‘Clinically Meaningful’ Results With First-Line Osimertinib in EGFR–Positive NSCLC

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“Osimertinib should be considered a new standard of care for first-line therapy of EGFR mutation–positive non–small cell lung cancer.”
— Suresh Ramalingam, MD

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OSIMERTINIB (TAGRISSO) showed encouraging results as first-line therapy for patients with epidermal growth factor receptor (EGFR)–mutated non–small-cell lung cancer (NSCLC) in the phase III FLAURA trial, according to results presented at the 2017 European Society for Medical Oncology (ESMO) Congress.1 

Patients who received first-line osimertinib had a 54% reduced risk of disease progression and death compared with standard first-line therapy with gefitinib (Iressa) or erlotinib (Tarceva). Median progression-free survival was 18.9 months with osimertinib vs 10.2 months with standard therapy (P < .0001). Median overall survival appeared to favor osimertinib (hazard ratio [HR] = 0.63), but data are only 25% mature, and longer follow-up is needed. 

“Osimertinib achieved significant improvement in progression-free survival over standard of care, and improvement was consistent in patients with and without brain metastasis. The improvement is robust and clinically meaningful. Duration of response was more than twofold higher with osimertinib. Interim overall survival data show a promising trend favoring osimertinib. Osimertinib should be considered a new standard of care for first-line therapy of EGFR mutation-positive NSCLC,” said lead investigator Suresh Ramalingam, MD, Deputy Director of the Winship Cancer Institute at Emory University in Atlanta. 

Enriqueta Felip, MD

Enriqueta Felip, MD

Commenting on this study, ESMO expert Enriqueta Felip, MD, Head of the Lung Cancer Unit, Oncology Department at Vall d’Hebron University Hospital in Barcelona, said: “These results are clearly meaningful. There was a median of 9-month difference in progression-free survival favoring osimertinib. I agree with Dr. Ramalingam. Osimertinib should be considered a new standard of care for patients with EGFR-mutated NSCLC as first-line therapy.” 

EGFR mutations are observed in 15% to 35% of patients with lung adenocarcinoma, and EGFR tyrosine kinase inhibitors are the standard of care. However, nearly all patients treated with an EGFR inhibitor will develop resistance, and T790M accounts for about 50% to 60% of resistance, Dr. Ramalingam explained. 

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that potentially inhibits both EGFR and T790M, whereas other EGFR tyrosine kinase inhibitors used to treat NSCLC are not specific for the T790M mutation. Osimertinib is currently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC that has progressed on prior EGFR tyrosine kinase inhibitor therapies. The FLAURA data provide a strong rationale for using this drug as first-line therapy in patients with EGFR-mutated NSCLC, especially in patients with central nervous system (CNS) metastasis. 

Key Study Findings 

FLAURA IS A PROSPECTIVE, randomized double-blind, placebo-controlled phase III trial designed to compare third-generation osimertinib vs standard of care (gefitinib or erlotinib) in treatment-naive EGFR-positive locally advanced or metastatic NSCLC. Patients from Asia, Europe, and North America were accepted in the trial if they had sensitizing EGFR mutations, including those with CNS metastasis. The study randomized 556 patients in a 1:1 ratio to treatment with osimertinib (80 mg/d) or gefitinib (250 mg/d) or erlotinib (150 mg/d). Patients were treated until disease progression. Patients whose disease progressed on standard of care with T790M-mediated resistance were allowed to cross over to osimertinib. 

The overall response rate was 80% with osimertinib vs 76% with erlotinib and gefitinib. Median duration of response was 17.2 months vs 8.5 months, respectively. 

The progression-free survival benefit reported with osimertinib was consistent across all subgroups, including Asian/non-Asian patients, those with or without a history of smoking, those with exon deletion/EGFR L858R mutation, and those with or without CNS metastases at study entry. 


Survival data in the FLAURA trial were only 25% mature at the time of the ESMO Congress, and median overall survival had not been reached.

In 116 patients with CNS metastasis, median progression-free survival was 15.2 months with osimertinib vs 9.6 months with the standard of care, representing a statistically significant 53% improvement favoring osimertinib (P < .0001). In patients without CNS involvement (n = 440), median progression-free survival was 19.1 months vs 10.9 months, respectively (P < .0001). In the total patient population, CNS metastasis occurred in 6% of those patients who received osimertinib vs 16% of those who received the standard of care. 

“As clinicians, we are constantly aware of CNS as a potential site of metastasis These data suggest that osimertinib penetrates the brain,” he noted. 

Survival data were only 25% mature at the time of the ESMO Congress. Median overall survival had not been reached. However, the hazard ratio of 0.63 at this time point favored osimertinib. Dr. Ramalingam explained that the P value fell short of statistical significance, but that “a strong and promising survival trend was encouraging.” 

Safety Profile 

“THE SAFETY PROFILE showed clear benefits to patients receiving osimertinib,” he continued. “Treatment was much better tolerated with osimertinib, and the rate of grade 3 and 4 all-cause adverse events was about 12% lower than with standard therapies.” 

Adverse events were reported in about 98% of patients in both treatment arms. The most common all-grade adverse events with osimertinib were diarrhea (58%) and dry skin (32%). In the standard-of-care arm, diarrhea was reported in 57% of patients and skin rash, in 48%. 

Grade 3 or higher adverse events were reported in 33.7% of the osimertinib-treated patients and 44.8% of the control arm. Treatment discontinuation due to adverse events occurred in 13.3% and 18.1% of patients, respectively. 

Dr. Ramalingam was excited about the potential to use osimertinib as a platform to develop more effective combinations of therapy. “Its safety lends itself to be a good platform to explore new therapies,” he noted. ■

DISCLOSURE: Dr. Ramalingam reported no conflicts of interest. Dr. Felip has been a consultant, advisor, and/or on the speakers bureau for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Merck Sharp & Dohme, Novartis, Pfizer, and Takeda. 


1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al: Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA. 2017 ESMO Congress. Abstract LBA2_PR. Presented September 9, 2017.