Experts Debate the Significance of ADAURA Data With Adjuvant Osimertinib in EGFR+ NSCLC

Charu Aggarwal, MD, MPH

The phase 3 ADAURA trial continues to generate a lot conversation, debate, and excitement in the lung cancer community after results showed that adjuvant osimertinib (Tagrisso) showed a statistically significant improvement in disease-free survival in patients with stage IB-IIIA EGFR-positive non–small cell lung cancer (NSCLC), making it the first agent to do so in the space.

In this phase 3, double-blind, randomized, placebo-controlled trial, 682 patients with completely resected state IB, II, IIIA NSCLC, with or without adjuvant chemotherapy, were stratified by stage, EGFR mutation, and race and randomized 1:1 to receive either osimertinib at 80 mg once daily or placebo once daily. The primary end point of the trial was DFS in patients with stage II/IIIA disease.

Results presented during the 2020 ASCO Virtual Scientific Program showed a that the DFS had not been reached with osimertinib (95% CI, 38.8–not calculated [NC]) versus 20.4 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001) in those with stage II/IIIA disease. In the overall population, the DFS still was not reached with osimertinib (95% CI, NC-NC) versus 28.1 months (95% CI, 22.1-35.8) with placebo (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).

In a special episode of OncLive On Air, we passed the mic to Charu Aggarwal, MD, MPH, a medical oncologist at Abramson Cancer Center and the Leslye M. Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania’s Perelman School of Medicine, who moderated a discussion on the trial.Aggarwal was joined by:

• Lecia V. Sequist, MD, MPH, the Landry Family Professor of Medicine at Harvard Medical School, director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital, and a medical oncologist at Massachusetts General Hospital Cancer Center
• Nathan Pennell, MD, PhD, professor of medicine and member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center, a medical oncologist at the Taussig Cancer Center, and director of the Lung Cancer Program at Cleveland Clinic

In their discussion, the expert panel covered the encouraging findings from the trial, potential clinical and financial concerns of using osimertinib in the adjuvant setting, and the next steps for this approach in practice.

ADAURA Shows Promise of Adjuvant Approach

Aggarwal: We're here today to discuss results from the ADUARA trial, which has made quite a few waves in the lung cancer community since it was presented at the 2020 ASCO Virtual Scientific Program. Just to bring everyone up to speed, this was a phase 3 randomized trial that included 682 patients with completely resected stage IB, II, or IIIA nonsquamous NSCLC that harbored the exon 19 deletion or the LA58R mutation in the EGFR domain.

Following receipt of standard-of-care therapy, patients were randomized to receive up to 3 years of osimertinib or placebo. We saw data that reported a significant improvement in DFS for patients who received adjuvant osimertinib. It's important to note that we saw 2-year DFS data and a hazard ratio (HR) of 0.17 in favor of patients who received osimertinib, necessitating an early reporting of these data at the meeting.

[Dr. Sequist and Dr. Pennell], I was very impressed when I saw these HRs, and [results were] especially spectacular in the patients that had stage II and IIIA disease. What are your thoughts?

Pennell: I agree; it was incredibly impressive. I’m trying to put myself in the shoes of the independent data monitoring committee when they saw this interim analysis. I think it's important to stress that this wasn't the planned analysis of the trial. In fact, there was only 22 months of follow up on the trial and the treatment duration is 3 years. Almost everyone was still in the treatment phase of the trial when it was unblinded.

The primary end point, which was in patients with stage II and IIIA disease, a HR of 0.17 is [impressive]’ I don't remember another trial with that level of a difference. That translated to an absolute difference in 2-year DFS of 46%; 90% of patients were disease free at 2 years in the osimertinib arm versus 44% in the placebo arm. In one way, this was not unexpected because in previous trials with EGFR TKIs, we have seen that approximately 90% of patients would be disease free at 2 years on the TKIs. However, for the first time in a randomized study, we saw how devastating the recurrences are in patients who don't receive TKIs with this disease. We are left with this very impressive curve and we now have to decide what to do with this data. Dr. Sequist, what do you think?

