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Researchers Seek Best Approach to Identify Lung Cancer Patients With MET-Based Resistance

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NEW YORK (GenomeWeb) – While researchers are developing a combination treatment approach for some lung cancer patients who have developed MET-based drug resistance, there's not yet a gold standard for identifying people who harbor resistance-inducing MET amplifications.

The US Food and Drug Administration approved AstraZeneca's Tagrisso (osimertinib) last year as a first-line treatment for patients with metastatic non-small cell lung cancers containing EGFR mutations.

But some patients develop resistance to the treatment. Up to 10 percent of patients with EGFR-mutated NSCLC who progressed on first- or second-generation EGFR TKIs and up to a quarter of those who progressed on the third-generation EGFR TKI osimertinib have MET-amplification or other MET-based resistance mechanisms.

At the American Association for Cancer Research annual meeting held in Atlanta earlier this month, researchers from the Phase Ib TATTON study presented results indicating that a combined therapy of osimertinib and the MET inhibitor savolitinib, also from AstraZeneca, could lead to treatment response in some EGFR-positive lung cancer patients who developed MET-based resistance. But they also noted that there are different approaches to detect MET-based resistance, each of which identifies a slightly different group of patients.

"Not all of the tests necessarily find the same patients to be positive," Lecia Sequist, an associate professor at Harvard Medical School, who presented the TATTON study results at AACR, said in an interview afterward.

In TATTON, Sequist and her colleagues examined the safety and tolerability of combining osimertinib and savolitinib treatment in two cohorts of EGFR mutation-positive NSCLC patients who developed MET mutations: one group that progressed on first- or second-generation EGFR TKIs and one that progressed on the third-generation EGFR TKI osimertinib.

In the study, MET status was gauged by either fluorescence in situ hybridization, next-generation sequencing, or immunohistochemistry. When they could, based on tissue availability or quality, the researchers centrally confirmed MET status using FISH.

Based on this, Sequist reported at the meeting that, in the first cohort of patients, treatment with osimertinib together with savolitinib resulted in an objective response rate of 52 percent and a median duration of response of 7.1 months, while in the second cohort, osimertinib plus savolitinib led to an objective response rate of 28 percent and a median duration of response of 9.7 months.

"It's impressive early data," Yale University's Roy Herbst said in an AACR discussion presentation, noting that randomized trials are needed to confirm the results.

However, Herbst added that an established way to gauge MER amplification is needed. "The question is, how do you measure this? By FISH, by immunochemistry, by next-generation sequencing? And that, I think, is something that the authors grappled with as well," he said.

MET amplification status can be trickier to determine than a typical mutated oncogene, said Dana-Farber Cancer Institute's Geoffrey Oxnard, a principal investigator on one of the follow-up studies to TATTON, dubbed SAVANNAH.

"Mutated is black or white. But amplified is inherently grey; you can be highly amplified or a little bit amplified," he said in an interview. "And so it's harder to identify your population."

Historically, he noted that FISH has been the approach investigators have used to determine MET amplification, based on criteria for HER2 amplifications in breast cancer of a gene-to-centromere ratio greater than 2-to-1 or a gain of the gene. But, he said, the criteria developed for breast cancer might not be applicable in other cancers. Because of this, investigators have been pursuing other means of detecting MET amplifications, he added.

The TATTON investigators have begun to compare the three different approaches for determining MET amplifications: FISH, IHC, and sequencing.

"We really wanted to see how the technologies compare," said AstraZeneca's Ryan Hartmaier, who presented a poster on this aspect of the study at AACR this month. "We wanted to put them all together and see how do they overlap? How does that impact our patient population?"

He and his colleagues found that though there was some overlap between the patients identified through these different approaches, they each uncovered patients with MET amplifications the others did not. But, Hartmaier reported, with FISH alone, they could identify about twice the number of MET-positive patients than sequencing alone could — 95 patients versus 24 patients — in this study. At the same time, sequencing identified only one MET-positive patient who wasn't also detected by FISH.

It's similar, he added, for IHC, which detected more MET-positive tumors than sequencing, though there were a few cases that sequencing caught in this study that IHC did not.

But when FISH and IHC are combined — as those approaches identify largely different populations — they can identify about 2.6-fold more patients than sequencing alone.

"There remains a question of what is truth," Oxnard added. "Because in the end, truth is response to a MET inhibitor."

Even though the TATTON trial used different MET detection approaches, Sequist said that as they observed a number of responses — and durable responses — it offered a proof of concept that their approach could work.

Oxnard added that the follow-up SAVANNAH study would in part evaluate these different ways of determining MET-based resistance. This study, which recently began, is a single-arm Phase II study that is examining osimertinib and savolitinib in patients who have previously received osimertinib and have become resistant.

According to Oxnard, it will also collect enough tissue from the patients — which wasn't always possible in the TATTON trial — so that it can study the concordance of FISH, IHC, and sequencing to determine which approach might be the best to use going forward to uncover MET-addicted cancers.

"One of the purposes of the SAVANNAH trial is to come away with better certainty about what is the best biomarker to steer people toward this combination," Sequist added.

Another follow-up study, called ORCHARD, is to start later this year of patients who progressed on first-line osimertinib. It is to be a multi-armed study, in which some arms will be biomarker-matched and some will not, but those with MET amplification after front-line osimertinib will be shuttled toward the osimertinib and savolitinib arm.

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