Novel Gastric Cancer Immunotherapy Scores Robust Phase II Results

Salah-Eddin Al-Batran, MD

A novel immunotherapy agent that targets claudin18.2 (CLDN18.2) reduced the risk of death or progression by approximately 50% when added to standard chemotherapy for patients with CLDN18.2-positive advanced gastric cancers during a phase II trial, raising the possibility of a new therapeutic in a tumor type with relatively few options.

IMAB362, a monoclonal antibody, improved median progression-free survival (PFS) by 3.1 months and median overall survival (OS) by 4.8 months when combined with a 3-drug chemotherapy regimen compared with chemotherapy alone in results of the FAST trial, presented at the 2016 ASCO Annual Meeting. The benefit was more pronounced among patients with high expression levels of CLDN18.2.

CLDN18.2 is a component of the tight junction protein, which is important for cell adhesion, integrity, and other tissue-specific functions, lead study author Salah-Eddin Al-Batran, MD, a medical oncologist and director at the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurt am Main, Germany, said during a press briefing at ASCO.

IMAB362, the first antibody developed to target CLDN18.2, attaches to the proteins on the surface of cancer cells to promote antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and, when combined with chemotherapy, immune modulation of the tumor microenvironment.

“The antibody is a classical immune therapy,” said Al-Batran.

CLDN18.2 is highly expressed in gastric cancers and is also present in multiple other tumor types including pancreatic, lung, esophageal, and ovarian cancers.

“This is an important study documenting activity of a first-in-class antibody in patients with advanced gastric and GE junction cancers,” said Smitha Krishnamurthi, MD, an ASCO spokeswoman who served as moderator for the press conference. She suggested that CLDN18.2 could emerge as a target in other malignancies.

In gastric cancer, half of all patients might be candidates for the treatment, said Al-Batran. He also noted in a press release the need for new therapies for the malignancy, which has a 5-year survival rate of 20% or lower for patients in the United States diagnosed with stage III disease, according to the American Cancer Society.

The FAST trial recruited patients with locally advanced or metastatic gastric, esophageal, or gastroesophageal junction cancers who had not received prior chemotherapy for advanced disease.

Participants were required to have CLDN18.2-positive tumors, defined as 2+/3+ intensity in ≥40% of tumor cells as measured by immunohistochemistry. Results were stratified by the level of positivity.

In all, 730 people were screened for the study but nearly half of those patients were excluded because they had either negative or low CLDN18.2 expression levels, Al-Batran said. Additional patients were excluded from the study because of inadequate tissue samples, not meeting other inclusion criteria, or baseline adverse events.

As a result, 246 patients have participated in the 3-arm trial. They were randomized to receive the combination of epirubicin (50 mg/m²), oxaliplatin (130 mg/m²), and capecitabine (625 mg/m² bid) with or without IMAB362 at a loading dose of 800 mg/m², followed by 600 mg/m². A third arm that tested a 1000 mg/m² dose of IMAB362 plus the chemotherapy regimen was added as the trial progressed but results missed ASCO’s abstract deadline, said Al-Batran.

Al-Batran reported results for patients in the chemotherapy-alone group (n = 84) and the lower-dose IMAB362 group (n = 77).

Among these patients, the median PFS was 4.8 months for the chemotherapy-alone group versus 7.9 months for the IMAB362 group (HR, 0.47; P = .0001) and the median OS was 8.4 months versus 13.2 months, respectively, (HR, 0.51; P = .0001).

The results were more dramatic among participants who were “high expressors” of CLDN18.2. Among these patients, those who received chemotherapy alone (n = 59) had a median PFS of 5.6 months compared with 7.2 months for those received the IMAB62 regimen (n = 57), and a median OS of 9 months versus 16.7 months, respectively. The hazard ratios for PFS and OS significance were 0.36 (P = .0005) and 0.45 (P <.0005), respectively, in favor of the IMAB62 regimen.

Although the benefit was higher among patients with greater CLDN18.2 expression, IMAB62 Al-Batran said lower expressors should not be ruled out as candidates for therapy.

“It’s a clearly targeted agent so we have to ensure that the target is there,” he said, but added that there would be other clinical trials for low expressors.

The objective response rate by RECIST criteria was 25% (21 of 84 patients) for the chemotherapy-alone group including 3 participants with a complete response (CR) and 18 people with a partial response (PR). For the IMAB62 arm reported in the ASCO results, the ORR was 39% (30 of 77 patients), with 8 CRs and 22 PRs.

In terms of adverse events (AEs), Al-Batran said IMAB62 had a manageable safety profile with the number of patients with grades 3/4 AEs in the single digits for most toxicities. He noted 2 areas in which AEs were higher in the IMAB62 arm compared with the chemotherapy-alone group: grade 3/4 neutropenia (32.5% vs 21.4%, respectively), and vomiting both for grade 1/2 events (55.8% vs 34.5%, respectively) and for grade 3/4 AEs (10.4% vs 3.6%, respectively).

Ganymed Pharmaceuticals AG, a privately held company based in Germany that is developing IMAG362, is planning a phase III trial to evaluate the drug in gastroesophageal cancer, according to the company’s website.

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 (GEJ) adenocarcinoma. J Clin Oncol. 2016;34(suppl; abstr LBA4001).

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