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Adding the investigational anticancer therapeutic tivantinib to standard erlotinib treatment substantially increased progression-free survival for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who had tumors positive for epidermal growth factor receptor (EGFR) gene mutations. That was the conclusion of a subset analysis from the Phase III MARQUEE trial reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

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"EGFR inhibitors like erlotinib are effective treatments for patients with advanced NSCLC with and without EGFR mutations," Wallace Akerley, MD, Director of Thoracic Oncology at Huntsman Cancer Institute at the University of Utah, said in a news release. "However, MET overexpression is associated with resistance to EGFR therapy, and the Phase III MARQUEE clinical trial set out to investigate whether adding the MET inhibitor tivantinib to erlotinib treatment could improve patient outcomes."

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Previously published results for all 1,048 patients enrolled in the clinical trial showed that the combination of tivantinib and erlotinib was well tolerated and extended progression-free but not overall survival.


"We are now reporting a preplanned analysis of the outcomes for the subset of patients enrolled in MARQUEE who had tumors positive for EGFR mutations, the mutations most commonly associated with lung cancer in never smokers, "Akerley noted. "We were excited to see that the addition of tivantinib to the standard-of-care EGFR inhibitor erlotinib improved progression-free survival and tended to improve overall survival and response rates for these patients. There were few side effects and both agents were oral, so patients had improved outcomes without additional side effects or inconvenience.


"Given the small number of patients in this subset analysis, we were pleasantly surprised by the magnitude of the difference in response rate, progression-free survival, and overall survival, as well as the finding of statistical significance in progression-free survival."


Among the 1,048 patients with advanced non-squamous NSCLC that had disease progression after one or more prior treatments enrolled in the MARQUEE trial were 109 who had tumors positive for EGFR gene mutations. At randomization, 56 of these patients were assigned to the combination of tivantinib and erlotinib and 53 to erlotinib and placebo.


Adding tivantinib to erlotinib significantly increased the median progression-free survival: from 7.5 months among those patients assigned to receive erlotinib and placebo to 13.0 months among those assigned to the investigational combination. The overall response rate and median overall survival were also increased, from 43 to 61 percent and from 20.0 months to 25.5 months, respectively, although neither increase was considered statistically significant.


He noted, though, that statistically, greater numbers of patients give a greater chance to show small differences, so this subset analysis was capable of showing only major differences in outcome. Still, the data are "striking and provide firm evidence to support a confirmatory study," he said.


At data cutoff, six of the 56 patients who received tivantinib and erlotinib were still on therapy, with the duration of treatment ranging from 16 to 25 months.


The study was supported by ArQule and Daiichi Sankyo (Tokyo), and in Akerley's disclosure, he noted receiving "travel, accommodations, and/or expenses" from Daiichi Sankyo, Genentech, Clovis Oncology, and Bristol-Myers Squibb.


Leptomeningeal Disease

In another study reported at the meeting, the EGFR receptor-tyrosine kinase inhibitor (EGFR-TKI) AZD9291 crossed the blood-brain barrier and showed clinical activity in heavily pretreated NSCLC patients with leptomeningeal disease.


Dae Ho Lee, MD, PhD, Associate Professor in the Department of Oncology in the University of Ulsan College of Medicine and Asan Medical Center in Korea, reported the data for the Phase I BLOOM trial.


"Leptomeningeal disease at initial diagnosis of NSCLC is rare; however, as their lung cancer progresses, up to 15 percent of patients will develop this devastating complication. Additionally, an increased risk of central nervous system [CNS] involvement has been reported among patients with EGFR-mutant NSCLC-in particular, those treated with a first-generation EGFR-TKI," he said.


"Patients with EGFR-mutated NSCLC and leptomeningeal disease have an average survival of seven to 11 months, and currently there is no established effective treatment for this condition.


"Preclinical studies and anecdotal patient reports have indicated that AZD9291, an oral EGFR-TKI that selectively acts against lung tumors driven by specific mutations in the EGFR gene, including the T790M resistance mutation, crosses the blood-brain barrier that usually prevents drugs from having an effect in the brain, and had activity against brain tumors with EGFR mutations," Lee explained.


Based on the preclinical evidence and anecdotal reports of activity in brain metastases, the decision was made to study AZD9291 in NSCLC patients with leptomeningeal disease or brain metastases.


Of the 13 heavily pretreated EGFR-mutant NSCLC patients enrolled, 10 had received other EGFR-TKIs as prior therapies, and seven had received radiotherapy to the brain. Four patients had T790M-positive disease detected in their plasma, and two had DNA with the T790M mutation detected in their cerebrospinal fluid (CSF). All patients received 160 mg of AZD9291 once daily until disease progression. Treatment beyond progression was allowed at the discretion of the investigator.


"There is no standardized way to measure the response of leptomeningeal disease to therapy, but a combination of clearing cancer cells from the fluid surrounding the brain-i.e., CSF cytology-changes on brain MRI imaging, and improvement in neurologic symptoms is likely to be the best composite endpoint to assess clinical benefit," Lee noted.


As of the time of his report in October, 11 patients were evaluable for response. Of these, six had improvements in brain imaging and three of seven patients with abnormal neurological exams at baseline had symptomatic improvement, as judged by the investigator. One patient had confirmed clearance and four patients had unconfirmed clearance of cancer cells from the CSF.


Eight of nine patients from whom pre- and post-treatment CSF samples were available had a decrease in EGFR-mutant DNA, with the decrease more than 50 percent in five of them, Lee reported, adding that the adverse events were consistent with those published previously.


"Our results show that AZD9291 is a well-tolerated compound in this difficult-to-treat setting, and demonstrated that it crosses the blood-brain barrier.


Although preliminary, these results show encouraging activity and a manageable safety profile in a patient population with few treatment options. The results support further investigation of AZD9291 in central nervous system disease," Lee said.


The study was funded by AstraZeneca, and Lee disclosed being an advisory board member of BMS Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and receiving lecture fees from AstraZeneca, Ely Lilly, MSD, and Roche.