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Osimertinib Superior TKI as First-Line Treatment of Advanced NSCLC with EGFR Mutation

TOP - January 2020, Vol 13, No 1

Barcelona, Spain—Osimertinib (Tagrisso), a third-generation EGFR tyrosine kinase inhibitor (TKI), extended overall survival (OS) compared with older TKI EGFR inhibitors, including gefitinib (Iressa) or erlotinib (Tarceva), as first-line treatment for patients with advanced non–small-cell lung cancer (NSCLC) and EGFR mutation in the phase 3 clinical trial called FLAURA.

The median OS was 38.6 months with osimertinib versus 31.8 months with first-generation EGFR TKIs, for a 21% improvement in survival favoring osimertinib. At 3 years, 54% of patients who received treatment with osimertinib were alive compared with 44% in the control arm. These findings were presented at the ESMO Congress 2019.

“There was a clinically meaningful and statistically significant improvement in OS with osimertinib as first-line treatment for EGFR-mutated NSCLC. Osimertinib is the first TKI to show a survival improvement over another TKI in NSCLC. These data reinforce osimertinib as the preferred standard of care for front-line therapy,” said lead investigator Suresh S. Ramalingam, MD, FASCO, Director, Lung Cancer Program, Winship Cancer Institute, Emory University, Atlanta, GA.

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

Unlike erlotinib and gefitinib, osimertinib was designed to overcome the EGFR T790M resistance mutation and can penetrate the blood–brain barrier. Responses to osimertinib are observed in 70% to 90% of patients with NSCLC and brain metastases, Dr Ramalingam told listeners.

The primary analysis of this study previously showed that osimertinib improved progression-free survival from 10.2 months to 18.9 months versus first-generation TKI, a 54% improvement (P <.001).

Patient Population

FLAURA enrolled 556 patients with newly diagnosed, treatment-­naïve, stage IV NSCLC with EGFR mutation. Stable central nervous system metastases were allowed. Patients were randomized to osimertinib 80 mg daily or to the investigator’s choice of EGFR TKI gefitinib 250 mg daily or erlotinib 150 mg daily. Crossover to osimertinib was allowed at disease progression and evidence of EGFR T790M mutation.

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

Exploratory analysis showed a consistent survival benefit for osimertinib across all subgroups. The duration of benefit was almost twice as long (25.9 months) with osimertinib versus 13.4 months with the older TKIs.

No new safety signals were reported with osimertinib in the extended survival analysis. Adverse events more common in the comparator arm were skin rash and transaminitis.

Sequencing of EGFR TKIs

“Optimal sequencing of available EGFR TKIs remains to be defined. FLAURA shows you should give the best agent first,” Dr Ramalingam said at a press conference. “Thirty percent of patients never got a subsequent therapy afterwards, so for some patients first-line treatment is the only shot they had. Only about 35% will have a chance to get 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,” Dr Ramalingam said.

“I agree with Dr Ramalingam: give the best drug first,” said press conference moderator, Pilar Garrido, MD, PhD, Head, Thoracic Tumours Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain.

“If osimertinib is used as first-line therapy, there is no TKI available when the disease progresses. Patients should be told that osimertinib offers a survival advantage and is well-tolerated, but when the treatment fails, chemotherapy is the only option. Maximizing the duration of chemotherapy-free treatment is important for patients, but if we want to know the most effective sequence of TKIs, we need studies specifically designed for that,” Dr Garrido said.

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