Response to Xalkori Linked to MET Gene Amplification in NSCLC

A new study has identified a small group of patients with non-small cell lung cancer (NSCLC) who may benefit from the kinase inhibitor Xalkori (crizotinib).

The report, published in the Journal of Thoracic Oncology, finds patients with high-level amplification of the gene METare more likely than those with lower levels of amplification to respond to the therapy. The findings come in the form of a subanalysis of the PROFILE 1001 trial, which examined the drug’s effectiveness in patients with advanced NSCLC and certain genetic characteristics.

Corresponding author D. Ross Camidge, M.D., Ph.D., of the University of Colorado Cancer Center, told Managed Healthcare Executive®that the idea that METmight play an important role in some cancers is not new.

D. Ross Camidge

“Activation of MET has been noted to drive aspects of multiple different cancers in preclinical models,” he said. “The challenge was to identify why it worked in this or that model, or more specifically, why it might work in this or that patient.”

Xalkori was approved as an anaplastic lymphoma kinase (ALK) and ROS1 inhibitor, but Camidge said it was primarily developed to be a METinhibitor, so MET has always been on the radar of investigators and the drug’s developers. Earlier research suggested Xalkori is more effective in patients with MET exon 14 skip mutations, but Camidge and colleagues believed METamplification might also be a potent biomarker. The challenge, he said, is that unlike genetic mutations, amplification is not a binary “yes” or “no,” but a continuous variable. Thus, the question became: How should investigators define “amplification”?

“If you set the bar low, there are more cases, but less activity,” Camidge said. “If you set the bar high, there are fewer cases, but more activity in those cases.”

In the study, the investigators categorized patients into 3 MET amplification groups, based on the ratio of MET to CEP7 as determined by local fluorescence in situ hybridization (FISH) testing. Those with an MET to CEP7 ratio of greater than four were considered “high” amplification. Those with a ratio between 2.2 and 4 were placed in the “medium” category. Those with ratios from 1.8 to 2.2 were listed as “low.”

A total of 38 patients who fit into one of those three categories were analyzed and treated with Xalkori a dose of 250 mg twice daily. Most of the patients (21), had high amplification, 14 had medium amplification, and three had low amplification.

The high amplification group had the highest objective response rate (38.1%), compared to 14.3% among the medium amplification group. One of the three patients in the low group also achieved an objective response. The median duration of response was 5.2 months for the high amplification group, 3.8 months for the medium amplification group, and 12.2 months for the single responder in the low amplification group. Median progression-free survival was 6.7 months, 1.9 months, and 1.8 months in the high, medium, and low amplification groups, respectively.

“In this study, we showed that the level (of METamplification) really does matter,” Camidge said, adding that estimates suggest about 1% of lung cancers would fit into the high amplification category, most commonly older patients or those with a history of smoking.

A subset of 19 archived patient tumor samples were analyzed by next-generation sequencing and 15 of those were found to have a METamplification gene copy number of at least 6. Among those patients, 6 had objective responses, of whom 2 also had MET exon 14 alterations. None of the 5 patients who had concurrent KRAS, BRAF, or EGFRmutations experienced a response to the therapy.

Camidge said the findings suggest that for a small subset of patients, MET amplification alone is the driver of their cancer. If such patients can be identified, Xalkori could offer new hope of an effective treatment. Yet, Camidge said identifying those patients can be challenging. Next-generation sequencing is widely available, but he said it will not identify all responders, and is also hampered by the fact that different companies quantify amplification in different ways. FISH, which was used to quantify amplification in this study, is less widely used, but Camidge said it also will not be able to detect all responders.

“The headline for me is neither technique is perfect,” he said. That means METamplification testing can be a worthwhile option if there are no other identified driver oncogenes in a particular case. However, Camidge said in the future, investigators ought to try to better clarify what makes particular patients benefit most, “for example, showing that there is no other driver mutation or that high levels of MET are indeed being produced.”

Jared Kaltwasser, a regular contributor to Managed Healthcare Executive®, is a freelance writer in Iowa.