1. Fuerst, Mark L.

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ATLANTA-The addition of the investigational MET inhibitor savolitinib to the EGFR inhibitor osimertinib yields clinical responses in patients with MET-driven advanced non-small cell lung cancer (NSCLC) who experienced disease progression on EGFR targeted therapies.

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To date, targeted therapy for lung cancer patients with EGFR mutations has consisted solely of monotherapy with various EGFR tyrosine kinase inhibitors (TKIs). "We have known for more than 10 years that a proportion of resistance to EGFR TKIs results from activation of the MET bypass pathway," said Lecia V. Sequist, MD, MPH, thoracic medical oncologist and Director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center, at a press briefing before the American Association for Cancer Research annual meeting (Abstract CT033).


Prior research has shown that MET amplification is a bypass pathway observed in about 5-10 percent of patients whose disease has progressed after treatment with first-generation or second-generation EGFR TKIs, and in about 25 percent of those whose disease has progressed after treatment with third-generation EGFR TKIs, Sequist explained.


"Preliminary ctDNA next-generation sequencing revealed that MET amplification was the most common resistance mechanism following first-line osimertinib in the FLAURA trial (15% of patients). Similarly, 19 percent of patients in the AURA3 trial had MET amplification as a mechanism of resistance to second-line osimertinib," said Sequist.


Prior clinical trials of combinations of EGFR-targeted and MET-targeted therapies have not been successful, partly due to the drug combinations studied and largely because patients were not chosen based on appropriate biomarkers, she said. The TATTON trial used newer TKIs that have increased specificity for EGFR and MET, and patients with EGFR-mutant NSCLC were required to have documented MET-driven resistance.


TATTON Trial Details

Sequist presented interim results from two distinct expansion cohorts of the TATTON trial. In the first cohort, 46 patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with a first-generation or second-generation EGFR TKI received a combination of osimertinib and savolitinib. These patients' tumors were also negative for T790M mutation.


In the second cohort, the same combination was administered to 48 patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with osimertinib or another experimental third-generation EGFR TKI.


Both cohorts received oral osimertinib 80 mg daily and oral savolitinib 600 mg daily. The median age in both cohorts was 59 years.


"Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance mechanisms, but further research is needed to determine the final effectiveness of this therapy," said Sequist. "The study has shown efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option."


In the cohort who had received prior first-generation or second-generation EGFR TKI, combination therapy with osimertinib plus savolitinib yielded an objective response rate (ORR) of 52 percent (24 patients), all partial responses (PR). Another 16 patients achieved stable disease, including four patients with unconfirmed PR, she said. The median duration of response was 7.1 months. Two-thirds of patients had just one prior line of therapy and 20 percent had three or more lines of therapy.


In the cohort who had received prior third-generation EGFR TKI, treatment with osimertinib plus savolitinib yielded an ORR of 28 percent, with 12 partial responses. Another 21 patients had stable disease, including five patients with unconfirmed PR. The median duration of response was 9.7 months.


All responders tested positive for MET, she noted. More than half of patients (54%) had already received three or more prior lines of therapy, including chemotherapy and other EGFR-targeted agents.


Overall, the regimen was tolerable, though there was added toxicity with the combination of osimertinib and savolitinib compared to osimertinib alone.


"We saw that some patients discontinued treatment due to toxicity," Sequist said. The most frequent adverse events in both cohorts were nausea, diarrhea, and lowered numbers of leukocytes and platelets. One patient who had brain metastases died from kidney failure a few days after starting the combination therapy. "Our understanding of the adverse event profile of the osimertinib-savolitinib combination, and how to manage the adverse events, is improving," said Sequist.


Implications, Next Steps

"Our findings illustrate the value of careful patient selection in studies of targeted therapies," she added. "These clinically meaningful responses also demonstrate that as different heterogeneous resistance clones come up, they can in turn be brought under control by tailoring therapy."


Since the TATTON trial was initiated, osimertinib was approved for treatment in the first-line setting for patients with EGFR-mutant NSCLC. Therefore, only a subset of patients in the trial had received prior first-line osimertinib and had developed MET-driven resistance.


The newly opened phase II SAVANNAH study will further explore the combination of osimertinib plus savolitinib in patients with advanced EGFR-mutant, MET-positive NSCLC whose disease has progressed on osimertinib.


Another trial, ORCHARD, is a planned phase II study of patients with advanced NSCLC who progressed on first-line osimertinib. The study will have multiple treatment arms which will examine both targeted and non-targeted combination options.


"ORCHARD will be an important step towards understanding the resistance spectrum acquired following progression on first-line osimertinib, and potential treatments to overcome it," concluded Sequist.


Mark L. Fuerst is a contributing writer.