CHICAGO (FRONTLINE MEDICAL NEWS) The novel antibody IMAB362 extended survival of patients with advanced gastric cancer when added to chemotherapy, according to a phase II trial presented at the annual meeting of the Society of Clinical Oncology.

IMAB362 is a first-in-class monoclonal antibody targeting claudin18.2, a protein component of cellular tight junctions abundant in gastric tumors, as well as tumors of the pancreas, lung, esophagus, and ovaries.

IMAB362 significantly extended median overall survival (OS) when added to standard chemotherapy (13.2 vs. 8.4 months, hazard ratio [HR] = 0.51, P = .0001). Patients with the highest levels of claudin18.2 had an even longer median overall survival (16.7 vs. 9.0 months, HR = 0.45, P less than .0005).

The FAST (Phase II First-Line Therapy in Patients With Advanced CLDN18.2+ Gastric and Gastroesophageal Junction Adenocarcinoma) trial included patients who had no prior chemotherapy for locally advanced or metastatic disease. Tumors had to have 2+/3+ CLDN18.2 expression in 40% or more of tumor cells, and patients had an Eastern Cooperative Oncology Group performance status of 0-1.

Patients with tumors that expressed higher levels of claudin18,2, the target antigen, did better than the overall cohort in terms of progression-free survival (PFS), the primary endpoint.

“The FAST trial clearly met its primary endpoint, and there is a significant improvement in PFS and OS in the entire cohort and also in the higher expressers,” lead author Dr. Salah-Eddin Al-Batran, medical director of the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurst am Main, Germany, said in a news conference at the meeting.

The IMAB362 monoclonal antibody is highly specific for CLDN18.2 and works through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In combination with chemotherapy, by binding to tumor debris, it is an immunomodulator of the tumor microenvironment.

About 50% of gastric tumors express CLDN18.2. After screening, the investigators randomized 246 patients to three treatment arms: epirubicin/oxaliplatin/capecitabine (EOX), n = 84; EOX + IMAB362 at a loading dose of 800 mg/m2, then 600 mg/m2 on day 1 every 3 weeks, n = 77; or a higher dose of IMAB362 with EOX, n = 85. Dr. Al-Batran reported results of the first two arms and will present results for the third arm at a later time.

Median progression-free survival was 4.8 months with EOX and 7.9 months with EOX plus IMAB362 (HR = .47; P = .0001).

If 70% or more of the tumor cells expressed CLDN18.2, IMAB362 improved the median PFS from 5.6 months for EOX alone to 7.2 months (HR = 0.36, P less than .0005), and OS improved from 9 months to 16.7 months (HR = 0.45, P less than .0005).

Response rates were also better with the addition of IMAB362. The objective response rate by RECIST criteria was 39.0% with EOX + IMAB362 vs. 25.0% with EOX alone. Most of the responses were partial (28.6% vs. 21.4%, respectively) or stable disease (44.2% vs. 51.2%, respectively). There were only 10.4% complete responses with IMAB362 and 3.6% with EOX alone. About 12% of the patients in each arm were not evaluable, or the data were missing.

Both treatments were well tolerated, with most adverse effects being grade 1/2. However, there was more grade 3/4 neutropenia with the combination (32.5% vs. 21.4% for EOX alone) as well as grade 3/4 vomiting (10.4% vs. 3.6%, respectively). Grade 1/2 vomiting was common in both arms, with about one-third of patients receiving EOX alone and just over half of patients on EOX + IMAB362 being affected.

Dr. Al-Batran said that there may have been more vomiting with IMAB362 because tight junction proteins, including claudin, are present in the gastric mucosa. Diarrhea was largely grade 1/2, affected about one-third of patients receiving EOX alone, and was only about half as common among patients receiving the combination.

Dr. Al-Batran said this trial “provides a strong rationale for a confirmatory phase III trial.”

Press conference moderator Dr. Smitha Krishnamurthi said the study is important because it documents the activity of a first-in-class antibody in patients with advanced gastric and gastroesophageal junction cancers. Since CLDN18.2 is expressed in about 50% of these cancers, “this treatment could apply to many patients,” she said.

The study was initiated and sponsored by Ganymed Pharmaceuticals. Dr. Al-Batran has had a consulting or advisory role with Merck, Roche, Celgene, and Lilly; has been on the speakers bureau of Lilly, Roche, Celgene, and Nordic Bioscience; and has received research funding from Celgene, Roche Pharma, Lilly, Novartis, Vfor Pharma, Medac, and Hospira.

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