ELCC 2016: Osimertinib Given as First-Line Treatment May Alter Biology of EGFR-Mutated Non–Small Cell Lung Cancer
The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib (Tagrisso) is effective in the first-line treatment of EGFR-mutated non–small cell lung cancer (NSCLC), according to a late-breaking abstract presented by Ramalingam et al (Abstract LBA1_PR) on April 14 at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland. A second late-breaking abstract by Yang et al (Abstract LBA2_PR) confirms the drug’s effectiveness in patients with the EGFR T790M point mutation.
EGFR inhibition is the standard of care for NSCLC patients with EGFR-activating mutations, but nearly 50% to 60% of patients develop resistance by developing a T790M mutation. Osimertinib is a potent inhibitor of the original EGFR mutations (exon 19 and exon 21) and the T790M mutation.
EGFR-Mutated Study Findings
The first study presented investigated whether the use of osimertinib as first-line therapy for EGFR-mutated NSCLC would result in favorable efficacy due to delayed T790M-mediated resistance. It included 60 patients from two phase I expansion cohorts of the AURA trial diagnosed with locally advanced or metastatic EGFR-mutated NSCLC. Thirty patients received 80 mg/d and 30 received 160 mg/d in the first-line setting. The median follow-up was 16.6 months.
The overall response rate was 77%. Median progression-free survival was 19.3 months for the 160-mg dose and has not yet been reached for the 80-mg dose. Median duration of response has not been reached. The drug was well tolerated with few adverse events, particularly at the approved 80-mg dose, where just 10% of patients required dose reduction to manage toxicities.
Suresh Ramalingam, MD, Professor of Hematology and Medical Oncology at Emory School of Medicine and Deputy Director of Winship Cancer Institute, said, “The overall response rate was among the best reported for first-line therapy of EGFR-mutated NSCLC. The progression-free survival results are exciting, well exceeding the historical control rates of 10 to 13 months with first- or second-generation drugs. Many of the patients have not had disease progression on the study and are still benefitting from treatment.”
Initial data suggest that patients who had disease progression did not have T790M mutation as the mechanism of resistance. “That tells us that we may be changing the biology of the disease with the use of first-line osimertinib,” said Dr. Ramalingam.
The findings will be further investigated in a phase III clinical trial in more than 500 patients comparing osimertinib to either erlotinib (Tarceva) or gefitinib (Iressa) for front-line therapy. Results are expected in up to 18 months.
T790M-Mutated Study Findings
A second late-breaking abstract presented today reveals the mature results of two AURA studies that investigated osimertinib at the recommended 80-mg dose in EGFR-mutated and T790M-positive NSCLC patients who had disease progression on previous EGFR tyrosine kinase inhibitor therapy. Response rates were 71% in the phase I dose-expansion cohort of 63 patients and 66% in pooled results from two phase II studies of 411 patients. Progression-free survival was 9.7 and 11 months for the phase I cohort and phase II studies, respectively.
“We found a response rate and progression-free survival that were consistent between the two studies and with earlier reports from the AURA studies,” said James Yang, MD, PhD, Director of the Department of Oncology and Department of Medical Research, National Taiwan University Hospital. “Adverse events such as interstitial lung disease and QT prolongation were infrequent, with similar rates to our previous analyses.”
He concluded, “In this mature pooled analysis for T790M-positive EGFR-mutant patients [with disease progression] on prior EGFR [tyrosine kinase inhbitors], we were able to show a high overall response rate, encouraging duration of response and good tolerability profile. [Progression-free survival] was long compared to the 4 to 5 months provided by chemotherapy. This is good news for patients with EGFR mutations [in whom EGFR tyrosine kinase inhibitors have failed], for whom osimertinib is now standard of care. Molecular diagnosis for T790M must now be the standard as well.”
Osimertinib recently received accelerated approval as the first indicated treatment for patients with EGFR and T790M mutation–positive metastatic NSCLC in the United States, European Union, and Japan.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
