Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, making up more than 80% of cases. Actuate's lead investigational drug Elraglusib (9-ING-41) is a first-in-class GSK-3ß inhibitor that disrupts cancer cell survival, proliferation, and immune evasion by targeting key signaling pathways and enhancing T and NK cell activation. In early-phase studies, it showed antitumor activity both alone and with chemotherapy, with the dose adjusted to 9.3 mg/kg twice weekly in mPDAC due to toxicity. 

In the ongoing Part 3B of a Phase II trial [Actuate-1801 Part 3B study (NCT03678883)], untreated mPDAC patients were randomized to receive gemcitabine/nab-paclitaxel with elraglusib weekly or chemotherapy alone, later amended to 2:1 favoring weekly dosing due to better adherence and comparable efficacy. The primary endpoints are median and 1-year overall survival (OS), with secondary endpoints including overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), time to treatment failure (TTF), and disease control rate (DCR). Among 287 enrolled patients, median age was 65 (elraglusib) vs 68 (control), with liver as the most common metastatic site. 

The combination of elraglusib and chemotherapy led to a 37% reduction in the risk of death compared to chemotherapy alone (HR 0.63; p = 0.01). Median OS improved to 10.1 months vs 7.2 months, with notable gains at 12, 18, and 24 months (24-month OS: 13.8% vs 0%). 

Median PFS was similar (5.6 vs 5.1 months), and TTF slightly favored elraglusib (5.1 vs 3.4 months), though not statistically significant.

In a Phase II study, patients receiving elraglusib experienced higher response rates, with an ORR of 29.0% vs 21.8%, a DCR of 61.3% vs 56.4%, and a median DOR of 5.5 vs 4.0 months. Additionally, seven patients in the elraglusib arm remained on treatment, indicating potential long-term benefits.

The trial also met its primary safety endpoint. Treatment-emergent adverse events (TEAEs) and Serious Adverse Events (SAEs) in the elraglusib/GnP combination arm were similar to those observed in the GnP arm, indicating a favorable risk-benefit profile for the elraglusib/GnP combination.

Safety was manageable, with serious adverse events and treatment discontinuation rates similar between arms. Treatment-related adverse events (TRAEs) were mostly Grade 1-2, with the most frequent TRAEs observed (in about two-thirds of patients) being transient visual impairments that were reversible and non-progressive

While Grade 3 or higher neutropenia was observed (61.3% vs 41.0%), similar rates of febrile neutropenia and sepsis were observed in both treatment arms.

Biomarker analysis showed that high baseline CXCL2 levels predicted better survival with elraglusib. Elraglusib also enhanced CD8+ and granzyme B+ immune cell infiltration, indicating immune modulation within the tumor microenvironment.

KOL insights

“This was a positive large Phase II randomized study. A recent press release suggested positive OS outcomes and as such it met its primary end point. The goal will be to confirm these results in a phase III randomized clinical trial that, if positive, will create a new SOC in this disease that desperately needs better ones.” – Expert Opinion

“You will note this rapid decline in the first 2 months of the study in both arms, reflecting the aggressive nature of metastatic pancreatic cancer, but then you see that the curves start to diverge early and remain separated with reduced event rates in the elraglusib cohort, pointing to the survival benefit” – Expert Opinion

Conclusion

To treat pancreatic cancer, there is a clear unmet need for innovative therapies like elraglusib that offer new mechanistic pathways and can be effectively combined without overlapping toxicities. It has been a long time since a therapy in pancreatic cancer has significantly improved patient outcomes using chemotherapy in combination, after a series of unsuccessful clinical trials. Experts have underscored the substantial survival benefit observed in the elraglusib trial, recognizing its potential impact. 

No doubt that the survival outcomes were great, but there were some limitations as well. One key issue was its open-label design, which led to some patients withdrawing early after being randomized to the control arm. Additionally, the median OS in the control group was lower than what is typically observed in interventional trials; however, this was consistent with real-world observational data.

Another notable limitation was the high rate of early deaths, which likely impacted the median OS. This could be attributed to a subgroup of patients having more advanced disease and/or biologically poorer prognoses. Furthermore, many patients had a poorer baseline performance status, which may have contributed to the observed outcomes. In addition, median PFS was similar between arms, does it mean survival benefit driven by tumor immune modulation?