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First-Line Osimertinib Effective in T790m-Mutated EGFR Lung Cancer

Goodwin, Peter M.

doi: 10.1097/01.COT.0000488535.74966.eb
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GENEVA, Switzerland—First-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib improved progression-free survival (PFS) in two phase I expansion cohorts of patients from the AURA trial whose advanced non-small cell lung cancer (NSCLC) had the T790m mutation, according to findings reported at the 2016 European Lung Cancer Conference (Abstract LBA1).

Lead study author Suresh Ramalingam, MD, Chief of Thoracic Oncology at Emory School of Medicine, Deputy Director of Winship Cancer Institute, Atlanta, said that the overall response rate to this “third-generation” anti-EGFR TKI was among the best reported for first-line therapy of EGFR-mutated NSCLC. “The PFS results are exciting—well exceeding the historical control rates of 10 to 13 months with first- or second-generation drugs,” he explained.

Additionally, he reported that many of the patients had not yet had disease progression on the study and were still benefitting from treatment. “Basically this suggests that osimertinib may be [suitable] de facto as first-line therapy for EGFR mutation-positive disease. However this has to be confirmed in a prospective trial.”

Commenting on the findings, Enriqueta Felip, MD, Head of the Medical Oncology Service of the Thoracic Tumors Committee at Vall d`Hebron University Hospital in Barcelona, Spain, who was not involved in the study, said, “The results with osimertinib in the first-line look promising. The ongoing randomized trial will define the role of osimertinib in the treatment of EGFR mutated patients who are treatment-naive.”

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Study Results

While osimertinib is already approved for patients whose EGFR mutation-positive NSCLC has progressed, this study investigated 60 treatment-naïve patients with locally advanced or metastatic EGFRm-positive NSCLC randomized to two 30-patient cohorts—one receiving 80 milligrams (mg) and the other 160 mg osimertinib daily.

After a median of 16.6 months the overall objective response rate was 77 percent (64% for patients receiving 80 mg osimertinib and, 87% for those treated with 160mg). Median PFS was 19.3 months in the 160 mg dose cohort and had not yet been reached among patients treated with 80 mg daily. Median duration of response had not been reached, and the proportion of patients who were progression-free at 18 months was 55 percent overall—57 percent in the 80 mg cohort and 53 percent in the 160 mg cohort.

According to Ramalingam, the drug was well tolerated with few adverse events, particularly in patients taking the 80 mg dose (approved for NSCLC progressing despite first or second generation EGFR TKI therapy) just three required dose reduction to manage toxicities. However, 14 patients in the 160 mg dose cohort needed dose reduction to manage adverse events including diarrhea, stomatitis, and paronychia.

The authors concluded that treating advanced EGFR-mutated NSCLC with osimertinib as a first-line therapy results in a high objective response rate, promising PFS and manageable tolerability.

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Ongoing Research

When discussing the rationale behind the study, Ramalingam said, that while EGFR inhibition was the standard of care for NSCLC with EGFR activating mutations nearly 50 to 60 percent of patients typically become resistant to this treatment by developing a T790m mutation. “T790 is the major mechanism of resistance to EGFR tyrosine kinase inhibitors,” Ramalingam explained. “So the main rationale is: you have a mutant-selective drug that can potentially inhibit the resistance pathway.”

While this appeared to be what osimertinib was doing in the AURA study, confirmation of the findings are being sought in a phase III clinical trial that's ongoing with more than 500 patients comparing the drug to either erlotinib or gefitinib as front-line therapy—with results expected in about 18 months, at which time questions about optimizing the sequence of EGFR-targeted therapies could perhaps be addressed.

On the question of which TKI to use for initial therapy for NSCLC, Wilfried Eberhardt, MD, a medical oncologist at the West German Cancer Center in University Hospital Essen University Duisburg-Essen and International Association for the Study of Lung Cancer Scientific Committee Chair, who was not involved in the study, agreed that phase III findings were needed to settle such issues.

Eberhardt compared future TKI therapy for lung cancer with treatments presently available for chronic myeloid leukemia (CML). “We at least look at the paradigm of CML, where sometimes you know that it is better to start with a more effective drug first. So if you have a drug that seems to be very effective, then give it first and at the earliest time point,” he concluded.

Peter M. Goodwin is a contributing writer.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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