Ground-Breaking Data: Phase 3 ADAURA Trial

Roy S. Herbst, MD, PhD: The ADAURA trial, which was presented in a plenary session at ASCO (the American Society of Clinical Oncology annual meeting), was a phase 3 randomized trial that looked at adjuvant therapy with osimertinib, a third-generation EGFR inhibitor, versus placebo. Placebo was used because there is no standard of care after surgery or appropriate chemotherapy for patients with resected stage I, II, and III lung cancer. This was a worldwide trial in which patients enrolled had a complete surgical resection of their disease, after which they received platinum therapy, as indicated. A few of the patients with stage I had platinum, and most patients were stage II and III. Patients were randomized to osimertinib for a planned 3-year duration, orally once a day, versus placebo. Patients were followed for disease-free survival, the primary endpoint.

Patients were stratified by region—about two-thirds were from Asia—by the type of EGFR mutation, whether it was L858R or exon 19 deletion, and by stage. The first result was presented at the ASCO meeting. I was surprised to be presenting this year because we did not expect these data to read out for another year or maybe 2. However, at a planned safety analysis, the data safety monitoring committee saw that there was a great imbalance in terms of efficacy. It is unusual for a safety committee to stop a study for being so positive when it wasn't a planned interim analysis.

However, the results speak for themselves. The study was unblinded, and the results are now available. In the primary study group, which was stage II and III disease, two-thirds of the patients in the osimertinib group achieved the primary endpoint of disease-free survival. At 2 years, 90% of patients were disease-free versus 44% in the placebo group, an incredible result.

We expected this would be positive. We had targeted 0.7 as our hazard ratio. I would've been happy as an investigator and a clinician, who uses this at 0.6 and even 0.5 or 0.4, but 0.17 was an amazing result. When you add in the stage I patients, these patients will have a much better prognosis just because it's a much earlier disease. The hazard ratio went up only slightly to 0.21, so still a 79% improvement in disease-free survival, which is highly statistically significant.

So, on both the primary and the secondary analysis, this trial really hit it out of the park with very exciting results, and I’m glad we could share these at ASCO. A couple of other things that one would ask: what about different subgroups? In a trial like this, you would do a forest plot. You would look at different subgroups based on age, sex, race, type of EGFR mutation, stage of disease. And you might even look at whether they got chemotherapy, that's an important one.

In every case, the benefit favored the osimertinib versus placebo. The drug was also well tolerated. There were very few grade 3 or 4 [adverse] effects. No patients died on the osimertinib arm. There were grade 3/4 effects: rash, diarrhea in the 1% to 2% range. There were slightly more grade 1/2 diarrhea, rash and other toxicities you see with EGFR inhibitors in the patients who got the study drug, as has been expected and would be expected based on the FLAURA data and the other studies looking at this drug.

Importantly, there were no severe cases of interstitial lung disease. There were 10 cases of interstitial lung disease in the treatment arm, all low-grade, suggesting the drug could be given for the planned period, which is really exciting. This is the first presentation of these data. Of course, everyone is going to be waiting for more explanation of how patients did recur. Was it distant? Was it local? If it was local, what are the sites of recurrence?

You would think the brain would be a site that would benefit from osimertinib with its high CNS (central nervous system) penetration. The liver, lung, bone will also be evaluated. Secondary therapies, quality of life, and survival will also be looked at. There is no survival benefit at this time; that will be looked at in the future.

Transcript edited for clarity.