"Adjuvant osimertinib is the first targeted agent in a global randomized trial to show a statistically significant and clinically meaningful improvement in disease-free survival in patients with stage IB/II/IIIA EGFR mutation–positive non–small cell lung cancer."
In the phase 3 ADAURA trial (NCT02511106), treatment with osimertinib (Tagrisso) in the adjuvant setting lead to an 83% reduction in the risk of disease recurrence or death in patients with stage II to IIIA EGFR-mutant non–small cell lung cancer (NSCLC), according to interim findings presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program demonstrate.1
Additionally, in patients with stage IB to IIIA disease, which was the overall study population, osimertinib demonstrated a 79% reduction in the risk of disease recurrence or death (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).
"Adjuvant osimertinib is the first targeted agent in a global randomized trial to show a statistically significant and clinically meaningful improvement in disease-free survival in patients with stage IB/II/IIIA EGFR mutation–positive non–small cell lung cancer," said lead author Roy S. Herbst, MD, PhD, who is the chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, and the associate cancer center director for Translational Research at Yale Cancer Center, in a press conference ahead of the program. "Therefore, adjuvant osimertinib provides a highly effective, practice-changing treatment for [these patients] after complete tumor resection."
In April 2020, a press release announced that the ADAURA trial results had been compelling enough that an independent data monitoring committee recommended early unblinding of the study. At the time of the unblinding, the trial had completed enrollment and all patients were followed up for at least 1 year.2
NSCLC represents 85% of all lung cancer cases, with an estimated 30% of these patients presenting with resectable disease at the time of diagnosis. While surgery is the primary treatment for patients with early-stage NSCLC, recurrence rates remain high.
Adjuvant chemotherapy is standard of care in patients with stage II to IIIA NSCLC who have undergone complete tumor resection and select patients with stage IB disease; however, outcomes need to be improved as the 5-year overall survival (OS) benefit with chemotherapy is 5%.
In patients with stage IB, II, and III disease, the 5-year recurrence rates are 45%, 62%, and 76%, respectively, Herbst explained.3 The efficacy and safety profiles of osimertinib, which is a third-generation EGFR TKI, suggest that the drug may be an effective treatment for patients with early-stage disease, he said.
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).
Results 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.
"I have done many of these [forest plots] over the years, and you almost never see this. In every category, [and regardless of] sex, age, smoking status, race, stage of disease, EGFR mutation status, and whether or not the patient received chemotherapy, all of the results are favoring the study drug osimertinib," said Herbst.
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.
Moreover, grade 3/4 AEs were low, Herbst said. 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.
Richard L. Schilsky, MD, FACP, FSCT, FASCO, ASCO chief medical officer and executive vice president, also provided commentary on the ADAURA findings during a presscast ahead of the 2020 ASCO Virtual Scientific Program.
"While osimertinib is already the frontline standard of care for patients with EGFR-mutated advanced non–small cell lung cancer, the improvement in disease-free survival following surgery that was seen in the ADAURA study supports the use of this targeted therapy in earlier-stage disease, which typically has a high recurrence [rate] despite surgical treatment and chemotherapy."
Osimertinib is currently approved by the FDA as a first-line treatment for patients with metastatic NSCLC with tumors that have EGFR mutations, which includes exon 19 deletions or exon 21 L858R mutations.
1. 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).
2. 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.
3. American Joint Committee On Cancer. AJCC Cancer Staging Manual: seventh edition. Published in 2010. https://bit.ly/2ZGnssM. Accessed May 26, 2020.