This study was conducted by Dr. Zhi Peng and his colleagues from Beijing Cancer Hospital, China, in collaboration with Sichuan University, Hunan Cancer Hospital, and Jiangsu Aosaikang Biopharmaceutical Co., Ltd. Their research provides significant insights into the potential of ASKB589 as a therapeutic agent in gastric and gastro-esophageal junction (G/GEJ) adenocarcinomas.Study Rationale
G/GEJ adenocarcinomas are among the most aggressive malignancies, necessitating the exploration of novel therapeutic strategies to improve patient outcomes. A promising investigational agent, ASKB589, is currently being evaluated for its efficacy in combination with CAPOX chemotherapy and a PD-1 inhibitor. ASKB589 is a non-fucosylated fully human IgG1 monoclonal antibody specifically targeting CLDN18.2 with high affinity and specificity, enhancing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Earlier findings indicated that ASKB589 is well tolerated at doses up to 20 mg/kg, demonstrating encouraging antitumor activity. Based on these promising initial results, a dose of 6 mg/kg has been selected for further clinical evaluation.
Study Design and Patient Selection
The current study presents updated efficacy data from an ongoing phase Ib/II trial (NCT05632939), evaluating ASKB589 in combination with CAPOX and a PD-1 inhibitor as first-line treatment for patients with advanced G/GEJ adenocarcinoma. The study consists of a dose-escalation segment followed by a dose-expansion phase. The primary objective of the expansion part is to assess the safety and efficacy of this triplet regimen in CLDN18.2-positive patients, irrespective of PD-L1 expression levels.
CLDN18.2 and PD-L1 expression were evaluated using immunohistochemistry (IHC) assays with DS-3 and E1L3N clones, respectively, at a central laboratory. Patients received intravenous ASKB589 at 6 mg/kg, and responses were assessed bi-monthly using RECIST 1.1 criteria. Adverse events were graded based on CTCAE v5.0 guidelines.
Efficacy Results
As of July 29, 2024, a total of 49 patients expressing CLDN18.2 at moderate-to-high levels (≥40% membrane staining intensity) were included in the analysis. The study demonstrated a strong overall response rate (ORR), with 81.6% of patients achieving either a partial or complete response. The confirmed objective response rate (cORR) was 73.5% (95% CI: 58.9%-85.1%), indicating significant antitumor activity.
The median duration of response was 11.4 months (range: 6.93 months to not estimable). Three patients required surgical intervention due to tumor shrinkage following treatment, further underscoring the impact of ASKB589 in tumor control. Stable disease or better was observed in all 49 patients, with a disease control rate (DCR) of 100%.
When stratified by clinical subgroups, patients with CPS≥1 (PD-L1 positive) had a disease control rate of 76.2%, while those with CPS<5 exhibited a DCR of 74.1%. Progression-free survival (PFS) at nine months was 58.1% (95% CI: 42.2%-71.0%), and the overall survival (OS) rate at 12 months was 77.1% (95% CI: 61.2%-87.2%). These promising efficacy results highlight the potential of ASKB589 in prolonging patient survival compared to historical data with standard chemotherapy alone.
Safety and Tolerability
The safety profile of ASKB589 in this triplet regimen was consistent with previous reports from clinical trials evaluating CAPOX-based combinations in G/GEJ cancer. Most treatment-emergent adverse events (TEAEs) were manageable and primarily consisted of on-target, off-tumor effects such as hypokalemia, nausea, and vomiting. There were no unexpected safety signals, reinforcing the favorable risk-benefit profile of ASKB589.
Conclusion and Future Directions
The combination of ASKB589, CAPOX, and a PD-1 inhibitor as a first-line treatment for G/GEJ adenocarcinoma appears to offer robust disease control with durable responses. This study confirms a high ORR, 100% disease control, and a promising survival benefit, independent of PD-L1 expression levels. Given these encouraging results, a phase III clinical trial evaluating the triplet regimen in a broader patient population is actively enrolling participants in China.
While CLDN18.2-directed therapies continue to evolve, ASKB589 represents a novel approach with the potential to redefine first-line treatment strategies for G/GEJ cancer. Further data from the ongoing study will provide additional insights into long-term survival benefits and potential biomarker-driven patient selection strategies.
