A novel immunotherapy agent, the first in its class, reduced disease progression by more than 50% when added to standard chemotherapy for patients with advanced gastric cancer, according to results from an international phase II trial presented at the 2016 ASCO Annual Meeting.¹ The drug, IMAB362, is a chimeric IgG1 backbone antibody that targets claudin18.2 (CLDN18.2), a component of tight junction protein that is important for cell adhesion, integrity, and other tissue-specific functions.

The antibody [IMAB362] is a classic immune therapy. The benefit was most pronounced in the group of high expressers, those with CLDN18.2 staining in ≥ 70% of tumor cells.

— Salah-Eddin Al-Batran, MD

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“The antibody is a novel immune therapy,” said lead author Salah-Eddin Al-Batran, MD, of the Institute of Clinical Cancer Research at the Nordwest Hospital in Frankfurt am Main in Germany.

The IMAB362/chemotherapy regimen promotes antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and immune modulation of the tumor micro­environment.

In the phase II FAST trial, when given along with epirubicin, oxaliplatin, and capecitabine (EOX), IMAB362 improved median progression-free survival by 3.1 months and median overall survival by 4.8 months vs EOX alone. The benefit was more pronounced among patients with high expression of CLDN18.2, whose median overall survival approached 17 months—nearly double that of the control arm of 9 months, reported Dr. Al-Batran.

Because CLDN18.2 is expressed in more than 50% of gastric tumors, the potential benefit of this agent in gastric cancers is great, Dr. Al-Batran added. CLDN18.2 is also present in other tumors, especially bile duct, pancreatic, lung, esophageal, and ovarian cancers. It does not appear to be expressed in healthy tissues, except for stomach mucosa.

FAST Details

The FAST trial enrolled 246 patients with locally advanced or metastatic gastric, esophageal, or gastroesophageal junction cancers who had not received prior chemotherapy for advanced disease. Patients were required to have CLDN18.2-positive tumors (2+/3+ intensity in ≥ 40% of tumor cells by immunohistochemistry). Eighty percent had stomach cancer, mostly the diffuse histologic type.

Patients were randomized to receive EOX (epirubicin at 50 mg/m², oxaliplatin at 130 mg/m², capecitabine at 625 mg/ m² twice daily) with IMAB362 (n = 77) or without IMAB362 (n = 84) at a loading dose of 800 mg/m² followed by 600 mg/m². Patients had the option of maintenance IMAB362, and 39% chose it.

One year after initiation, the investigators opened a third arm to test 1,000 mg/m² of IMAB362 plus chemotherapy (n = 85) “as an exploratory arm,” but these results were presented only briefly at the 2016 ASCO Annual Meeting.

There were no differences in exposure to chemotherapy between the arms. The mean number of IMAB362 cycles was 11.

Survival Improved

“The trial met its primary endpoint, with clearly a significant increase in progression-free survival and a significant improvement in overall survival, also,” Dr. Al-Batran reported.

Median progression-free survival was 4.8 months with EOX and 7.9 months with EOX plus IMAB362 (hazard ratio [HR] = 0.47; P = .0001). Median overall survival was 8.4 months vs 13.2 months, respectively (HR = 0.51; P = .0001). “The curves separated early and this was maintained,” he observed.

“Importantly, the benefit was most pronounced in the group of high expressers, those with CLDN18.2 staining in ≥ 70% of tumor cells,” noted Dr. Al-Batran. In this group, median progression-free survival was 5.6 months vs 7.2 months (HR = 0.36; P < .0005), and median overall survival was 9.0 months vs 16.7 months (HR = 0.45; P < .0005). The response rate was 25% with EOX and 39% with the combination, including complete response rates of 3.6% and 10.4%, respectively.

Toxicity

The most common adverse event with the combination was vomiting; grade 1/2 vomiting was observed in 55.8% of this arm, and grade 3/4 vomiting was seen in 10.4%, compared with 34.5% and 3.6%, respectively, with EOX alone. Dr. Al-Batran suggested that the vomiting seen with the antibody could stem from the presence of CLDN18.2 expression in the stomach.

Anemia grade 1/2 occurred in 37.7% and anemia grade 3/4 occurred in 11.7% with the combination, vs 38.6% and 7.1%, respectively, with EOX alone. Grade 3/4 neutropenia occurred in 32.5% of the combination arm and 21.4% of the EOX arm.

“FAST provides a strong rationale for a confirmatory phase III trial,” Dr. Al-Batran said. This trial is set to launch early in 2017. The drug will also be evaluated in pancreatic cancer. ■

Disclosure: The study was sponsored by Ganymed Pharmaceuticals AG, Mainz/Germany. Dr. Al-Batran has consulted for Celgene, Lilly, Merck, and Roche; been on the speakers bureau for Celgene, Nordic Bioscience, and Roche; and received research funding from Celgene, Hospira, Lilly, Medac Pharma, Novartis, Roche Pharma AG, and Vifor Pharma.

Reference

1. Al-Batran SE, Schuler MH, Zvirbule Z, et al: 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 adenocarcinoma. 2016 ASCO Annual Meeting. Abstract LBA4001. Presented June 3, 2016.