ADAURA Trial: Adjuvant Osimertinib and Clinical Implications

Dr. Zofia Piotrowska: To frame this conversation about early-stage disease, we really have to start by talking about the ADAURA study. And so, Ashish, we heard about ADAURA first in 2020 in the plenary session of that virtual ASCO, and maybe, let's start by actually just diving right into the ADAURA data. Can you tell us a little bit more about that study?

Dr. Ashish Saxena: Yeah, so, the ADAURA trial was a phase three, double-blind, randomized-control study of patients with surgically resected stage 1b to 3a non-squamous non-small cell lung cancer whose tumors harbored actionable eGFR mutations, specifically, the exon 19 deletion mutation or the eGFR L858R mutation. Now, all of these patients, as they said, had to have had a complete resection. They were allowed to get adjuvant chemotherapy, which they did about 60% of the time, but it wasn't required. But regardless of that, they were randomized one-to-one to either get osimertinib at 80 milligrams daily for up to three years or a placebo. So, it was a placebo-controlled trial. The population was- I should start with the endpoints. The primary endpoint was disease-free survival in the group that was stage 2 to 3a, and then that was the primary endpoint. The secondary endpoint was disease-free survival in the total population as well as overall survival and safety. And the population was pretty much what you would expect in this group as we talked about, there was about 60% of the patients were Asian, 70%, roughly, were female, and 70% were never smokers. The age was a little bit on the younger side around the early 60s, and most of the patients, about 97% ended up getting a lobectomy. And so, the data itself was really encouraging and was positive in that the median disease-free survival was 66 months in the group that got osimertinib both in the group that was stage two to stage three A and the overall population. And that was compared to the placebo population had a median disease-free survival of about 22 months in the stage 2 to 3a population and about 28 months in the overall population. So, it was highly statistically significantly positive. The hazard ratio was 0.23 in the primary endpoint population from stage two to three A, and in the overall population, it was also high at 0.27. The patients had a higher chance of not having CNS progression, than the ones that got osimertinib. So, that was also an important endpoint with a really statistically significant high hazard ratio in that as well. In terms of safety, it had no new safety signals. It basically showed the toxicities that we're used to seeing paronychia, diarrhea, and dry skin. It was about a 3% ILD risk, and maybe, a 6% or so risk of cardiac events. There was maybe about a 13% dose reduction rate and a 12%- Or 12% dose reduction rate and 13% dose continuation rate. So again, pretty well tolerated, which is what we're used to seeing in the stage-4 setting. And even in the quality-of-life assessments, there was no difference in time to deterioration in those metrics.

Dr. Zofia Piotrowska: Thank you so much for that overview. It was really, I think, such an important study and really such a paradigm shift for us back in 2020 when this was presented. I remember thinking at the time that it was too bad, that it was the kind of peak of the pandemic, and we were all watching it from home and not being able to share it together because it was such an important moment. So, I'm curious, and maybe, Jay, for you and for all of us, as a- What was your take on ADAURA back then if we rewind a little bit to three years ago? Did you feel like the disease-free survival benefit was enough to change your practice and start referring patients to medical oncology to consider this or did you feel like you needed more data to convince you? And I'll ask the same question to the rest of our medical oncologists as well.

Dr. Jay Moon Lee: Well, first of all, ADAURA was a landmark study in that it really thrusts forward the role of targeted therapies in the resectable space. It is a landmark study and doing that, it introduced the concept of the need for biomarker testing, and molecular testing in the early-stage setting. So, with that respect, it's such an important study and a hallmark study. The hazard ratios for the DFS were so impressive, but the track record of TKS prior to that was that it was either neither significant in the DFS/EFS hazard ratios or it didn't get confirmed or validated in the OS data. So, there was skepticism about whether is this going to play out and be validated with the OS data. But for me, I think the DFS data was sufficient. The CNS efficacy with osimertinib and the superiority of that in preventing CNS events was, at minimum, a quality-of-life issue that improved that issue amongst patients in the resectable space. So, very meaningful study.

Dr. Zofia Piotrowska: Absolutely, and-

Dr. Nicholas Rohs: I'd say- I'd have to agree with Jay there, is that he touched on some really important points there. This is a landmark study. I think the DFS hazard ratio was striking to us. These are numbers that we're not used to seeing in lung cancer. And the CNS protection, because eGFR-mutated lung cancers love to go to the CNS to see that CNS protection is really important. But as you said also, DFS has not always translated into OS. So, I harbored some reservations, but this seems striking enough that I did start adopting it, at least for my stage 2bs and 3as, the more advanced patients. I was a little bit more reserved for my earlier-stage patients, but at that point, I thought it probably had enough importance, but we also will probably touch on this a little bit later, is that I also thought there is a subset of patients that don't deserve any sort of therapy. They're cured by their surgery. So, which is that subset that we shouldn't be treating with osimertinib? But given the dramatic benefit that seemed to be coming, it seemed like a really good conversation, and a conversation I had with my patients pretty much right after that data came out.

Dr. Zofia Piotrowska: I think such important points. Lyuda, what was your take?

Dr. Lyudmila Bazhenova: I agree with what you guys did. I think the decisions we make when we are treating patients with adjuvant therapy are done with the patient and not for the patient. So, when the first results of the other trial were presented when I was explaining the data to the patients, I would explain that we don't know if it increases survival. We don't know if it provides a higher cure rate, but what we know is that it will delay the recurrence. And the meaning of delay recurrence has a different feel for different patients. If we have a young patient, for them, delaying the recurrence means that they're not going to tell their kids that “my cancer's coming back,” and they don't have to put their life on hold, versus for some elderly person, 85, 90-year-old, maybe for them, delaying recurrence is not as important. So, I think it is- As for us as medical oncologists, it's important to make sure we translate the data of the study into a patient-understandable language and make a decision together with the patient.

Dr. Nicholas Rohs: And I'll say- Probably, the other thing is, my concern was what would happen after osimertinib? If that patient progresses after osimertinib, what's going to be the genetic landscape I'm dealing with? And I assume I've essentially used up osimertinib as a therapy, and if there isn't an overall survival benefit, did I use a really good therapy and not use it the right way? But again, I still wanted to adopt it pretty early on.

Dr. Ashish Saxena: I think it's always during the time we were worried about what's the overall survival going to be, but I think, as Nick said, we weren't used to seeing such impressive numbers. So, I think that's what made me also adopt it, and thinking the patient is here right now in front of me who has this resected cancer, who has an EDFR mutation, and am I going to withhold it and say, "Well, I just want to wait for more data," which is hard to do in the real-life setting?

Dr. Zofia Piotrowska: I am totally on the same page. I think, Lyuda, your point about individualizing these decisions for patients is so incredibly important, and it's not the same calculus for each patient, but I was actually surprised by the patients who came to me. I think they were also very much on board having read and kind of studied this. I think many patients were also really excited by this data. But of course, as we all alluded to, I think the elephant in the room was, what is the overall survival going to look like? Are we actually curing these patients or are we simply delaying the time to recurrence? Which I think is still an important factor, but clearly, what we are looking for in that adjuvant setting is the cure.