Novel MET Inhibitor Elicits 'Dramatic Response' in GI Cancer

Roxanne Nelson

January 19, 2015

SAN FRANCISCO — The results are preliminary, but a novel small-molecule MET inhibitor has shown promise in the treatment of MET-amplified gastroesophageal junction, gastric, and esophageal cancers.

In a small subset of patients with MET-amplified gastrointestinal (GI) tumors, monotherapy with the investigational agent AMG 337 (Amgen) produced a "dramatic" response, said lead author Eunice Kwak, MD, PhD, from Massachusetts General Hospital in Boston.

"All of the patients who achieved a response had some sort of MET abnormality in their tumors," said Dr Kwak, who presented the findings here at the 2015 Gastrointestinal Cancers Symposium. "This demonstrates that MET is an oncogenic driver in some of these cancers."

The MET signaling pathway is abnormal in a wide variety of cancers and stimulates cell growth, invasion, and metastasis and promotes resistance to apoptosis. Because of its ubiquitous role in cancer cells, MET is an attractive target for cancer therapies, she noted.

Of the 13 patients with MET-amplified gastric and esophageal cancers, eight experienced a response. "The overall response rate in this small group of patients was 62%," Dr Kwak reported. "Response was rapid, with time to response being 4 weeks in most cases."

"Patients achieved tumor shrinkage and symptomatic improvement," she explained. "In particular, there are a few patients who have been on study for 2 years or more."

One patient achieved a complete response and is still on treatment at 155 weeks; the others achieved partial responses or stable disease.

AMG 337 is a potent and highly selective inhibitor of wild-type and some mutant forms of MET. Preclinical trials showed an affinity for MET, which led to this first-in-human study. In a competitive binding assay conducted on 402 human kinases, AMG 337 bound only to MET, explained Dr Kwak.

In a cell viability study, the only cell lines that responded to an AMG 337 analog were gastric cancer cells harboring MET gene amplification. None of the other cell lines were sensitive to the AMG 337 analog and none harbored MET gene amplification. In secondary pharmacology assays with transporters, enzymes, ion channels, and receptors, binding to the adenosine transporter was the only activity inhibited.

The right biomarkers could change the current paradigm of small incremental improvements in survival, Dr Kwak pointed out. "In GI cancer, we have had a lot of phase 3 trials that have been successful but only modestly improved survival or progression-free survival."

"If we have robust biomarkers that tell us we have cancers that are driven by specific signals, it can change the way we think about treating patients, with the goal being that we can make huge — or at least larger — impacts on patient survival," she explained.

The impressive cytoreductive activity of AMG 337 was emphasized by Jaffer A. Ajani, MD, from the University of Texas M.D. Anderson Cancer Center in Houston. "Granted, it was only 13 patients, but in 13 patients, eight is a big number," he said. "We can say that the biomarker and the drug are good and this should really be pursued further."

However, he noted, there is always a risk for drug resistance. "We know from the literature and the clinic that resistance will emerge, and we should start planning to combine molecules," he said.

Phase 2 Trial Upcoming

The results Dr Kwak presented come from a larger study of AMG 337 in patients with solid tumors. About a quarter of the 90 patients (23.3%) in that trial had gastroesophageal junction, gastric, or esophageal tumors, and 19 (21.1%) had MET amplification.

The starting dose was 25 mg, with planned dose escalation of 50 to 500 mg once a day and 100 to 200 mg twice a day. Patients with MET overexpression, amplification, or mutation were permitted to escalate to the highest dose deemed safe at any time.

The most common treatment-emergent adverse events (in more than 20% of all patients) were headache, nausea, fatigue, vomiting, and constipation.

"The most common dose-limiting grade 3 event was headache, which caffeine seems to help," Dr Kwak said. "A cup of coffee was part of the management strategy we used for patients who had headache."

The daily maximum tolerated dose is 300 mg; the maximum tolerated twice-daily dose has not been reached. In a dose-expansion phase of the trial, up to 50 patients with MET-amplified tumors will be treated with the maximum tolerated dose. A phase 2 trial for patients with solid MET-amplified tumors is currently enrolling patients.

The study was funded by Amgen. Dr Kwak reports receiving research funding from Amgen. Several of her coauthors report financial relationships, including employment, with Amgen and other companies.

2015 Gastrointestinal Cancers Symposium (GICS): Abstract 1. Presented January 15, 2015.

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