Eisai's investigational drug E7820, a targeted protein degrader, has shown promising anti-tumor activity in preclinical studies, particularly in patient-derived xenograft (PDX) models of bile duct and uterine cancers. These findings have led to the launch of a Phase I investigator-initiated clinical study to assess the safety and efficacy of E7820 in Japanese patients with solid tumors. The research, a collaboration between the National Cancer Center and Eisai Co., Ltd., aims to accelerate the development of new anticancer drugs for rare and refractory cancers.
Preclinical Efficacy in PDX Models
The non-clinical study evaluated E7820 in 42 PDX models, including pancreatic, bile duct, gastric, and uterine cancer models. The results indicated that E7820 administration at 100 mg/kg led to tumor shrinkage in 38.1% of the models. Notably, bile duct cancer models exhibited a 58.3% response rate, while uterine cancer models showed a 55.6% response rate. These findings suggest that E7820 may be particularly effective in treating these cancer types. According to the original publication, pancreatic cancer was significantly more resistant to treatment than other tumor subtypes (HR = 11.0, 95% confidence interval (CI) = 1.26–96.2, p = 1.5×10-2).
Identification of Predictive Biomarkers
To identify biomarkers correlated with E7820's tumor-shrinking effect, whole-exome sequencing was performed on the PDX models. The analysis revealed frequent mutations in genes related to homologous recombination repair (HRR), such as BRCA1, BRCA2, and ATM, in the PDX models that responded to E7820. This suggests that mutations in these genes may serve as predictive biomarkers for E7820 response. ATM mutations were significantly enriched in responders (p = 4.5×10-3, FDR = 0.14) while BRCA2 mutations (p = 4.8×10-2, FDR = 0.51) was mildly enriched in the responder group.
Mechanism of Action and Further In Vitro Studies
E7820 functions as a molecular glue, binding ubiquitin ligase DCAF15 to splicing factor RBM39, leading to selective degradation of RBM39. This action is expected to induce antitumor efficacy by dysregulation of RNA splicing. In vitro studies further explored the impact of E7820 on cancer cells with HRR deficiencies. The study found that deletion of ATM, ATR or BAP1 sensitized DLD1 cells to E7820. Additional experiments showed that BRCA2 dysfunction increases E7820-induced DNA double-strand breaks, suggesting a mechanism by which E7820 selectively targets cells with HRR deficiencies.
Phase I Clinical Study Details
Based on these preclinical results, a Phase I investigator-initiated clinical study (NCCH2303) has been initiated at the National Cancer Center Hospital and the National Cancer Center Hospital East. The study aims to evaluate the safety, tolerability, and exploratory efficacy of E7820 in Japanese patients with solid tumors. The dose-finding portion of the study will assess the tolerability and pharmacokinetics of E7820 in patients unresponsive or intolerant to standard therapies. The dose expansion phase will then evaluate the efficacy and safety of E7820 in patients with bile duct cancer, uterine cancer, or solid tumors harboring HRR gene mutations, using the dosage and administration confirmed tolerable in the first phase. The maximum tolerated dose (MTD) in overseas clinical studies using once-daily oral consecutive day administration has been set at 100 mg.
Leveraging J-PDX Library for Drug Discovery
The National Cancer Center's J-PDX library, which comprises PDX models derived from Japanese cancer patients, plays a crucial role in this research. These models retain tumor heterogeneity and many of the gene mutations found in the original patient tumors, offering high predictive accuracy for clinical outcomes. By utilizing the J-PDX library, researchers can evaluate drug efficacy in various cancer types, identify predictive biomarkers, and launch clinical studies in a streamlined process. This approach aims to accelerate the development of new anticancer drugs and address unmet medical needs in rare and refractory cancers.
