Video
Phase 3 ADAURA Study: EGFR-Mutated NSCLC
Author(s):
Benjamin P. Levy, MD: Let’s move on to a strategy that has worked recently, at least from a disease-free survival [DFS] end point, and that is adjuvant osimertinib. There clearly were very thought-provoking and potentially practice-changing data presented at ASCO [American Society of Clinical Oncology Annual Meeting], and we’ve had updates at ESMO [European Society for Medical Oncology Congress] that are also clinically important.
Dr Naidoo, can you talk to us a little about ADAURA’s study design and outcomes and then highlight some of the updates we found out about at ESMO this year?
Jarushka Naidoo, MBBCh: Sure. So ADAURA is causing a stir on every possible airwave. This was a phase 3, double-blind, randomized study. Theoretically, this was a simple study design of adjuvant osimertinib vs placebo in patients with stage IB, II/IIIA EGFR-mutant non–small cell lung cancer. This was a simple study where just over 600 patients were randomized in equal parts to placebo vs osimertinib.
The study was stopped early because of efficacy seen on the investigational arm by an independent data-monitoring committee. This was based on the outcome for the disease-free survival end point for patients with stage II to IIIA disease who had been enrolled. It showed a hazard ratio of 0.17, which was highly statistically significant. And then in the overall population, there was a DFS hazard ratio of nearly 0.21. Again, highly significant.
This equated to an 89% 2-year disease-free survival rate, compared with 53% on placebo. We saw the full publication about this in the New England Journal of Medicine very recently.
Controversially, the overall survival outcome was immature—only 4% maturity. Of course, this is because the study was stopped early, which obviously complicates our ability to interpret some of these things and has created quite a war between the believers and nonbelievers regarding the DFS vs OS [overall survival] end points.
Moving on to the second part of your question about ESMO, what is really interesting is Dr [Masahiro] Tsuboi and colleagues presented an abstract at ESMO looking at the sites of recurrence in patients treated as part of ADAURA. This was an exploratory end point within the study.
All patients enrolled in the study were mandated to have some form of brain imaging, but only in the absence of symptoms, and this could have included MRI or CT scans of the brain—whichever was available at that particular institution. Very interestingly, 45 patients had CNS [central nervous system] events. Only 6 CNS events were noted in the osimertinib arm compared with 39 CNS events in the placebo arm.
The median CNS DFS was not reached. It was 48.2 months for the placebo arm, and a very impressive Kaplan-Meier curve of the CNS DFS presented showed that the osimertinib arm nearly looked parallel, with a hazard ratio of 0.18.
Obviously, as we know, brain metastases is a very common outcome in patients with oncogene-addicted lung cancers—EGFR-mutant lung cancers, and others. Patients can be very symptomatic. This can be a very difficult complication of this disease. It is difficult to manage. The idea that 1 could actually prevent CNS disease from occurring with adjuvant osimertinib is clinically important.
Obviously, there are some issues here in terms of the interpretation of these data. Not every patient was necessarily required to have baseline imaging, and that baseline imaging may have been different. As we know, CTs of the brain may miss about 10% of brain metastases compared with MRIs of the brain.
This may complicate our ability to interpret these results and may sort of say that these results may actually be telling us that osimertinib was treating subclinical disease in some cases. But regardless, a very impressive CNS DFS, and different and interesting data.
Benjamin P. Levy, MD: That was a very nice summary, highlighting the pros and cons of both the original presentation and now the ESMO update with this potential theoretical protection of the CNS that we’re seeing but without mandated MRIs.
Dr Leal, what is your take on this? Is DFS enough? Do we need OS? We’ll probably never have it. The study was stopped prematurely. We’ve talked about how challenging and unforgiving lung cancer can be, even with resected lung cancer, and high rates of relapse. How do you put this all together, and what are you doing in your clinic?
Ticiana Leal, MD: The results presented are very impressive, and there’s room for a lot of optimism. Obviously, we’d love to have OS results. That’s the gold standard. If we’re not going to get that data, I’ll take DFS. For patients who have this disease and for whom we worry about their outcomes, these results are meaningful. They are meaningful enough that if we don’t get OS data I would definitely still take action on it, with approval on DFS end point.
That being said, I have not yet changed my practice. I’ve been waiting to see the data evolve. I’m waiting to see an FDA approval. We have the ALCHEMIST trial at our institution. We are still enrolling patients to ALCHEMIST. There is an EGFR targeted therapy arm. But I think it will come soon, and I am having the discussion with patients. I’m explaining to patients, “These are the results. This is what’s coming.” It’s just a matter of time before I really incorporate it into my clinical practice.
Benjamin P. Levy, MD: Dr Zhang, what are your thoughts on this? Does this change things for you?
Jun Zhang, MD, PhD: Yes. When you look at the initial design of study and their defined hazard ratio, they still ended up with 0.17. This is of dramatic significance. And I agree with Dr Leal. Even if there’s no OS data, I definitely will still prescribe osimertinib once it’s FDA approved for those patients based on these significant, unprecedented results of DFS.
Benjamin P. Levy, MD: Dr Salgia, what are your thoughts on ADAURA?
Ravi Salgia, MD, PhD: Because we have a large patient population with EGFR mutations, patients have been very well informed through social media, through the various articles, and their families. If you don’t bring it up, in terms of thinking about osimertinib in the adjuvant setting, patients will.
For early stage disease, we’ve been doing a molecular analysis. If they potentially have a L858R exon 19 deletion, we do consider that if they don’t qualify for a clinical trial. But the more important issue is getting payer approval. We have to make sure this is paid for because the cost-effectiveness analysis does not give us the opportunity to give osimertinib to everyone. It’s almost $18,000 a month. So we have to make sure that it’s affordable.
Benjamin P. Levy, MD: Nicely done. This is a balanced discussion. I’ll play naysayer, and I’d love to get people’s reactions. How can we justify the routine use of the drug given the cost of $20,000 a month in the absence of OS data and with a poorly designed trial? You know, we’re not looking at early vs delayed.
How many patients with metastatic disease who met it out in the control arm actually get osimertinib? And why give the drug now when you can give it when patients relapse? Is there an answer to this? These are the common questions that we continually get on this—cost, no OS, poorly designed. Also, a high percentage of patients didn’t get adjuvant chemotherapy and weren’t properly treated. So can we routinely justify this in the absence of OS data given the challenges posed?
Jarushka Naidoo, MBBCh: I’m normally on that side of the fence, but just to play the other side, it would be very difficult, very challenging to do a study where we actually compared, head-to-head, the outcomes for a patient who got adjuvant treatment vs if they got it in a metastatic setting. That would be a very challenging study to do.
Also, the feeling or the basis on which we believe or we advocated for adjuvant therapy in the past is that once patients develop metastatic disease, treatment is not given with the intent of cure. But we know that in the adjuvant setting this is the goal. Let’s face it, that is the most meaningful, the most powerful goal we can every achieve as cancer specialists.
If we have a shot at cure, therein lies the reasons why many would be open to the use of adjuvant osimertinib, even with an end point that isn’t necessarily considered the gold standard.
Transcript Edited for Clarity
