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FDA Grants Priority Review to Adjuvant Osimertinib for EGFR-Positive NSCLC

Wednesday, October 21, 2020
The FDA has granted osimertinib (Tagrisso) a priority review designation to a supplemental new drug application for the adjuvant treatment of patients with early-stage EGFR-mutated non–small cell lung cancer (NSCLC) following complete tumor resection with curative intent.1

The application was based on data from the pivotal phase 3 ADAURA trial, which showed that adjuvant osimertinib resulted in a statistically significant and clinically meaningful improvement in disease-frees survival (DFS) in patients with stage IB/II/IIIA EGFR-mutated NSCLC.2 Specifically, the targeted agent resulted in a 79% reduction in the risk of disease recurrence or death (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).

Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the application during the first quarter of 2021.

“Patients with early-stage EGFR-mutated lung cancer are still at considerable risk of recurrence after surgery and adjuvant chemotherapy, and new targeted treatment options are critical to improving outcomes for these patients,” said Dave Frederickson, executive vice president of the Oncology Business Unit at AstraZeneca.1 “This expedited review underscores the unprecedented disease-free survival benefit [osimertinib] brings to patients in the adjuvant setting, and we will continue working with the FDA to provide this practice-changing treatment to patients as quickly as possible.”

The double-blind, randomized, placebo-controlled phase 3 trial enrolled patients 18 years of age or older with a World Health Organization (WHO) performance status of 0 or 1 and confirmed primary nonsquamous NSCLC who underwent a complete resection with negative margins. Patients were stratified by stage (IB vs II vs IIIA), EGFR mutational status (exon 19 deletion vs L858R), and race (Asian vs non-Asian).

A total of 682 participants were randomized 1:1 to receive either 80 mg of osimertinib once daily versus once-daily placebo. Patients will continue to receive treatment until either recurrent disease, treatment has been completed at 3 years, or discontinuation criteria are met. The primary end point of the trial is DFS per investigator assessment, while key secondary end points include DFS in the overall population; DFS at 2, 3, 4, and 5 years; overall survival (OS), safety, and health-related quality of life.

In April 2020, an Independent Data Monitoring Committee recommended that the trial be unblinded 2 years early based on efficacy. At the time of the unblinding, ADAURA had completed enrollment and all patients had been followed up for at least 1 year.

In both the osimertinib and placebo arms, the majority of participants were male, at 68% and 72%, respectively. The median age in the investigative and control arms was 64 years and 62 years, respectively. The majority of participants in the osimertinib and placebo arms were non-smokers (68% and 75%, respectively) and had a WHO performance status of 0 (64% and 64%, respectively). Fifty-five percent of patients in the osimertinib arm had exon 19 deletion, while 45% harbored a L858R mutation; these rates were 56% and 44%, respectively, in the placebo arm. A little more than half of patients in the investigative and control arms had received adjuvant chemotherapy, at 55% and 56%, respectively.

Additional results presented during the 2020 ASCO Virtual Scientific Program showed that the median DFS in the subset of patients with stage II/IIIA disease had not yet been reached in the osimertinib arm versus 20.4 months in the placebo arm (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). Notably, the DFS benefit proved to favor osimertinib across all subgroups analyzed.

The 2-year DFS rates with osimertinib versus placebo in those with stage IB disease were 87% versus 73% (HR, 0.50; 95% CI, 0.25-0.96), respectively; these rates were 91% versus 56%, respectively, in those with stage II disease (HR, 0.17; 95% CI, 0.08-0.31) and 88% versus 32%, respectively, in those with stage IIIA disease (HR, 0.12; 95% CI, 0.07-0.20).

The OS data are still immature, at just 5% maturity, and the median OS has not yet been reached in either arm (HR, 0.40; 95% CI, 0.18-0.90).

With regard to safety, any-grade adverse effects (AEs) were reported in 97% of those in the osimertinib arm versus 89% of those in the placebo arm. Twenty percent of patients in the investigative arm experienced AEs that were grade 3 or greater versus 14% in the control arm. One AE resulted in death on the control arm versus 0 in the investigative arm. Serious AEs occurred in 16% of patients who received osimertinib versus 13% who received placebo.

Eleven percent of those in the osimertinib arm experienced a toxicity that resulted in treatment discontinuation versus 4% of those in the placebo arm. Moreover, 7% versus 1% of those in the investigative and control arms, respectively, had an AE that required a dose reduction.

Toxicities determined to potentially be causally related to study drug occurred in 90% of those on osimertinib versus 55% of those on placebo. Ten percent versus 3% of those in the investigative and control arms, respectively, experienced any toxicity that was grade 3 or higher. None of these AEs resulted in death. Three percent versus 1% of those in the osimertinib and placebo arms, respectively, experienced serious AEs.

The most commonly reported AEs included diarrhea (46% with osimertinib vs 19% with placebo), paronychia (25% vs 1%, respectively), dry skin (23% vs 6%), pruritis (19% vs 9%), cough (18% vs 17%), stomatitis (17% vs 4%), nasopharyngitis (15% vs 10%), decreased appetite (13% vs 4%), upper respiratory infection (13% vs 9%), dermatitis acneiform (11% vs 5%), and mouth ulceration (12% vs 2%).
“With osimertinib, we have an oral TKI that can be used in the earliest stages of lung cancer,” Roy S. Herbst, MD, PhD, lead author of ADAURA and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, told OncLive in a recent interview. “I think that really heralds a new age for how we’re treating this disease.”

In July 2020, the FDA granted a breakthrough therapy designation to osimertinib for the adjuvant treatment of patients with stage IB, II, and IIIA EGFR-mutated NSCLC after complete resection with curative intent. Osimertinib received regulatory approval for frontline use in patients with locally advanced or metastatic EGFR-mutated NSCLC; it is also indicated for the treatment of patients with locally advanced or metastatic EGFR T790M mutation–positive NSCLC in the United States, Japan, China, and the European Union, among others.

1. Tagrisso granted priority review in the US for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer. News release. AstraZeneca. October 20, 2020. Accessed October 20, 2020.
2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5

This article was originally published on OncLive as, "FDA Grants Priority Review to Adjuvant Osimertinib for Early-Stage EGFR+ Lung Cancer."

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