Adjuvant Osimertinib On Way to Becoming New Standard in EGFR-Mutant NSCLC
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Roy S. Herbst MD, PhD, discusses the ADAURA trial and the impressive data seen with adjuvant osimertinib and highlights ongoing research efforts being made with the agent in lung cancer.
Roy S. Herbst MD, PhD
The significant and clinically meaningful improvement in disease-free survival (DFS) demonstrated with adjuvant osimertinib (Tagrisso) in patients with EGFR-mutated, stage I, II, and IIIA non–small cell lung cancer (NSCLC) in the phase 3 ADAURA trial is practice-changing, according to Roy S. Herbst MD, PhD, who added that these data underscore the importance of treating patients earlier, when less disease is present.
“With osimertinib, we have an oral TKI that can be used in the earliest stages of lung cancer,” said Herbst, lead author of the ADAURA trial and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital. “I think that really heralds a new age for how we're treating this disease.”
In the phase 3 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 at the 2020 ASCO Virtual Scientific Program showed 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).
The 2-year DFS rate with osimertinib in patients with stage IB, II, IIIA disease was 87%, 91%, and 88%, respectively, versus 73%, 56%, and 32%, respectively, with placebo (overall HR, 0.50, 0.17, and 0.12, respectively). The overall survival (OS) data are still early, according to Herbst, and the median OS has not yet been reached in either arm (HR, 0.40; 95% CI, 0.18-0.90). The data are only at 5% maturity.
“Biology is the foundation of therapy. We're in a precision-guided world and we have ways to target the patients with the right drug at the right time—and that time is now an earlier time in the disease,” stressed Herbst. “It makes sense to do that because if you know that someone [has] EGFR-mutated [disease], if you get them earlier, [when they have] less disease, there's clearly going to be less heterogeneity and less of a chance for a secondary mutation to develop. That could be the most curative setting, and that's what adjuvant trials like [ADAURA] do.”
In an interview with OncLive, Herbst, who is also the Ensign Professor of Medicine (Medical Oncology), professor of pharmacology, and associate cancer center director for Translational Research at Yale Cancer Center, further discusses the ADAURA trial and the impressive data seen with adjuvant osimertinib and highlights ongoing research efforts being made with the agent in lung cancer.
OncLive: Could you start off by providing some background on osimertinib and its overall impact on the treatment of patients with EGFR-mutated NSCLC?
Herbst: It's amazing to me, having participated in some of the earlier trials 23 years ago with gefitinib (Iressa) and erlotinib (Tarceva), that now we have taken these agents [and applied them to practice], we have developed new agents, and we have uncovered the EGFR mutation. We now have mutation-specific TKIs that are better tolerated and can be given for longer periods of time. As we saw in the ADAURA trial, patients with stage I, II, III disease worldwide who had complete resection of their disease with surgery and then received adjuvant therapy when appropriate, were randomized to receive either osimertinib or placebo.
Why placebo? Because that was the standard of care; there really was nothing more that was done at that point. [The results that were seen were] incredible. Even though these patients had a defined genetic abnormality, EGFR, 50% of patients with stage I disease might recur; with stage II, [that estimate increases to] 66%, and at stage III, [that likelihood is as high as] 75%.
Could you expand on the ADAURA study and the results that read out at this year’s virtual ASCO meeting?
ADAURA was a simple, large, global trial, and the results speak for themselves. DFS was the primary end point of the trial. We targeted a HR of 0.7, and the trial came in with a topline result of 0.17, an 83% improvement in DFS in patients who received osimertinib versus the placebo in [patients with] stage II and III disease. The key secondary analysis was to add in the [patients with] stage I disease. So then, [when we] had [patients with] stage I, II, III disease together—stage I, of course, having the best prognosis without intervention—the HR was 0.21, translating to a 79% improvement in DFS.
These numbers were fantastic. We assumed that these agents would be active, but [we didn’t realize it would be] to this extent. These data speak to the fact that these are more active third-generation agents that are more potent in areas such as the brain and the central nervous system, and they are better tolerated; patients can take them for longer [durations]. We saw that across many variables. Every variable was hit in a positive way, meaning age, sex, type of EGFR mutation, whether or not the patient received chemotherapy, whether the patient was from Asia or someplace else in the world—all of the groups ended up being positive in favor of osimertinib, with a toxicity profile that proved to be quite tolerable.
So, what do these data mean? Right now, we have a trial with topline results that show a large difference in DFS in favor of a new study drug. This, in my opinion, is practice changing. I think the debate now is going to be that we're going to hopefully make this a new standard of care. [We’re still awaiting] some of the other data from this trial regarding patterns of recurrence, the impact of secondary therapies, quality of life analyses, and sites of recurrence like in the brain, liver, bone, or lung. All of that information will further support the case for using this agent, in my opinion.
