MET Inhibition Shows Some Promise in Advanced Gastroesophageal Cancer

Published: Friday, Jan 16, 2015

Eunice L. Kwak, MD, PhD

Patients with advanced, MET-amplified gastroesophageal cancer had a high likelihood of response to an investigational MET inhibitor, results from a preliminary, dose-escalation trial suggested.

An overall analysis showed no significant effect of AMG-337 in patients with advanced gastroesophageal junction, gastric, and gastroesophageal cancer. However, a subgroup analysis of 13 patients with MET overexpression showed that eight had objective responses, which were dramatic and sustained in some instances.

The results have provided the basis for a prospective clinical investigation of AMG-337 MET-amplified gastroesophageal cancers, according to an abstract presented at the 2015 Gastrointestinal Cancers Symposium in San Francisco.

“We observed dramatic responses to AMG-337 in a subset of patients with MET-amplified gastroesophageal junction, gastric, or esophageal cancer,” Eunice L. Kwak, MD, PhD, a gastrointestinal cancers specialist at Massachusetts General Hospital in Boston. “The most common adverse treatment-related adverse events were headache, nausea, vomiting, and fatigue.”

MET activation has a key role in multiple types of cancer. Activation can involve several factors and potential mechanisms, including ligand binding, overexpression and amplification of the gene, activating mutations, and crosstalk with several other oncogenic signaling pathways.

MET activation can initiate or contribute to multiple activities that are characteristic of cancer development and progression: proliferation, survival, motility, migration, and invasion. Laboratory and clinical studies have provided evidence that MET overexpression is associated with worse outcomes in gastroesophageal cancers.

Prior laboratory studies demonstrated that AMG-337 selectively and potently inhibits MET. A competitive-binding study involving 402 human kinases showed that AMG-337 bound only to MET. Secondary pharmacology assays showed that AMG-337 specifically inhibited the adenosine transporter, but not other enzymes, transporters, ion channels, or receptors. Other studies showed that two MET-amplified cell lines were highly sensitive to AMG-337, whereas examination of the small-molecule inhibitor in cell lines that did not exhibit MET amplification showed no sensitivity to AMG-337.

The accumulation of basic and clinical evidence led to a multicenter, phase I dose escalation trial of AMG-337. Kwak reported findings from the multicenter, open-label study of AMG-337 monotherapy in patients with various types of advanced solid tumors. The study protocol required confirmation of MET expression status by a central or experienced laboratory. MET analyses including amplification by fluorescence in situ hybridization (FISH), amplification by next-generation sequencing (NGS), and overexpression by immunohistochemistry (IHC).

During two dose-escalation phases (one involving once-daily dosing and the other twice-daily dosing), investigators enrolled cohorts comprised of from three to nine participants, testing AMG-337 doses of 25 to 400 mg once daily and 100 mg to 250 mg twice-daily doses. Treatment continued until disease progression.

Investigators enrolled a total of 90 patients with various types of tumors, included 21 patients with gastroesophageal junction (GEJ), gastric, or esophageal cancer and 18 with colorectal cancer. The patients had received a median of two prior therapies, and MET amplification was confirmed in 19 patients.

The primary objectives of the trial were safety/tolerability, pharmacokinetics, and maximum tolerated dose. The secondary objective was response to AMG-337, as determined by RECIST criteria. As an exploratory analysis, investigators evaluated correlations between MET amplification and tumor response to AMG-337.

The most frequently reported adverse events (all grades) were headache (52.2%), nausea (33.3%), vomiting (17.9%), fatigue (13.3%), dry skin (12.2%), peripheral edema (12.2%), and hypoalbuminemia (11.1%). Grade ≥3 adverse events consisted of headache (7.8%), fatigue (3.3%), hypoalbuminemia (1.1%), and rash (1.1%).

Six of the eight patients who met RECIST criteria for tumor response had ≥50% tumor shrinkage. The shrinkage was dramatic and persistent in some cases.

Kwak discussed the case of a 63-year-old man with MET-amplified cancer of the gastroesophageal junction. Tumor volume decreased by more than 90% after 33 weeks on treatment, and the response was ongoing at 105 weeks.

On the basis of the results, evaluation of AMG-337 will continue in a dose-expansion study limited to patients with MET-dependent tumors, said Kwak. The trial has an accrual target of 50 patients.

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