Three years ago, the phase 3 ADAURA trial associated osimertinib (Tagrisso, AstraZeneca) with a large disease-free survival (DFS) advantage when it was tested as an adjuvant therapy in resected EGFR-mutated non-small cell lung cancer (NSCLC). But the overall survival (OS) benefit newly established with longer follow-up is a big deal, according to the trial investigators. The trial findings were reported at the 2023 annual meeting of the American Society of Clinical Oncology (abstract LBA3).

“[Despite the substantial DFS benefit] we know that some clinicians have still been reserving osimertinib for later lines of therapy,” explained Roy Herbst, MD, PhD, the chief of medical oncology at Yale School of Medicine, in New Haven, Conn. “Now that we have shown improvement on OS, it should instill confidence that adjuvant osimertinib is the standard in this setting.”

In the ADAURA trial, 682 patients with stage IB to IIIA EGFR-mutated NSCLC were randomized to 80 mg of once-daily osimertinib, a selective inhibitor of EGFR, or placebo, remaining on therapy until disease recurrence or unacceptable side effects. At the first analysis, there was an 83% advantage for the primary end point of disease recurrence or death for osimertinib after 24 months of follow-up (hazard ratio [HR], 0.17; P<0.001). 

For the newly reported OS outcome, a secondary end point that was evaluated after nearly four years of median follow-up, osimertinib was associated with a 51% reduction in all-cause mortality (HR, 0.49; P<0.001). For the subgroup of patients with stage II to IIIA disease, the five-year survival was 85% and 73% in the osimertinib and placebo arms, respectively, producing the same relative OS reduction (HR, 0.49; P<0.001).

The relative advantage of osimertinib was consistent, and in most cases statistically significant within stratifications for age, sex, smoking history, disease stage, type of EGFR mutation and exposure to adjuvant chemotherapy.

At the data cutoff earlier this year, more than half (54%) of the placebo patients versus only 22% of those in the osimertinib arm had received a subsequent anticancer therapy, which in most cases was the same or another small-molecule tyrosine kinase inhibitor targeted at EGFR. A minority of patients received chemotherapy (<30%) or radiotherapy (<40%) in either arm.

The tolerability of osimertinib was essentially unchanged in the more recent follow-up relative to the previously reported ADAURA results. Grade 3 or higher adverse events were more common on osimertinib (11% vs. 2%), but low in both arms.

Dr. Herbst cited data that NSCLC patients are not uniformly tested for EGFR mutations, but he said this study provides compelling evidence for uniform testing in NSCLC. “If we do not identify the patients with EGFR mutations, then we will not be able to select them for a therapy that reduces mortality,” he said.

The ASCO-invited discussant, Nathan Pennell, MD, PhD, of the Cleveland Clinic Taussig Cancer Institute, agreed. “In this select group of NSCLC patients, adjuvant osimertinib unequivocally and dramatically improves survival,” said Dr. Pennell, reiterating that this should be a new standard. He said the study supports uniform EGFR testing in order to supplant the one-size-fits-all NSCLC treatment approach that was used previously but is no longer appropriate. 

—Ted Bosworth

Dr. Herbst reported financial relationships with more than 40 pharmaceutical companies, including AstraZeneca, which provided funding for the ADAURA trial. Dr. Pennell reported no relevant financial disclosures.