPDAC) treatment.1
The findings indicate a notable improvement in overall survival (OS) among patients receiving at least 1 complete cycle of elraglusib in conjunction with standard chemotherapy, particularly within the challenging subgroup of patients with liver metastases.
For patients who completed at least one 4-week cycle of therapy, the elraglusib/GnP combination arm achieved a median OS of 12.5 months compared with 8.5 months in the control arm. This represented a 43% reduction in the risk of death relative to the control group, underscoring the potential for early disease control with elraglusib.
Beyond OS, the combination therapy also demonstrated improved outcomes across several other key efficacy metrics. The disease control rate (DCR) was 53.4% in the elraglusib arm vs 44.8% in the control arm, while the overall response rate (ORR) improved to 37.9% compared with 29.3%. Median progression-free survival (PFS) was 6.9 months with elraglusib, an improvement over 5.6 months in the control group.
A particularly impactful finding emerged from the analysis of patients with liver metastases; a subpopulation historically associated with an exceptionally poor prognosis in mPDAC. In this group, treatment with elraglusib led to a 2.5-fold increase in 1-year OS and a 38% reduction in the risk of death compared to the control arm. While the GnP control arm showed 0% OS probability at 18 months, patients receiving elraglusib maintained a survival probability of 13.6% OS at 18 months. Additional efficacy metrics within this liver metastases subgroup further supported these observations: DCR was 36.8% vs 27.9%, ORR was 29.8% vs 19.7%, and PFS was 4.9 months vs 3.9 months in the elraglusib and control arms, respectively. The pronounced benefit observed in this high-risk population highlights elraglusib’s potential to address a critical unmet need.
“We are highly encouraged by the significant clinical benefit provided by elraglusib demonstrated in this study,” said Daniel Schmitt, president and chief executive officer of Actuate Therapeutics, in a press release. “These results underscore the potential of elraglusib to generate rapid and durable benefit in high-risk patients, which could be highly impactful in future development and commercial pathways.”
mPDAC represents an advanced and aggressive disease and accounts for approximately 90% of all pancreatic cancers. It is widely recognized as one of the deadliest malignancies, with a 5-year survival rate for metastatic cases under 10%.2 This prognosis underscores the urgent need for novel and more effective therapeutic strategies.
Elraglusib’s mechanism of action involves the inhibition of GSK-3β, a serine/threonine protein kinase implicated in numerous cellular processes, including cell proliferation, differentiation, and survival.1 GSK-3β plays a complex role, often promoting tumor growth and contributing to resistance against conventional cancer therapies, such as chemotherapy. By inhibiting GSK-3β, elraglusib aims to disrupt key molecular pathways in cancer that are involved in promoting tumor growth and resistance. Specifically, its activity targets pathways such as NF-kB of activated B cells and the DNA damage response.
Furthermore, preliminary research suggests elraglusib may also mediate antitumor immunity through the regulation of multiple immune checkpoints and immune cell function, potentially enhancing the body’s natural defenses against cancer. These multifaceted effects contribute to the drug’s observed clinical benefits.