Adjuvant Osimertinib Extends DFS in Localized NSCLC

Neil Osterweil

May 29, 2020

Adjuvant therapy with osimertinib was associated with a nearly 80% reduction in the risk of disease recurrence or death in patients with stage IB-IIIA non–small cell lung cancer (NSCLC) bearing EGFR mutations, results of the ADAURA trial showed.

The randomized, phase 3 trial was a comparison of osimertinib treatment with placebo following complete resection of localized or locally advanced NSCLC with negative margins. The trial was unblinded early and halted on the recommendation of the independent data-monitoring committee, due to the efficacy of osimertinib.

"If I were on the committee, I would have done the same thing. These are extraordinary results," said study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center and Smilow Cancer Center at Yale University in New Haven, Conn.

Dr. Herbst is scheduled to present results from ADAURA as part of the American Society of Clinical Oncology virtual scientific program.

In an online briefing prior to the meeting, Dr. Herbst said the impressive results reminded him of a lesson imparted by his mentor, the late Isaiah Fidler, DVM, PhD.

"He taught me, he taught all of us, that metastasis is a spread of tumor that kills patients," Dr. Herbst said. "Drugs such as this, based on biology, given to patients at the earliest possible time, prevent those metastases and allow patients to live longer and with a better quality of life."

Results from the ADAURA trial provide compelling evidence of the benefit of adjuvant osimertinib for a select group of patients, according to Tina Cascone, MD, PhD, assistant professor in the department of thoracic head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. She was not involved in the study.

"These are unprecedented results for a potentially curable, resected population of patients," Dr. Cascone said in an interview. "This definitely has the potential to shift the paradigm in the treatments that we have available for patients with resected disease. Its very important to emphasize how much weve learned from the metastatic setting and how were bringing what weve learned into early stage disease."

High Recurrence Rates

An estimated 30% of patients with NSCLC present with resectable disease at diagnosis, but 5-year recurrence rates following surgery and cisplatin-based adjuvant chemotherapy remain high, ranging from 45% among patients with stage IB disease to 62% for patients with stage II NSCLC and 76% for patients with stage III disease, Dr. Herbst noted.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) targeted to EGFR. It has been shown to offer improvements in both progression-free survival and overall survival compared with the EGFR-TKIs erlotinib and gefitinib for patients with advanced EGFR-mutated NSCLC, as well as in patients with central nervous system metastases.

Osimertinibs efficacy and safety profile against advanced disease suggests it may also be effective against early stage disease, a hypothesis the ADAURA trial was designed to test.

Study Details

The phase 3, randomized, double-blind trial was conducted at centers in the United States, Europe, Asia, and Australia. A total of 682 patients with completely resected stage IB, II, or IIIA NSCLC, with or without planned adjuvant chemotherapy, were enrolled.

After stratification by stage, EGFR mutation, and race (Asian vs. non-Asian), patients were randomized on a 1:1 basis to receive either osimertinib at 80 mg once daily or placebo. The planned treatment duration was a maximum of 3 years.

Members of the independent data-monitoring committee held a meeting in April 2020. Although they had not planned an efficacy analysis at that time, they decided the results were clearly in favor of osimertinib. So they recommended unblinding and halting of the trial.

At the time of unblinding, the study had completed enrollment, and all patients had been followed for at least 1 year.

Efficacy and Safety

For the primary endpoint of disease-free survival (DFS) in patients with stage II to IIIA disease, the median DFS was not reached for patients assigned to osimertinib, but it was 20.4 months for patients assigned to placebo (hazard ratio, 0.17; P < .0001).

The numbers were similar for the secondary endpoint of DFS in the overall population, including patients with stage IB disease. The median DFS was not reached for patients on osimertinib but was 28.1 months for patients on placebo (HR, 0.21; P < .0001).

DFS was significantly superior with osimertinib across all subgroups in the overall population, including sex, age, smoking status, race, stage, EGFR mutation, and adjuvant chemotherapy (yes or no).

Dr. Herbst said patients tolerated osimertinib well, and the drugs safety profile was consistent with that already known. There were no adverse events leading to death in the osimertinib arm, and the incidence of grade 3 or 4 adverse events of any kind was low.

In all, 10 patients (3%) in the osimertinib arm were reported to have interstitial lung disease. Prolongation of the QT interval was reported in 22 patients (7%) on osimertinib and 4 patients (1%) in the placebo arm.

The results show that "adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB, II, IIIA, EGFR mutation-positive non–small cell lung cancer after complete tumor resection," Dr. Herbst said.

Dr. Herbst disclosed relationships with AstraZeneca, which funded the study, as well as Jun Shi Pharmaceuticals and other companies. Dr. Cascone is the international principal investigator of the NeoCOAST trial evaluating durvalumab, an AstraZeneca product.

SOURCE: Herbst RS et al. ASCO 2020, Abstract LBA5.

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