Adjuvant osimertinib demonstrated a statistically significant and clinically meaningful benefit for patients with stage IB, II, or IIIA EGFR-mutant non-small cell lung cancer (NSCLC) with complete tumor resection in the phase 3 ADAURA trial, presented at the Virtual ASCO Annual Meeting held 29-31 May 2020 [1]. Physician Weekly interviewed the study’s principle investigator and presenter at ASCO, Prof. Roy Herbst (Yale Cancer Center, USA), to get some additional information.
Trial results found that adjuvant therapy with osimertinib (Tagrisso) was associated with a nearly 80% reduction in the risk of disease recurrence or death in patients with stage IB-IIIA non–small cell lung cancer (NSCLC) bearing EGFR mutations.
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, with demonstrated efficacy as a frontline agent for metastatic NSCLC with confirmed EGFR-mutation, which was published in the New England Journal of Medicine [2]. The phase 3 ADAURA clinical trial attempted to assess whether this agent is also effective in earlier stages of metastatic disease characterized by EGFR mutation, namely as an adjuvant therapy after complete surgical resection of stage IB, II, or IIIA disease.
Briefly, oral osimertinib (80 mg, once daily) was compared with placebo for a treatment duration of up to 3 years or until disease recurrence; median duration of exposure was 22.3 months (range 0-43). The primary endpoint was disease-free survival (DFS), and the key secondary endpoint was overall survival (OS).
The study was unblinded early under the recommendation from an Independent Data Monitoring Committee due to efficacy. At the time of the unblinding, randomized patients (n=682) had been followed up for at least 1 year. For the primary endpoint in stage II-III patients, the DFS curves separated early on and showed an 83% reduced risk of disease recurrence for the osimertinib arm (HR 0.17; 95% CI 0.12-0.23; P<0.0001). Adding in the early-stage IB patients to the overall population did not change this trend (HR 0.21; 95% CI 0.16-0.28; P<0.0001), indicating that osimertinib benefits early-stage patients as well. Osimertinib was well tolerated. Overall, at 2 years, 90% of patients were disease-free versus 44% in the placebo group, an incredible result.
The main conclusion of ADAURA was that adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB/II/IIIA EGFR-mutant NSCLC after complete tumor resection.
Physician’s Weekly asked ADAURA senior investigator Roy Herbst, MD, PhD, for some additional information:
What about the overall survival, will you be able to get that data from ADAURA?
“Overall survival is, of course, critical. However, I think that the PFS measure here is so strong, that there is no discussion that patients still benefit by time before their cancer comes back. Waiting for the survival data will take a few more years. I think we’ll still be able to file based on the clinical evidence to date. Patients will have access to osimertinib anyhow when they fail the control arm; we’ll make sure the study provides that for them. The OS data could be hard to obtain for those patients on the control arm, if they end up switching to osimertinib. But they have all been at least one year on the trial, so why would someone switch? They’ve had surgery, they’ve had actual therapy with chemo, that was at 24 weeks, now they’re 72 weeks or so post-enrollment. Are they going to now switch with no measurable disease and start on osimertinib? I think if I were in that position I’d wait, and just be followed. And whether or not we should continue giving them a placebo every day or not -we’re still discussing that with regulatory- we will still follow the trial for survival. Sure, there will be some crossover that could pull the survival curves a little closer together, but I would predict we’ll still see a survival benefit. Even in the absence of that, it’s such a high magnitude of disease-free survival benefit, I think it will change practice.”
Speaking of practice-changing, will we start sequencing for EGFR mutations in every early-stage disease patient?
“For every non-squamous lung cancer, you can make the case for sequencing at some point. Yes, I think to sequence EGFR in early-disease patients can be useful, but we should start off in Asia, where EGFR mutation is about 30%. This practice might be slower to catch on in the US where EGFR mutation is only 10-15%. I expect soon that at the time of the initial pathology, we’ll probably get an immune profile, including PD-L1 expression, and some data on EGFR status, and you can even make a case that the paradigm might include some of the other targeted alterations like MET, ALK, or RAS.”
Do you anticipate resistance to develop?
“Preexisting or acquired, we know that there are these dormant persister cells, which are resistant. We also know that with treatment, resistant populations will emerge. Yes, I do anticipate we’ll see resistance develop, and when patients fail on osimertiniib, either early or late. Because osimertinib selectively targets activating EGFR mutations, as well as the T790M-resistance mutation, through the formation of a covalent bond to the C797 residue in the ATP-binding site of mutant EGFR, we will need to screen patients for EGFR C797X/S alterations. If C797 is mutated, we have other trials and combinations that we’re looking at to treat those patients. I would not avoid using osimertinib because I’m worried about resistance developing; hopefully, there will be less resistance because we have an early-stage setting, therefore fewer cells will become resistant leading to less heterogeneity.”
What about the patients on the tail of the curve?
“Why do some patients respond better than others? Every time someone got a pharmacokinetic timepoint, or every time they came in for one of their 12- or 24-week visits, we gathered blood, to allow us to analyze cell-free DNA. Therefore, we will be able to look at liquid biopsies and we’ll get a sense for any other mutations present. In addition, we should be able to gain insight from these samples as to how quickly resistance may be developing. What triggers this change, when does this occur? I think we’ll begin to learn about how resistance emerges. There’s a lot of science to be gained from this trial too, from the longitudinal follow-up.”
Next steps?
“We next get to do some of the science end of the trial, while continuing to keep the trial running and moving forward. To expand this knowledge base, the LAURA trial will look at osimertinib after chemoradiation in the locally advanced unresectable stage IIIA-3B setting, and the FLAURA2 trial will combine with chemotherapy in the metastatic setting. Furthermore, there will be the neo-ADAURA trial, which is going to look at osimertinib in patients before they had any therapy, before they even had surgery, which will provide good data on response rates as opposed to progression, or disease-free-survival, because you are starting with a tumor that is intact. One can actually imagine a trial where you cut out the whole tumor to determine whether it might be resistant to a given agent, so you can know what to do next. You might even think about combining it with chemotherapy in some instances. For the time being, we can be satisfied that the ADAURA trial results give another 30% of lung cancer patients, albeit only 10-15% of those in the US but 2-3 times that number in Asia, another sliver of a win. A good number of patients, in fact 5-10%, now have the ability to get a targeted agent to prevent reoccurrence.”
References
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- Herbst RS, et al. Phase III study assessing the efficacy of adjuvant use of targeted agent osimertinib in patients with localized non-small-cell lung cancer and EGFRmutation after complete tumor resection and adjuvant chemotherapy. ASCO Virtual Meeting, 29-31 May 2020, Abstract
Written by Physician’s Weekly medical writer, Rebecca Shover.
