IMAB362, a novel chimeric IgG1 backbone antibody highly specific for CLDN18.2, extended median overall survival by 4.8 months when added to standard chemotherapy in patients with advanced gastric cancer.
Salah-Eddin Al-Batron, MD
IMAB362, a novel chimeric IgG1 backbone antibody highly specific for CLDN18.2, extended median overall survival (OS) by 4.8 months when added to standard chemotherapy in patients with advanced gastric cancer, according to findings presented at the 2016 World Congress on Gastrointestinal (GI).
In the phase II study, median OS was 13.2 versus 8.4 months, with IMAB362 and without, respectively (HR, 0.51;P= .0001). The magnitude of response seen with IMAB362 was proportional to the expression level of CLDN18.2, which is a splice variant of the claudin-18 protein. Patients with the highest levels of CLDN18.2 staining (IHC 2+/3+) had a median OS of 16.7 with IMAB362 versus 9.0 months with chemotherapy alone (HR, 0.45 (P<.0005).
“CLDN18.2 is expressed in pancreatic, lung, esophageal, and ovarian cancers but is most abundant in gastric tumors; we estimate that half of all patients with advanced gastric cancer may be candidates for this new treatment,” noted principal investigator Salah-Eddin Al-Batran, MD, medical oncologist and Director at the Institute of Clinical Cancer Research at Nordwest Hospital in Frankurt, Germany. “In combination with chemotherapy, IMAB362 enhances T-cell infiltration and induces pro-inflammatory cytokines.”
CLDN18.2 belongs to the claudin family of proteins that are major structural components of tight junctions, which control the flow of molecules between cells and become disrupted in tumors. IMAB362 attaches to CLDN18.2 on the tumor cell surface to stimulate cellular and soluble immune effectors that activate antibody dependent cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
The phase II study, also known as the FAST trial, enrolled 246 patients with advanced or recurrent gastric or gastroesophageal junction cancer that had tumors expressing CLDN18.2. Only patients that had not received prior therapy for metastatic cancer were eligible. Patients were randomized to IMAB362 at 800 or 600 mg/m2(arm 2) or 1000 mg/m2(arm 3) plus standard chemotherapy comprising epirubicin, oxaliplatin, and capecitabine or to the same chemotherapy alone. Comparisons were made between arm 2 and chemotherapy, which together contained 161 patients.
The study met its primary endpoint, which was progression-free survival (PFS). Median PFS was 7.9 months with IMAB362 versus 4.8 months with chemotherapy (HR, 0.47;P= .0001). In patients with tumors that had high expression of CLDN18.2, median PFS was 7.2 versus 5.6 months, for IMAB362 and chemotherapy, respectively (HR, 0.36;P= .0005).
The objective response rate by RESIST was 39% with IMAB362 compared with 25% with chemotherapy. In the IMAB362 cohort, 8 patients (10.4%) achieved a complete response (CR), 22 patients (28.6%) had a partial response (PR), and 34 patients (44.2%) had stable disease (SD). With chemotherapy, 3 patients (3.6%) achieved a CR, 18 (21.4%) had a PR, and 43 (51.2%) had SD. Disease progression was experienced by 5.2% and 11.9% of patients receiving IMAB362 versus chemotherapy, respectively.
The authors stated that the treatment was well tolerated but noted increased vomiting in patients receiving IMAB362. Overall, 55.8% of patients in the investigational cohort showed grades 1/2 vomiting and 10.4% had grades 3/4 events compared with the chemotherapy arm, wherein 34.5% of patients had grades 1/2 vomiting and 3.6% had grades 3/4 events.
Vomiting experienced by patients was proportional to the dose of IMAB362 administered. Overall, vomiting was reported in 60% to 69% of patients receiving medium and experimental doses of IMAB362 compared with <40% of patients on chemotherapy alone. This adverse event may be tied directly to the mechanism of action, postulated Al-Batran.
“The incidence and severity of vomiting was dose dependent,” he said. “CLDN18.2 is a unique target that is not present in any healthy tissues except the mucosal lining of the stomach.”
A phase III study is planned for launch in early 2017. The researchers are also planning a phase II study of IMAB362 in patients with pancreatic cancer.
“The chemotherapy used in FAST was appropriate at the time but an alternative and less emetogenic chemotherapy backbone such as FOLFOX will be taken through to the phase III trial,” noted discussant Florian Loedick, MD, PhD, University Cancer Center Leizpig, University Medicine Leipzig, Leipzig, Germany.