FDA Grants Adjuvant Osimertinib Breakthrough Status in Early-Stage EGFR+ NSCLC


The FDA has granted a breakthrough therapy designation to osimertinib for the adjuvant treatment of patients with stage IB, II, and IIIA EGFR-mutated non–small cell lung cancer following complete resection with curative intent.

José Baselga, MD

The FDA has granted a breakthrough therapy designation to osimertinib (Tagrisso) for the adjuvant treatment of patients with stage IB, II, and IIIA EGFR-mutated non–small cell lung cancer (NSCLC) following complete resection with curative intent.1

The breakthrough designation is based on data from the phase 3 ADAURA trial, in which adjuvant osimertinib demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in patients with stage IB to IIIA EGFR-mutant NSCLC. Results showed that the EGFR TKI reduced the risk of disease recurrence or death by 79% in this patient population (HR 0.21; 95% CI, 0.16-0.28; P <.0001).2

In April 2020, an Independent Data Monitoring Committee recommended that the trial be unblinded 2 years early based on the efficacy findings.3

“Patients with early-stage EGFR[-mutant] lung cancer often experience recurrence even after successful surgery and adjuvant chemotherapy, yet there are currently no approved targeted treatments to improve outcomes,” José Baselga, MD, executive vice president, Oncology R&D, of AstraZeneca, the developer of osimertinib, stated in a press release. “The phase III ADAURA trial with Tagrisso demonstrated an unprecedented level of clinical benefit in these patients, and we are working closely with the FDA to deliver this potentially curative treatment to patients as quickly as possible.”

Up to 30% of patients with NSCLC may be diagnosed early enough to have potentially curative surgery, AstraZeneca stated in the press release. However, disease recurrence is common in early-stage disease and nearly half of patients diagnosed with stage IB disease, and over 75% of patients diagnosed with stage IIIA disease, will experience recurrence within 5 years.

In the international, randomized, placebo-controlled, double-blind, phase III ADAURA trial, 682 patients with primary nonsquamous stage IB to IIIA NSCLC harboring EGFR mutations, with exon 19 deletions or L858R mutations, were randomized 1:1 to receive 80 mg of osimertinib daily or once-daily placebo. Patients received treatment for 3 years, or until disease recurrence or discontinuation criteria were met.

The primary end point was investigator-assessed disease-free survival (DFS) in patients with stage II to IIIA disease. Secondary end points comprised DFS in the overall population; DFS at 2, 3, 4, and 5 years; overall survival (OS), safety, and quality of life.

Inclusion criteria comprised patients who had and had not previously received adjuvant chemotherapy. Patients also must have been at least 18 years old, had a World Health Organization performance status of 0 or 1, brain imaging if it was not completed in the preoperative setting, had undergone complete resection with negative margins, and had a maximum interval between surgery and randomization of either 10 weeks without adjuvant chemotherapy or 26 weeks if patients did undergo adjuvant chemotherapy.

Patients were also stratified by stage (IB vs II vs IIIA), EGFR aberrations (exon 19 deletions vs L858R substitution mutations), and race (Asian vs non-Asian).

Findings showed that, at 33% maturity, the median DFS was not reached (95% CI, 38.8—not calculable [NC]) with osimertinib compared with 20.4 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001).

Moreover, when looking at the overall population of patients with stage IB to IIIA disease, the median DFS was also not reached with osimertinib (95% CI, NC—NC) and was 28.1 months (95% CI, 22.1-35.8) with placebo at 29% maturity.

In the stage II to IIIA population, the DFS rates at 1, 2, and 3 years were 97%, 90%, and 80% with osimertinib, respectively; these rates were 61%, 44%, and 28% with placebo.

In the overall population, osimertinib led to DFS rates at 1, 2, and 3 years of 97%, 89%, and 79% with osimertinib, respectively. In the placebo arm, these rates were 69%, 53%, and 41% with placebo.

The DFS benefit with osimertinib was also observed in subgroups across the entire population, regardless of race, stage of disease, and type of EGFR aberration.

The OS data remain immature. Results to date show that the median OS was not reached in both arms, with a 60% reduction in the risk of death (HR, 0.40; 95% CI, 0.18-0.90).

Osimertinib was well tolerated with a safety profile that was consistent with its known safety profile. The median duration of exposure to osimertinib was 22.3 months (range, 0-43) compared with 18.4 months for placebo (range, 0-48), and there were no adverse effects (AEs) leading to death in the osimertinib arm.

The most frequent AEs were diarrhea, paronychia, and dry skin, though Herbst explained that the majority of these were of grade 1/2 in severity. Interstitial lung disease was reported in 3% (n = 10) of patients on osimertinib; additionally, QTc prolongation was reported in 7% (n = 22) of patients in the osimertinib arm versus 1% (n = 4) of patients on placebo.

Osimertinib is approved by the FDA for the first-line treatment of patients with locally advanced or metastatic EGFR-mutant NSCLC, and for the treatment of locally advanced or metastatic EGFR T790M mutation–positive NSCLC in the United States, Japan, China, and the European Union, among others.


1. Tagrisso granted Breakthrough Therapy Designation in the US for the adjuvant treatment of patients with Stage IB-IIIA EGFR-mutated lung cancer. News release. AstraZeneca. Published July 30, 2020. Accessed July 30, 2020. https://bit.ly/2P8Lgin.

2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl; abstr LBA5).

3. Tagrisso Phase III ADAURA trial will be unblinded early after overwhelming efficacy in the adjuvant treatment of patients with EGFR-mutated lung cancer. Published April 10, 2020. https://bit.ly/34xHVAd. Accessed May 26, 2020.

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