Early ASP2138 Data Show Encouraging Activity and Improved Safety in Gastric, GEJ Cancer

In an interview with Pharmacy Times, Sam Klempner, MD, provides an overview of emerging early clinical data for ASP2138, a bispecific T-cell engager targeting claudin in gastric and gastroesophageal junction (GEJ) cancers. He outlines the rationale behind the therapy, unmet needs in claudin-positive disease, and the design of monotherapy and combination cohorts. Klempner also highlights encouraging activity signals, manageable safety, and the transition from intravenous (IV) to subcutaneous (SC) administration to further improve tolerability.

Q: Could you summarize the key findings from the early clinical data for ASP2138, both as monotherapy and in combination with standard therapy?

Sam Klempner, MD: Sure. So ASP2138 is a bispecific T-cell engager, and the background rationale for this is that we know claudin is a target in gastric and GEJ cancers. We have approval for zolbituximab-clzb (Vyloy; Astellas), which is a monoclonal antibody against claudin in combination with chemotherapy in patients that have high levels of claudin expression. So, there are several unmet needs in claudin. One is: can we find drugs that are active across a broad range of claudin expression, and can we improve upon the activity of zolbituximab, particularly in later-line patients as well?

So, 2138 was launched initially to do safety dose escalation—to define the safety and the early activity, as with many other drugs. Then, interestingly, they did very early expansions into combinations with standard-of-care chemotherapy. In second line, ASP2138 was combined with our standard Taxol and ramucirumab chemotherapy. In frontline, it was FOLFOX and pembrolizumab with ASP2138, and that’s really to explore the activity in combination with standard of care to understand if we’re safe but also increasing effectiveness beyond the current standard.

The main findings were that there is activity. In monotherapy, the response rate was around 10% in a more heavily pretreated population, but the safety was relatively encouraging. We did not see a lot of high-grade nausea or vomiting; in fact, there was really no significant high-grade nausea or vomiting. We also did not see a lot of cytokine release syndrome, which is always a concern with bispecific T-cell engagers.

As the study proceeded to further improve the safety profile, the IV administration was converted to subcutaneous administration, and this is something that has also been done in other bispecifics. It further reduced the rates of cytokine release syndrome—really to minimal, if any, significant cytokine release.

The preliminary efficacy, again in relatively small numbers—roughly around close to 40 patients in each cohort—showed encouraging results. In combination with paclitaxel and ramucirumab, we saw a response rate around 38%, and the historical response rate for paclitaxel and ramucirumab in phase 3 trials is more like 27–28%, so it’s an encouraging early signal. In the frontline combination with FOLFOX and pembrolizumab, we saw an ASP2138 response rate around 68%, also an encouraging response rate. Certainly, more patients and longer follow-up will be necessary to see if this truly holds up, and also to evaluate durability—the progression-free and overall survival.