Investigational EGFR Inhibitor May Hold Promise for Some Patients With Treatment-Resistant NSCLC
Approximately 50% of non–small cell lung cancer (NSCLC) patients who develop resistance to inhibitors of the epidermal growth factor receptor (EGFR) have acquired a second mutation, T790M, which no current EGFR inhibitors target. This may change if the AstraZeneca investigational compound AZD9291 proves as effective in patients as it appears in preclinical studies.
At the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston, Susan Galbraith, MD, PhD, Head of the Oncology Innovative Medicines Unit at AstraZeneca, reported early results at a press briefing (Abstract B212).
Current treatments are essentially lacking for advanced NSCLC of the resistant “double-mutation” type, and “this remains a key area of unmet need,” she said.
AZD9291 Potent Against T790M
AZD9291 is an oral, irreversible, third-generation, selective inhibitor of both EGFR-activating mutations and resistance (T790M) mutations.
“AstraZeneca chemists designed a compound that overcomes the limitations of earlier therapies. We developed a novel scaffold that could overcome the double-mutant kinase,” she said. “The innovative breakthrough was finding a series of molecules that could target both the activating and resistant mutant forms of EGFR more potentially than normal EGFR, which led to the development of the new EGFR kinase inhibitor AZD9291.”
The mechanistic and functional activity of AZD9291 was characterized in vitroand in vivo across a number of cell lines harboring various EGFR mutations or wild-type EGFR. Wild-type EGFR inhibition is believed to drive the observed dose-limiting toxicities seen with current EGFR inhibitors, such as skin rash and diarrhea.
AZD9291 potently inhibits EGFR phosphorylation in activating mutations and resistance cell lines in vitro, with much less activity against wild-type EGFR lines. Additionally, AZD9291 causes “profound regression” of tumors, she reported. Growth inhibition of 178% has been observed in activating cell lines, and 119% growth inhibition has been noted in resistance (double-mutation) models.
“Assuming that human tumors and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7 to 17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR-activating and T790M (resistant) mutations,” Dr. Galbraith said.
Preliminary Phase I Trial Results Impressive
At the 2013 European Cancer Conference in Amsterdam, preliminary results from an ongoing phase I study (Abstract 33) demonstrated partial tumor shrinkage in 12 of 26 (46%) patients receiving the drug. Twelve of these patients had tumors that carried the T790M mutation, and seven (58%) responded, with many other patients achieving stable disease.
“As for durability, I can tell you that the first patient we dosed in March continues to respond. It’s difficult to say, at this early stage, what the median progression-free survival will be, but we do see patients continuing to respond,” Dr. Galbraith said.
The global study is enrolling additional patients, and higher doses of AZD9291 are being tested. “The trial is going very well, and we are excited by the data,” she told the media
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