Suresh S. Ramalingam, MD

First-line treatment with osimertinib extended overall survival compared with the older tyrosine kinase inhibitors gefitinib and erlotinib in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to late-breaking final overall survival results of the phase III FLAURA trial presented by lead author Suresh S. Ramalingam, MD, of Winship Cancer Institute, Emory University, Atlanta, at the European Society for Medical Oncology (ESMO) 2019 Congress.¹ The median overall survival was 38.6 months with osimertinib vs 31.8 months with first-generation EGFR tyrosine kinase inhibitors, representing a relative improvement in survival of 21%. At 3 years, 54% of patients treated with osimertinib were alive compared with 44% in the control arm.

FLAURA is the first trial to show improved overall survival with a third-generation tyrosine kinase inhbitor vs first-generation tyrosine kinase inhibitors in NSCLC. These results support the clinical efficacy of the third-generation tyrosine kinase inhibitor osimertinib. In the primary analysis of the trial, reported previously, osimertinib improved progression-free survival from 10.2 months to 18.9 months vs a first-generation tyrosine kinase -inhibitor—a 54% improvement (P < .001).

“There was a clinically meaningful and statistically significant improvement in overall survival with osimertinib as first-line treatment for EGFR-mutated NSCLC. Osimertinib is the first tyrosine kinase inhibitor to show a survival improvement over another tyrosine kinase inhibitor in NSCLC,” said Dr. Ramalingam. “At 3 years, 28% of the osimertinib group and 9% of the control group remain on first-line treatment. These data reinforce osimertinib as the preferred standard of care for front-line therapy.”

Osimertinib is the first tyrosine kinase inhibitor to show a survival improvement over another tyrosine kinase inhibitor in NSCLC.

— Suresh S. Ramalingam, MD

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Dr. Ramalingam continued: “Overall survival for the control arm is among the highest ever reported for tyrosine kinase inhibitors, because 31% of patients in the control group crossed over to osimertinib at disease progression. Even with that in play, we see a 6- to 8-month improvement in overall survival in the osimertinib arm.”

Osimertinib was originally developed to overcome the EGFR T790M resistance mutation and has better penetration in the brain than older tyrosine kinase inhibitors. Responses were observed in 70% to 90% of patients with NSCLC who have brain metastases, Dr. Ramalingam told listeners.

Study Details and Key Findings

FLAURA enrolled 556 patients with newly diagnosed, treatment-naive, EGFR-mutated stage IV NSCLC and a World Health Organization performance status of 0 to 1. Stable central nervous system metastases were allowed. Two-thirds of patients were women.

Patients were randomly assigned 1:1 to osimertinib at 80 mg/d or to a comparator EGFR tyrosine kinase inhibitor (gefitinib at 250 mg/d or erlotinib at 150 mg/d). Crossover to osimertinib was allowed at disease progression and evidence of T790M positivity. At data cutoff, 22% of the osimertinib group and 5% of the comparator group were still on first-line study drug.

At 24 months, 74% of the osimertinib group and 59% of the comparator arm were alive. The 36-month survival rates were 54% and 44%, respectively.

Although the study was not powered to show statistical significance in subgroups, a consistent survival benefit with osimertinib was observed across subgroups. Both Asian and non-Asian individuals benefited from osimertinib, noted Dr. Ramalingam, with a greater magnitude of benefit in non-Asian patients.

In addition, osimertinib seemed to have a longer duration of benefit. The time to subsequent treatment was almost twice as long with osimertinib: 25.9 months vs 13.4 months, respectively.

Thirty percent of patients in both groups did not receive subsequent therapy after disease progression. Of controls who received subsequent therapy, 47% received osimertinib. Among those in the osimertinib group treated with second-line therapy, 68% received cytotoxic chemotherapy.

There were no new safety signals related to osimertinib in the extended survival analysis. The median duration of exposure to the drug was 20.7 months for osimertinib vs 11.5 months for the comparator. Adverse events more common with the comparator were skin rash and transaminitis.

Sequencing of Treatment

The optimal sequencing of osimertinib and other drugs for EGFR-mutated NSCLC needs to be defined, and the mechanisms of resistance other than the T790M mutation require further study.

At a press conference at the ESMO Congress, Dr. Ramalingam was asked about drug sequencing, given current evidence from trials. “FLAURA shows you should give the best agent first. Thirty percent of patients never received a subsequent therapy afterward, so for some patients, first-line treatment is the only shot they had. Only about 35% will have a chance to receive second-line osimertinib. You can either give the best drug first or roll the dice. This is why we believe the best drug should be given first,” he said. ■

DISCLOSURE: Dr. Ramalingam reported financial relationships with AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro.

REFERENCE

1. Ramalingam SS, Gray JE, Ohe Y, et al: Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. ESMO 2019 Congress. Abstract LBA5_PR. Presented September 28, 2019.