FDA Grants Priority Review to Osimertinib Plus Chemotherapy for EGFR+ Locally Advanced or Metastatic NSCLC

FDA

The FDA has granted priority review to the supplemental new drug application (sNDA) seeking the approval of osimertinib (Tagrisso) in combination with chemotherapy for the treatment of patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC).¹

The sNDA is supported by data from the phase 3 FLAURA2 trial (NCT04035486), which showed that first-line treatment with osimertinib plus chemotherapy reduced the risk of disease progression or death by 38% compared with osimertinib alone (HR, 0.62; 95% CI, 0.49-0.79; P < .0001). Per investigator assessment, patients treated with the combination (n = 279) experienced a median progression-free survival (PFS) of 25.5 months (95% CI, 24.7-not calculable [NC]) compared with 16.7 months (95% CI, 14.1-21.3) for those given osimertinib alone (n = 278).^2,3

Per blinded independent central review (BICR) assessment, patients administered osimertinib plus chemotherapy achieved a median PFS of 29.4 months (95% CI, 25.1-NC) vs 19.9 months (95% CI, 16.6-25.3) for patients treated with osimertinib monotherapy (HR, 0.62; 95% CI, 0.48-0.80; P = .0002).

The FDA’s target action date under the Prescription Drug User Fee Act is expected to be in the first quarter of 2024.¹

“The FLAURA2 results reinforce [osimertinib] as a backbone of standard of care in first-line EGFR-mutated NSCLC, providing patients with an additional 9 months of median PFS when combined with chemotherapy,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a news release. “This option is particularly important for patients with a poorer prognosis such as those with brain metastases. We look forward to working with the FDA on an accelerated timeline to bring this treatment regimen to patients as quickly as possible.”

The randomized, open-label, multicenter, global FLAURA2 trial enrolled patients at least 18 years of age with previously untreated, locally advanced stage IIIB/C or metastatic stage IV NSCLC harboring EGFR mutations that was not amenable to curative surgery or radiotherapy.⁴ Patients were also required to have a World Health Organization performance status of 0 or 1 and a life expectancy of more than 12 weeks.

Key exclusion criteria included spinal cord compression, unstable brain metastases, a history of interstitial lung disease, evidence of severe or uncontrolled systemic diseases, QT prolongation, or inadequate bone marrow reserve or organ function.

Notably, patients with stable brain metastases who completed definitive therapy, were not on steroids, and had a stable neurological status for at least 2 weeks after completion of the definitive therapy and steroids were allowed to enroll. Patients with asymptomatic brain metastases were also permitted if immediate definitive treatment was not indicated, in the opinion of the investigator.

Patients were randomly assigned 1:1 to receive 80 mg of oral osimertinib once per day in combination with 500 mg/m2 of pemetrexed (Alimta) plus 75 mg/m² of cisplatin or area under the curve 5 of carboplatin once every 3 weeks for 4 cycles, followed by osimertinib plus pemetrexed as maintenance therapy given once every 3 weeks; or osimertinib alone.

Investigator-assessed PFS per RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included overall survival (OS), objective response rate, duration of response, disease control rate, time to second progression, quality of life, and safety.

Additional data from FLAURA2 showed that a clinically meaningful PFS benefit was observed across all prespecified subgroups, including sex, race, type of EGFR mutation, age at diagnosis, smoking history, and central nervous system (CNS) metastases status at baseline.² OS data remained immature; however, a trend was observed favoring osimertinib plus chemotherapy.

No new safety signals were reported, and toxicities and adverse effects (AEs) leading to discontinuation were consistent with the established profiles of osimertinib and the chemotherapy regimen. All-cause grade 3 or higher AEs were reported in 64% of patients in the combination arm compared with 27% of patients in osimertinib monotherapy arm.

References

1. Tagrisso plus chemotherapy granted priority review in the US for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. October 16, 2023. Accessed October 16, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-granted-priority-review-us-patients-egfr-mutated-advanced-lung-cancer.html
2. Tagrisso plus chemotherapy extended median progression-free survival by nearly 9 months in EGFR-mutated advanced lung cancer in FLAURA2 phase III trial. News release. AstraZeneca. September 11, 2023. Accessed October 16, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-extended-median-progression-free-survival-by-nearly-9-months-in-egfr-mutated-advanced-lung-cancer-in-flaura2-phase-iii-trial.html
3. Jänne PA, Planchard D, Cheng Y, et al. Osimertinib with / without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract PL03.13.
4. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2). ClinicalTrials.gov. Updated August 2, 2023. Accessed October 16, 2023. https://clinicaltrials.gov/study/NCT04035486#participation-criteria