Sequist: I agree with you both. I was blown away in a positive manner with this data. It was great to see, because as Dr. Pennell alluded, this trial doesn't stand in isolation. There's 10-plus year history of looking at this type of strategy, of genotype-directed therapy in the adjuvant setting. The main critique of prior studies were that the trials designs; we couldn't move this into practice because the design wasn't quite right. This is the first study with an excellent design that we can really feel comfortable talking to patients about.

Back around 2011, Memorial Sloan Kettering Cancer Center first published some retrospective data on some of their patients who were treated with adjuvant TKIs. Of course, that [research] was interesting, and parameter setting, for what the treatment [approach] might [eventually] show. However, [the study] wasn't randomized; it was based on physician choice. We had the RADIANT study and the ADJUVANT/CTONG1104 study from China that were both randomized, but maybe not designed quite right. Then we had the SELECT trial, which was very informative, but it was a single-arm trial. These are the data we have all been waiting for with regard to this strategy.

Addressing Concerns Raised By Community

Aggarwal: There's been a lot of concern with the maturity of the trial. There’s only about 29% maturity for even the DFS data. Some of these results may not translate into an overall survival (OS) benefit. I've been very mindful of the fact that we don't have an OS advantage yet, but at least in the preliminary analysis that was presented, a HR of 0.4 in favor of the osimertinib arm looks favorable. Of course, we have to wait and see how these results translate into an actual OS benefit.

However, still, for patients who have this particular mutation, this is a therapy based on these results that really argues for a discussion in the clinic about the benefit that we see with DFS and the lack of OS data at this point in time. What are your thoughts about the clinical concern regarding lack of OS [data]?

Pennell: It's absolutely valid to be concerned about this. Ultimately, what we care most about is: Are we actually curing more patients with the drug? Short of potential cure, are we significantly prolonging their survival? Is it meaningful to delay recurrence in patients? The reality is, it's way too early for us to know whether there's a difference in OS. Because patients, even with stage 4 EGFR-positive disease live potentially, for a median of an excess of 3 years per the FLAURA trial, it’s going to be potentially years from now before we'll really know the difference. It's possible that we might see a result earlier than that; it depends on whether the patients who recurred had access to effective EGFR targeting therapy at the time of recurrence.

We also know that lung cancer is a devastating disease and many of these patients who recur may not even survive to go onto treatment. It's certainly a reasonable argument to make, to wonder if survival might be the same if they recovered and retreated at recurrence, but at the same time, I don't think we can make that assumption. If there isn't a survival benefit, despite a HR of 0.17, then that would put a nail in the coffin of adjuvant EGFR therapy, because this is about as big a difference as you can see. It would be hard to imagine there's not eventually going to be a difference. I certainly believe that the data are good enough to sit down and have a conversation with patients to discuss whether this is worth using at this point.

Sequist: One thing I've heard people say is that the fact that this study was unblinded and presented publicly at this early time point is going to somehow compromise or taint our ability to ultimately see OS. I'm still trying to wrap my head around how that would be. You know, I'm not directly involved with the study, but my understanding is that the patients actually have not been unblinded; the data have been unblinded. If I'm a participant in the study, I don't actually know if I'm on placebo or osimertinib.

Also, I believe that the patients on this study will all be offered osimertinib or will have access at the time of progression. If you wanted to suggest, how could such an impressive DFS fail to translate to OS? You would have to either imagine that there was a gross difference in availability to effective treatment at the time of recurrence that might impact survival in that way, or that the placebo-randomized patients somehow had a different outcome. In other words, maybe the osimertinib-treated patient on ADUARA had a horrible response to treatment if they recurred. To me, both of those don't really hold water.

As long as there is access to effective EGFR treatments upon recurrence, it's likely to be given to the same percentage of patients in both arms. The idea that the osimertinib-treated patients would somehow do much more poorly if they did recur does not hold with what we've seen with other data, specifically with the patients in the SELECTtrial who recurred on adjuvant erlotinib, were treated with erlotinib for first-line metastatic disease. Again, this wasn't a randomized trial, but those patients did very well. I'm having trouble figuring out how we have somehow tainted or ruined our ability to see a survival advantage. What do you think, Dr. Aggarwal?

