Responses with crizotinib in MET-amplified lung cancer show new targetable form of disease

May 31, 2014

A study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014 reports the results of a first-in-human, phase 1 dose escalation trial of crizotinib (XALKORI) in 14 patients with advanced, MET-amplified non-small cell lung cancer (NCT00585195).

In 2011, the drug crizotinib earned accelerated approval by the US FDA to target the subset of advanced non-small cell lung cancers caused by rearrangements of the anaplastic lymphoma kinase (ALK) gene, and subsequently was granted regular approval in 2013. The drug also has shown dramatic responses in patients whose lung cancers harbored a different molecular abnormality, namely ROS1 gene rearrangements. Previously unreported phase 1 clinical trial results now show that crizotinib may have a third important molecular target. In advanced non-small cell patients with intermediate and high amplifications of the MET gene, crizotinib produced either disease stabilization or tumor response. Sixty-seven percent of patients with high MET amplification showed prolonged response to the drug, which lasted from approximately 6 months to nearly 2.5 years.

"Though more patients are needed to really pin down the exact MET criteria that will predict benefit from MET inhibition, we're hopeful this line of research will define yet another key molecular subtype of lung cancer sensitive to a targeted drug," says Ross Camidge, MD, PhD, director of the thoracic oncology clinical program at the University of Colorado Cancer Center and the study's lead author.

Crizotinib showed early activity against MET-dependent cells in preclinical laboratory studies, and the phase I clinical trial design included plans for treatment of cancer patients preselected for evidence of MET activation once the recommended dose was determined.

Matching the drug to MET amplifications required testing for this genetic abnormality in patient tumors, something that hasn't been part of standard lung cancer screening in most clinical centers. Working at the CU Cancer Center, Marileila Garcia, PhD, was able to rapidly deploy an assay for MET for the trial based on fluorescent in situ hybridization (FISH).

Garcia's previous work, also shown for the first time in this presentation, gives insight into the frequency of MET amplification in lung cancer. Consistent with other reports, Garcia found some degree of MET amplification present in 7.4 percent of 800 consecutive samples of non-small cell lung cancer tested at the Colorado Molecular Correlates Lab from 2009 to 2012. However, the level of MET amplification in these samples was not uniform. Low MET amplification (MET/CEP7 ratio of ≥1.8–≤2.2) was present in 3.8 percent, intermediate amplification (MET/CEP7 ratio of >2.2–<5.0) was present in 3 percent, and high amplification (MET/CEP7 ratio of >2.2–<5.0) was present in 0.8 percent.

In the phase 1 clinical trial, while disease in the 2 patients with low MET amplification did not appear to benefit from the drug, 1 of 6 patients with intermediate MET amplification achieved a partial response with 4 of the 6 having more minor responses (stable disease), and in the high MET amplified group 1 of 6 achieved a complete response, 3 of 6 achieved a partial response and 1 of the 6 had a minor response (stable disease). Overall objective response rates in the low, intermediate and high MET amplified cohorts were 0, 17 and 67%, respectively.

"We've been through a similar experience with ALK-positive lung cancers – patients whose cancers depend on a specific molecular abnormality can see significant benefit when we remove the cancer's access to the driving abnormality," Camidge says. "However, unlike classical activating mutations or gene rearrangements, MET is likely to be a more challenging biomarker because it is not simply black or white – not simply off or on – but rather it is a continuous variable. Although the dataset is still pretty small, there is a strong suggestion that a definable cut-point in MET amplification exists which could really delineate who will or will not benefit from this drug. Screening for MET and treating these patients in clinical trials is the only way we will be able to discover this important threshold."

The implications of crizotinib used to target MET amplifications may go beyond non-small cell lung cancer. The gene is activated in many different ways in many different cancers, and patients with MET-amplified cancers continue to enroll in the crizotinib phase I study.

"With these targeted therapies, it can look at first like a drug may only be useful to a small percentage of patients with the targeted genetic abnormality. But then you start to see the same abnormality across cancer types and the drug that looked like it might have been useful in, say, 3 percent of lung cancer , turns out to have a use in x-percent of all these other cancer types as well. It's a new paradigm: we're working to pick off these molecular aberrations one by one," Camidge says.

Explore further: ALK rearrangement found in nearly 10 percent of patients in Lung Cancer Mutation Consortium

Related Stories

ALK rearrangement found in nearly 10 percent of patients in Lung Cancer Mutation Consortium

July 5, 2011
ALK rearrangement has been found in 9.6% of lung cancer patients tested in the Lung Cancer Mutation Consortium, and MET amplification in another 4.1%, reflecting how many patients might benefit from targeted therapies such ...

Crizotinib reduces tumor size in patients with ALK positive lung cancer

September 6, 2012
Crizotinib is effective in shrinking tumors in patients with anaplastic lymphoma receptor tyrosine kinase (ALK) positive non-small cell lung cancer, a cancer commonly found in people who never smoked, and should be the standard ...

Benefit of targeted lung cancer therapy confirmed

June 3, 2011
A drug that targets a specific type of lung cancer shows a dramatic response in more than half of the people who take it. The drug, called crizotinib, has been in clinical trials since 2006, and the results from the largest ...

Phase III trial shows crizotinib superior to single-agent chemotherapy for ALK-positive lung cancer

September 30, 2012
The results of a new phase III trial show that crizotinib, a targeted therapy, is a more effective treatment than standard chemotherapy for patients with advanced, ALK-positive lung cancer, researchers said at the ESMO 2012 ...

With early, obvious benefit of a targeted cancer drug, should expensive clinical testing continue?

August 8, 2013
Generally, FDA-approved clinical trials progress through three phases: the first shows safety, the second starts to explore effects and the third seeks to prove a drug's superiority over existing treatments. But when a drug's ...

Some patients with treatment-resistant colorectal cancers may have a new option

June 2, 2013
A subset of colorectal cancers responds to anti-epidermal growth factor receptor (anti-EGFR) therapies, but develops resistance within months. Among cancers that develop resistance to anti-EGFR therapy, some showed overexpression ...

Recommended for you

Vitamin C may encourage blood cancer stem cells to die

August 17, 2017
Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

Outdoor light at night linked with increased breast cancer risk in women

August 17, 2017
Women who live in areas with higher levels of outdoor light at night may be at higher risk for breast cancer than those living in areas with lower levels, according to a large long-term study from Harvard T.H. Chan School ...

Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

August 16, 2017
In a bid to detect cancers early and in a noninvasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.