Adjuvant Osimertinib Improved Overall Survival for Patients With EGFR-Mutant NSCLC

Overall Survival Analysis of the ADAURA Trial

At the 2023 ASCO Annual Meeting, Roy Herbst, MD, PhD, Yale Cancer Center, shares results from the overall survival analysis of the phase 3 ADAURA trial, evaluating adjuvant osimertinib for patients with resected EGFR-mutated non-small cell lung cancer. 

Osimertinib, as Dr Herbst said, "is the first drug in TKI in the adjuvant setting to improve survival in lung cancer. The first EGFR TKI, this survival is improved with minimal toxicity effect."

Transcript:

Hi, I'm Dr. Roy Herbst, Deputy Director of the Yale Cancer Center and Assistant Dean for translational research at the Yale School of Medicine. I'm very excited to tell you about my plenary abstract at the ASCO meeting last week. We presented the ADAURA study and the first trial to show that a [tyrosine kinase inhibitor] TKI, in this case, an EGFR TKI, improves survival in the adjuvant setting in EGFR-mutant non-small cell lung cancer.

Let me give a bit of a background. We know that lung cancer is a very devastating disease with almost 2 million deaths a year worldwide. We also know that about a third of lung cancers are found early and those are lung cancers that are potentially curable. Now, in that setting, we do surgery. Radiation is sometimes done and then, of course, adjuvant chemotherapy, but that has a minimal benefit. It does have a survival benefit, but a great deal of toxicity as well, but only in the order of 5% to 8%.

In patients that have EGFR gene mutations, which is a common abnormality, it's anywhere from 15% in the Western world to 40% in the East of patients have EGFR mutations. If we can identify those before surgery, we can treat these patients more effectively. Why? Because we can, after complete resection of their cancer, after adjuvant chemotherapy, when indicated, they can get osimertinib. And in this trial, they either got osimertinib or placebo and as we showed, there's a great benefit.

The trial basically was as follows. We took patients with stage IB to IIIA disease worldwide study. Two thirds of the patients enrolled in Asia. Two different EGFR mutations were allowed: exon 19 deletions, and exon 21 L858R were allowed as well. Patients had complete R0 resection. After resection, they were stratified by stage, by the type of mutation and by their region, and then they were randomized to either osimertinib 80 mg or a placebo for 3 years. Many people asked, "Dr. Herbst, why a placebo?" Because no other trial had even shown a successful disease-free survival [DFS] benefit for an EGFR TKI in this setting, not to mention survival benefit. The treatment proceeded for 3 years, as I mentioned, and 3 years ago, I actually presented a Plenary at ASCO virtually, and we showed that the disease-free survival in the primary population stage II and III disease was 0.17 hazard ratio or an 83% improvement in disease-free survival. When we added in the stage I patients, a secondary analysis, the hazard ratio was 0.2 or an 80% benefit. So we've known that for a while. We also knew from 3 years ago that brain metastases were prevented. That's probably why this is working. Metastases to the brain, liver, bones are prevented. The hazard ratio there was 0.18 or an 82% decrease. So that's where we stood at that point. The toxicity was as you would expect for an EGFR TKI, but this is a different type of EGFR TKI. It's EGFR mutation specific and has better potency in the brain and better potency against T790M. So it was really well tolerated, with some rash and diarrhea, and there are some side effects, but no one died from the drug on the trial.

Many people said, "Well, the drugs works" and it actually was approved in the US and many other countries, but other countries were waiting to reimburse the drug or to approve it based on survival data, the ultimate endpoint. And also many patients were asking, is there a survival benefit? And many doctors, I know surgeons that I've met across the world over the last several years have said, "Does this improve survival?" Well, the answer is a resounding, "Yes." At the Plenary Podium on June 4th, I showed that when you use this drug versus placebo, the hazard ratio is 0.49. These are survival curves that separate early at median followup of 5 years in both arms, 85% alive in the treatment group versus 73% in the control at 5 years with a hazard ratio of 0.49, that's a 51% improvement in survival, decrease in death, totally outstanding result. We also saw that when we added in the stage I patients.

Moral of the story, osimertinib is the first drug in TKI in the adjuvant setting to improve survival in lung cancer. The first EGFR TKI, this survival is improved with minimal toxicity effect, and it's a great thing for patients because it gives a very nice new option for patients around the world. Again, already approved based on DFS in many places, but now even more available and even more attractive to patients because of the survival benefit.

I presented on behalf of a worldwide team. My co-steering committee members are Dr Masahiro Tsuboi from Japan, Dr Yi-long Wu from China. We work with a team of physicians around the country with doctors from AstraZeneca, which supported this study. And now we're continuing to analyze these data. I'm very excited in the next month to look at the circulating tumor DNA data. We have blood specimens on these patients, so we can look at circulating tumor DNA and understand when patients become resistant, how they become resistant. And then we'll learn. Some patients might need more, some less osimertinib because we do know that resistance will be a problem and persistent tumor cells can exist.

For now, wonderful survival results. And we left ASCO with a new paradigm for the treatment of lung cancer, which I predict, will now be used with other driver mutation abnormalities. ALK is probably next up. Really great news for patients with this disease that we're making progress, we're bringing science from the lab and using these drugs to prevent metastases and allow patients to live longer.

Source:

Herbst R, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract LBA3