Aggarwal: Many factors are related to this. You know, looking at the significant improvement in DFS, it'll be very hard for me to not offer this to a patient or not have the discussion. Of course, we don't have the FDA approval just yet, but we all anticipate that this is coming.

Questions Arise in Light of the Data

Aggarwal: One of the things that becomes increasingly important, again, is this issue with testing. We don't really do a fantastic job in the stage IV setting and I believe that pathways will have to be put into place. Various academic institutions, as well as the mindset, will have to change amongst all practicing oncologists to ensure that these patients are identified appropriately. I would like to highlight that this population of patients consists of some smokers. About 25% to 30%, or 32% of the patients on the trial were once or are currently smokers. As such, I don't believe that we should let our phenotypes guide testing; I anticipate that to be a big challenge. Based on extrapolation from our stage IV setting, where we don't really do a fantastic job already.

I will also point out that there has been a lot of concern about whether or not adjuvant chemotherapy should be given to these patients at all. I have certainly spoken with my colleagues about adjuvant chemotherapy for patients with stage II and IIIA disease; it’s a modality that has actually shown survival benefit in many large randomized trials. We should not be abandoning that practice in favor of osimertinib use after patients have resection. I worry that, on one hand, we will have people concerned about lack of OS data. I also worry that, on the other hand, there will be people who will jump upon using an oral targeted therapy and give up adjuvant chemotherapy. I really feel that there's a disconnect and I wonder what your thoughts are about that. Do you feel concerned that people will stop receiving adjuvant chemotherapy, Dr. Pennell?

Pennell: After seeing these data on this highly effective therapy, many might want to question whether they can skip chemotherapy. However, the truth is, this trial doesn't answer that question. We do know the difference in DFS was about the same, whether patients received chemotherapy or not. However, you're absolutely right, platinum-doublet chemotherapy has a proven survival benefit. I don't think we can cavalierly reject that, unless we had a trial that was head to head. Combining it might be an intriguing question to ask. I know that there's a phase 3 trial examining osimertinib in the stage IV setting, with or without chemotherapy; that will be very interesting. Earlier treatment could potentially be more effective. This is a valid area where we might consider new trials. Although, since adjuvant trials take so many years, it's hard to imagine that this will happen in the patent life of the drug.

For now, I would certainly, for my own patients, recommend that they continue with adjuvant chemotherapy and then receive osimertinib. I do think the testing question is very important. Obviously, we can't use this drug unless we identify EGFR mutations and, currently, many places don’t test early stage patients for mutations. At the same time, however, this is almost an ideal scenario to do that. Patients who are eligible for this, if we're looking predominantly at stage II and IIIA disease, are going to be getting adjuvant chemotherapy, so there’s no rush. They also have an entire resected tumor, so there's going to be plenty of tissue to do the testing. As long as there's an awareness that it's necessary, I believe it would certainly be very doable to incorporate routine testing for EGFR mutations into the care of these patients.

Sequist: Another question about standard therapy that should or should not be included for patients like these, is radiation. The trial design was solely in patients who didn't receive radiation and several patients with stage IIIA disease were on the study. One could argue that they should have received radiation as per standard of care. If we typically use radiation, either pre0 or post-operative in our patients with stage IIIA disease, the question now is, should we continue that practice even though ADUARA doesn't include patients like that? For the same reasons that Dr. Aggarwal argued about chemotherapy, I would say yes, we should include radiation as per standard indications and this adjuvant osimertinib is just something that we should add on top of that.

Examining the Cost of Care

Sequist: It's funny, Dr. Pennell, you said something about the patent life. You know, another argument I heard after ASCO had to do with how much this is going to cost. I don’t believe targeted therapy, for a very specific population of patients, is all that costly, especially when you consider all of the immunotherapy that we’re giving for all of our patients with stage IV disease. However, at the same time, we don't have OS yet for these, as we do for some other situations. What do you think about the quality-of-life costs and the financial costs of giving a patient 3 years of adjuvant osimertinib?

Aggarwal: We can’t overlook the cost argument here. I agree with you, Dr. Sequist; we certainly use many more expensive therapies in situations where we may not have an OS benefit. This includes all of oncology; I think we're all guilty of using extremely expensive therapies without proven benefit. We can't really have an argument about 1 therapy and ignore all the other therapies that we use. But having said that, are we going to realistically stop osimertinib at 3 years? You know, if someone is doing really well and then we get into this possibility that oncologists will be prescribing osimertinib for a very long time with the added toxicity, albeit minimal, as well as the financial toxicity that comes with it.

