Initial results from the Phase 1 trial of Daiichi Sankyo's DS-9606, a Claudin-6 (CLDN6) directed antibody-drug conjugate (ADC), indicate promising clinical activity in patients with advanced solid tumors expressing CLDN6. The data, presented at the 2024 European Society for Medical Oncology (ESMO) meeting, highlight the potential of this novel therapeutic approach, particularly in tumors like germ cell tumors (GCT) known to express CLDN6.
The Phase 1 trial (NCT05394675) evaluated the safety, tolerability, and preliminary efficacy of DS-9606 in 53 heavily pretreated patients with various advanced solid tumors, including ovarian (n=19), GCT (n=11), gastric/esophageal (n=7), non-small cell lung cancer (NSCLC, n=7), pancreatic (n=5), breast (n=2), and endometrial cancer (n=2). The patients had received a median of four prior therapies (range, 1-9).
Safety and Tolerability
DS-9606 was evaluated at increasing dose levels from 0.016 mg/kg to 0.225 mg/kg. No dose-limiting toxicities were observed, and no patients withdrew from the trial due to treatment-related adverse events. The most common treatment-emergent adverse events (TEAEs) of any grade (≥7.5%) included nausea (18.9%), fatigue (18.9%), anemia (17.0%), abdominal pain (15.1%), and constipation (13.2%). Grade 3 or higher TEAEs occurred in 30.2% of patients (n=16), with anemia (3.8%), abdominal pain (3.8%), and pleural effusion (3.8%) being the most frequent.
Skin-associated events were also noted as common TEAEs (17%), with most being grade 1. There was one grade 2 event (skin hyperpigmentation) and one grade 3 event (rash), each leading to a dose reduction.
Efficacy Signals
Preliminary efficacy was observed at doses ≥0.072 mg/kg (excluding 0.190 mg/kg due to immature data). Four confirmed objective responses were reported, including two in patients with GCT and one each in patients with gastric/esophageal cancer and NSCLC. Among seven evaluable GCT patients, the two who achieved confirmed objective responses remained on treatment for over six months, and five experienced a ≥90% reduction in alpha-fetoprotein and human chorionic gonadotropin tumor markers. As of the data cutoff (June 14, 2024), 21 of the 53 patients were still receiving treatment with DS-9606.
Expert Commentary
"These initial results of DS-9606 are encouraging, particularly those observed in germ cell tumors which are known to express CLDN6 and where the majority of patients experienced a reduction in tumor markers," said Dr. Manish R. Patel, Director of Drug Development, Florida Cancer Specialists and Sarah Cannon Research Institute. "Enrollment continues into the study in order to determine the recommended dose for expansion and better understand how advanced solid tumors may respond to DS-9606."
About DS-9606
DS-9606 is an investigational CLDN6-directed, modified pyrrolobenzodiazepine (PBD) ADC developed using Daiichi Sankyo’s second ADC technology platform. CLDN6 is a protein involved in cell production and differentiation and is expressed in various tumor types, including endometrial, ovarian, gastric cancers, GCT, and NSCLC. Its association with poor prognosis makes it a promising therapeutic target.
Future Directions
Daiichi Sankyo is continuing to enroll patients in the Phase 1 trial to determine the recommended dose for expansion and to further evaluate the potential of DS-9606 across different tumor types expressing CLDN6. "While these results provide preliminary proof-of-concept for DS-9606, further clinical evaluation is warranted across different tumor types that are known to express CLDN6," said Dr. Ken Takeshita, Global Head, R&D, Daiichi Sankyo.