I was very lucky. We had such a wonderful investigative team worldwide. I worked on the Steering Committee with Masahiro Tsuboi, MD, and Yi-Long Wu, MD, from Japan and China respectively. We had investigators from all around the world and we are all going to get together this week to discuss the trial. Really, we just had an amazing team from AstraZeneca, [which] really helped us to coordinate this entire study. The winner, of course, are the patients.
We do surgery and use chemotherapy in patients and we hold multiple modality treatment boards around the world. But now, we have added targeted therapy and precision medicine to the mix. We put them together and biology has spoken. Pretty much like when trastuzumab (Herceptin) was first used in adjuvant therapy almost 15 years ago. Now, lung cancer, a very common disease that is the number 1 cause of death worldwide, is also moving in that direction. The best way to treat [this disease] is to take your best drugs and move them earlier; that's what we've done here with ADAURA.
What unanswered questions are left by these findings that you hope to see addressed with more data?
The trial was quite positive and met all of the primary end points; however, like anything else, there are going to be questions to ask. We'll need to look at the data and determine what the patterns of recurrence are. Was it local? Was it distant? We'll have to look at the different surgeries and whether there were regional differences in how the procedures were performed. The trial is quite well standardized in that everyone had to have a complete resection. Segmentectomies and wedge resections were not allowed. Everyone had a new CAT scan before they went on osimertinib, so I think the chance of having metastatic disease was small. Everyone had a scan of their brain before they started. We do have a pretty homogeneous group, but there will be differences. We'll want to look at the chemotherapy in the patients who received chemotherapy and those who did not and ask the latter [did not receive it]; that will be a relevant question. We'll need to figure out how to use these agents. Do we use them after chemotherapy? Or, perhaps we can avoid the chemotherapy completely. We’re going to start to await the survival data. However, I believe these data are quite compelling, even in the absence of those data. I know I wouldn't want to wait 2 or 3 years to treat patients with this drug, but we will continue to follow the trial very closely for survival and that's something that we'll be doing at all sites with all patients.
Are any other research efforts being made with osimertinib that you wanted to highlight?
Well, osimertinib now is the standard of care in the metastatic setting. The agent is used in the frontline based on data from the FLAURA trial. ADAURA now shows data with its use as adjuvant therapy in [patients with] stage I, II, and III disease. Beyond this, a couple of other trials are ongoing. For example, the LAURA trial is enrolling patients with EGFR-mutated, stage III A and B disease who [previously received] chemoradiation; [osimertinib is being given] after chemoradiation, so that's something to keep an eye on. Then there's the neo-ADAURA trial, which is actually taking patients and using the EGFR inhibitor before surgery. Again, really moving things up earlier to try and shrink tumors and perhaps even lessen the surgical procedures that need to be performed. These efforts are all ongoing.
Then, of course, let's be honest, there will be resistance to any agent, either primary or acquired. In that case, I think ADAURA is going to help us figure that out because we have samples from patients before they started therapy. We also have circulating tumor DNA and blood samples so we can look at the progression of disease, whether a patient progressed or not, and if they did, then what's happening at the cellular level. A lot of research needs to be done and that can ultimately inform on what to do after patients have received osimertinib.
We don't have that many patients who have [progressed on osimertinib] so far on the trial. However, in the metastatic setting, for example, patients do fail, and that's why we have trials like SAVANNAH and other trials that are adding c-Met inhibitors and EGFR antibodies. Dare I say, [we're] even starting to think about how immunotherapy or some type of immunomodulatory agent might [fit] in[to the mix].
There's a lot of work to do. We can never rest on our laurels when it comes to a disease like lung cancer. The progress is enormous. Osimertinib is a drug of this past decade; it is just 7 or 8 years that this drug has been developed and we already have it [being examined] in the earliest stage [of disease]. That’s how fast drug development is going.
One thing that I think will come out of this trial is the need for more sequencing. Every patient, at least those with non-squamous disease, need to be sequenced so that we can find these genetic abnormalities, whether it’s EGFR, ALK, ROS1, NTRK, and so many others that are relevant. Potentially, there’s a new paradigm now to use these targeted agents as early as possible.
What should your colleagues take away from this research?
The results really speak for themselves. A well-tolerated drug can be given for 3 years. These results that I was fortunate enough to present on behalf of our team really are extraordinary and speak to the fact that now we have new options for patients against this disease to prevent metastases. The late Josh Fidler, MD, who just passed away earlier this month, was one of my mentors at the University of Texas MD Anderson Cancer Center, always taught that patients die from cancer because of spread, because of metastases. These cells get out to the liver, the brain, the bone, the other lung, throughout the body. By preventing metastases with biologically-guided therapy, that's a paradigm that I feel is going to be so important as we move forward in the treatment of this deadly disease.
