Abstract
Patients with EGFR-mutant non–small cell lung cancer who develop MET-driven resistance to an EGFR inhibitor–be it a first-, second-, or third-generation drug–stand to benefit from follow-up treatment with a combination of EGFR-targeted osimertinib and MET-blocking savolitinib, according to an interim analysis of two expansion cohorts from the multiarm TATTON trial.
Lung cancers that harbor EGFR mutations are exquisitely sensitive to EGFR-targeted drugs, but the therapies inevitably stop working as the tumors evolve. For patients whose tumors develop resistance through the MET bypass pathway, a new dual-drug strategy could help prolong survival.
According to interim results from two expansion cohorts of the multiarm TATTON trial, combination treatment with two AstraZeneca drugs—the third-generation EGFR inhibitor osimertinib (Tagrisso) and the experimental MET inhibitor savolitinib—yielded frequent and durable responses among patients with EGFR-mutant non–small cell lung cancer (NSCLC) that had acquired drug resistance driven by MET amplification. Trial investigators presented the data on March 31 at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA.
Although missense mutations in EGFR—generally at positions 790 or 797 of the corresponding protein—are the most common resistance mechanism to EGFR inhibitors, MET amplification frequently causes drug resistance, too: Increased copy number is observed in 5% to 10% of relapsed tumors after treatment with older EGFR inhibitors, and up to 25% of relapses following third-generation agents.
In the phase I TATTON trial, patients with MET-driven resistance received osimertinib and savolitinib daily. One expansion cohort included 46 patients who had initially taken a first-generation EGFR inhibitor—erlotinib (Tarceva; Genentech/Astellas) or gefitinib (Iressa; AstraZeneca)—or a second-generation drug, such as afatinib (Gilotrif; Boehringer Ingelheim) or dacomitinib (Vizimpro; Pfizer; Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT032). Twenty-four patients experienced partial responses that lasted a median of 7.1 months.
The second cohort included 48 patients who had previously received osimertinib or another third-generation agent; 12 had partial responses that lasted for a median of 9.7 months (Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT033). The recently launched phase II SAVANNAH trial, with a target enrollment of 172 patients, will further assess the benefit of osimertinib plus savolitinib among patients with MET-amplified tumors following disease progression on osimertinib.
“Several patients who participated in this study from our institute achieved quite promising responses so far with tolerable side effects,” said SAVANNAH co–principal investigator Myung-Ju Ahn, MD, of the Samsung Medical Center in Seoul, South Korea, who also participated in TATTON.
Not all cases of MET-mediated resistance will be equally amenable to the drug strategy. Yi-Long Wu, MD, of Guangdong General Hospital in China, and his colleagues have tested combinations of EGFR- and MET-targeted therapeutics—including savolitinib plus gefitinib, and capmatinib (Novartis/Incyte) plus gefitinib—and found that only patients with five or more copies of MET responded to the drug regimens, whereas patients with other mutations that elevate gene expression levels gained little benefit (J Thorac Oncol 2017;12:suppl 2, S1769; J Clin Oncol 2018;31:3101–9). “It's important to define the MET aberration,” noted Wu.
However, diagnostic testing following progression focuses on EGFR mutational status; MET evaluations are not routinely performed at most medical centers. For trial investigator Lecia Sequist, MD, MPH, of Massachusetts General Hospital (MGH) in Boston, MA, the TATTON findings thus highlight the need to test other genes as well. “It's really important to genotype the cancer because you might find MET amplification, and our results suggest that's potentially treatable with effective targeted therapies,” she said. “There are things that are important to know before you jump to the default, which is still chemotherapy.”
Bolstering her case for more expansive testing: Last November, Sequist and her MGH colleagues described two patients with RET-mediated resistance to EGFR inhibition who responded favorably to combined treatment with osimertinib and the RET-targeted drug BLU-667 (Blueprint Medicines; Cancer Discov 2018;8:1529–39).
“What we're seeing here helps establish a paradigm for combination therapy,” following resistance to first-line targeted treatment, said Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. –Elie Dolgin
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