Final results of the FAST study, an international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma

Background

IMAB362, a chimeric monoclonal antibody that mediates specific killing of cancer cells expressing the tight junction protein Claudin18.2 (CLDN18.2) by activation of immune effector mechanisms, has demonstrated single-agent activity and tolerability in patients (pts) with heavily pretreated gastric cancer.

Methods

Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by immunohistochemistry (CLAUDETECT^® 18.2 Histology Kit). Eligible pts had a CLDN18.2 expression of ≥2+ in ≥40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m² and oxaliplatin 130 mg/m² d1, and capecitabine 625 mg/m² bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m², then 600 mg/m² d1, qd21). An exploratory arm (N = 85) was added to investigate a higher dose IMAB362 (1000 mg/m²) plus EOX. The primary study endpoint was PFS (Arm1 vs 2, 70% power, hazard ratio [HR] 0.72, 1-sided p = 0.1). Here we present the final study results.

Results

Of 686 biomarker-assessable pts, 334 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age 58 years; 80% gastric, 16% GEJ, 4% esophageal; 44% diffuse, 33% intestinal) were randomized into Arms 1 and 2. IMAB362 plus EOX improved PFS (median 4.8 vs 7.9 months; HR 0.47; 95% confidence interval [CI] 0.31–0.70, 1-sided p = 0.0001), OS (median 8.4 vs 13.2 months; HR 0.51, 95% CI 0.36–0.73, p = 0.0001) and ORR (28% vs 43%) compared to EOX. Common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTCAE grade 1 or 2. Grade 3/4 events were not significantly increased by IMAB362.

Conclusions

This final analysis confirms that addition of IMAB362 to first-line chemotherapy provides a clinically relevant benefit in patients with inoperable or recurrent gastric and GEJ cancer.

Clinical trial identification

ClinicalTrials.gov NCT01630083

Legal entity responsible for the study

Ganymed Pharmaceuticals AG

Funding

Ganymed Pharmaceuticals AG

Disclosure

M. Schuler: Corporate-sponsored research: BI, BMS, Novartis. Honoraria/Consultancy: Alexion, AstraZeneca, BI, BMC, Celgene, IQWig, GSK, Lilly, Novartis, Pfizer. Patents and employment: University Duisburg-Essen. S.–E. Al-Batran: Advisory role: Merck, Roche, Celgene, Lilly, Nordic Pharma. Speaker: Roche, Celgene, Lilly, Nordic Pharma. Research grants: Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly. F. Lordick: Research support: GSK, Fresenius Biotech. Lecture and Advisory honoraria: Amgen, Biontech, BMS, Eli Lilly, Ganymed, Merck-Serono, Merck-MSD, Nordic, Roche. Travel support: Amgen, Bayer, Roche, Taiho. C. Huber: Stock owner of Ganymed and of BioNTech shares. Member of Ganymed's and of BioNTech's supervisory board. Scientific Advisor of Ganymed, of BioNTech and of TRON. Executive board member of CI3-Cluster. Ö. Türeci: Stock ownership: Ganymed Pharmaceuticals AG. Advisory board: Ganymed Pharmaceuticals AG. Patents: Ganymed Pharmaceuticals AG, BioNTech Holding. Employment, leadership role: Ganymed Pharmaceuticals AG. U. Sahin: Stock ownership: BioNTech Holding Advisory Board: Ganymed Pharmaceuticals AG. Patents: Ganymed Pharmaceuticals AG, BioNTech Holding. Employment, leadership role: BioNTech Holding. All other authors have declared no conflicts of interest.