I feel that it also depends on what the out-of-pocket cost is for these patients. Is this completely covered? Is this a significant financial burden to these patients? These are important conversations to have, at least on our level, to see how providers can help in a particular situation. However, there is a larger discussion that we need to have in general, in terms of the cost of care overall.

Pennell: That's it's absolutely right. There's the larger discussion about costs of drugs, which is beyond this podcast; there’s nothing that we can solve personally here. However, it's very important to have that discussion on an individual basis with the patient. We need to discuss what their out-of-pocket costs will be because this drug is very expensive. Even if you only have to do a portion of the overall cost as a copay, that can still, for some patients, amount to several thousands of dollars a month. Not everyone is eligible for financial assistance or really is able to get enough to make it very affordable. You’re really going to have to have that discussion on an individual basis with each patient.

Dr. Sequist, you also mentioned the quality-of-life costs, as well. I'm a little less worried about that. I feel that osimertinib is a very well tolerated drug; it does cause some dry skin and nails get weak and some have intermittent diarrhea. Occasionally, people have much more significant adverse effects. However, with close monitoring and dose reduction, I believe most patients will be able to live with this [treatment] fairly well.

In terms of whether treatment is going to continue beyond 3 years, it’s fine to look that far ahead and worry about consequences of people's decisions down the road. The reason that is a very relevant topic is that in the SELECT study, we noted that after the 2 years of treatment were done, there was an excess of recurrences afterward; this suggests that a subset of patients may have had persistent disease that was suppressed by the drug. It's way too early in ADUARA to know if that's going to happen here. However, if we were to find that in years 4 and 5 patients who had completed 3 years of treatment and stopped went on to have an increased number of recurrences, it's hard to imagine that it won’t influence whether people would be willing to stop treatment at 3 years or not. What do you think, Dr. Sequist?

Sequist: This brings us back to something you mentioned earlier. Are there other important end points besides OS? Oncology has really grown as a field in this era where OS was the “be all, end all” end point. However, when we have newer therapies and subsets of patients who are living for a decade with their advanced lung cancer, survival is not the only end point. We now are lucky enough to be in an era where patients are advocates and are much more involved in helping us interpret research and helping us educate each other, as well as others.

I find it presumptuous maybe for us to say, “Here's a treatment that might delay recurrence for 6 years, but people still end up living 15 years at the end of the day.” For us to say whether or not that’s important [is tough]. It’s uncharted territory. It will be very interesting to see what the long-term outcomes of this study are. However, what I worry about is waiting years for those long-term outcomes before we start talking about it with our patients. It sounds like all 3 of us are on the same page with that.

Moving Beyond the Debate

Aggarwal: As both of you mentioned, within this group of patients who received osimertinib, there is a distinct subgroup that may benefit more than the other subgroups or may benefit from longer duration or longer suppression. I think all of us agree that we need to better identify these patients. Who are those patients who may derive the maximum benefit? Should we be using techniques like minimal residual disease (MRD) detection for all of our patients after surgical resection to further pinpoint our management for this group of patients who receive targeted therapy?

Pennell: That's a great point. My thought about this trial is, this as close to a homerun [as we have gotten], to use analogy that Roy S. Herbst, MD, PhD, used during his presentation. This is about as positive as it could be, given the limited data that we have and certainly good enough to have a discussion and start using it routinely. I would actually suggest that we move beyond having debates about whether this is meaningful or not because, within the limited data that we have, it is. We should take our questions up a level. Should we be using it earlier? Should we combine it with chemotherapy? Should we be use it in the neoadjuvant setting?

As you mentioned Dr. Aggarwal, should we be looking for factors such as MRD with ctDNA to detect patients who might benefit more, so that we're not necessarily treating patients who don't necessarily need years of expensive drugs? We need to identify the patients who will benefit the most. We need to start those studies rather than waiting years to decide whether this particular trial is worth applying [to practice].

Reference

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5