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

Abstract

LBA4001 Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 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). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX, (not subject here). The primary study endpoint was PFS (Arm 1 v 2, 70% power, HR 0.72, 1-sided p = 0.1). Results: 730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. The study met its endpoints. IMAB362 plus EOX improved PFS (median 5.7 v 7.9 mon; HR 0.5; 95% CI 0.35–0.78, 1-sided p = 0.001) and OS (median 8.7 v 12.5 mon; HR 0.5, 95% CI 0.28–0.73) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression ( ≥ 2+ intensity in ≥ 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362. Conclusions: IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile. Clinical trial information: NCT01630083.

Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer

“…Patients with CLDN18.2 expression of ≥2+ in ≥40% tumor cells (as validated by CLAUDETECT™ 18.2 Kit), Eastern Cooperative Oncology Group performance status of 0–1 and who were not eligible for trastuzumab were included in the study [27, 28]. Seven hundred thirty-nine patients were consented and 352 (48%) were tested CLDN18.2+ per protocol criteria.…”

“…Of note, only 48% of the patients in the FAST study were considered positive for CLDN18.2 [28]. The biomarker’s presence in tumor specimens was determined by CLAUDETECT™ 18.2, a pathology test developed by Ganymed (now acquired by Astellas), the drug maker and sponsor of the trial.…”

Recent advances in the management of gastric adenocarcinoma patients

“…IMAB362, an inhibitor of CLDN18.2, was assessed in clinical trials. In a randomized phase II trial, IMAB362 plus epirubicin, oxaliplatin, and capecitabine (EOX) significantly prolonged PFS (median 5.7 versus 7.9 months, HR 0.5, 95% CI 0.35–0.78) 78 . Moreover, the benefit of IMAB362 was more pronounced in the patients with CLDN18.2 high-expression (70% labeling index) GAC (PFS 6.1 versus 9.1 months, HR 0.46; OS 9.3 versus 16.6 months, HR 0.44) 78 .…”

Medical management of gastric cancer: a 2017 update

“…The phase 3 CHECKMATE‐577 trial will assess nivolumab administration as an adjuvant therapy for patients who have undergone surgery . A novel immunotherapy agent, the first in its class, reduced disease progression by more than 50% in 246 patients when added to standard chemotherapy with EOX in patients with advanced gastric cancer, in accordance with the results from the international phase 2 FAST trial . The drug, IMAB362, is a chimeric IgG1 backbone antibody that targets claudin18.2 (CLDN18.2), which is a component of tight junction protein crucial for cell adhesion, integrity, and other tissue‐specific functions.…”