SAN FRANCISCO – An investigational kinase inhibitor that blocks the MET signaling pathway is highly active and well tolerated in patients with gastric and related cancers that have amplification of the MET gene, according to a trial a reported at the annual Gastrointestinal Cancers Symposium.
Nearly two-thirds of such patients in the open-label phase 1 trial had a response to AMG 337, an oral, potent, and highly selective inhibitor of c-Met, reported lead investigator Dr. Eunice L. Kwak, a medical oncologist at the Massachusetts General Hospital, Boston.
“Dramatic responses to AMG 337 were observed in a subset of patients with MET-amplified esophagogastric cancers. This demonstrates that MET amplification is an oncogenic driver in some of these cancers,” she contended at the meeting, cosponsored by the AGA Institute, the American Society of Clinical Oncology, ASTRO, and the Society of Surgical Oncology .
The dose-limiting toxicity was headache, seen at any grade in half of the entire trial population and at grade 3 or 4 in about one-tenth. “This is an interesting toxicity thought to occur because of AMG’s binding of the adenosine transporter,” Dr. Kwak noted. “Interestingly, caffeine seems to ameliorate the headaches that people experience on this trial. A cup of coffee is part of the management strategy that we use for patients who get headaches while being treated.”
In an interview, session chair Dr. Peter C. Enzinger, who is director of the Center for Esophageal and Gastric Cancer at the associated Dana-Farber Cancer Institute but did not participate in the trial, said, “Certainly, these data suggest that there are a subgroup of patients that can respond to MET inhibition. [The investigators] have used amplification, and perhaps it is that group of patients that should be considered further for this type of therapy.”
“The problem is that unfortunately, not the majority of [unselected] patients respond to this type of therapy, and until we can better select patients or find better MET inhibitors, this drug is probably going to have difficulty having a positive result in a randomized, phase III study,” he added. “It will also be pretty difficult if we are only treating patients who have amplifications to find enough patients to do a large-scale study.”
Dr. Kwak and her coinvestigators enrolled 90 adults with a variety of advanced solid cancers in the Amgen-sponsored trial. The median number of prior therapies was two.
The patients were treated according to a dose-escalation scheme with AMG 337 until progression or unacceptable toxicity, or were enrolled as part of an expansion cohort that required MET-amplified cancers (established by fluorescence in situ hybridization or next-generation sequencing) and entailed treatment with the maximum tolerated dose of 300 mg daily.
Results showed that among all 90 patients, the rate of grade 3 or 4 adverse events was 21%. The most common was headache, seen in 8%.
Just 11% of patients overall had a response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria; of note, all had tumors showing either MET amplification or MET overexpression.
Among the 13 patients who had gastric, esophageal, or gastroesophageal junction cancers with MET amplification, the response rate was 62%.