Balazs Halmos, MD, MS, highlights the significance of the ADAURA trial in EGFR-positive NSCLC, questions raised by these data, and other efforts being made in the adjuvant setting.
Adjuvant osimertinib (Tagrisso) was the first targeted agent in a global trial to demonstrate a statistically significant improvement in disease-free survival (DFS) in patients with earlier-stage EGFR-mutated non–small cell lung cancer (NSCLC), according to Balazs Halmos, MD, MS, who added that the trial has raised many questions in this space.
Results from the double-blind, randomized, placebo-controlled ADAURA trial (NCT02511106) were presented during the 2020 ASCO Virtual Scientific Program and 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 patients with stage II/IIA disease. Moreover, in the overall population, the DFS still was not reached with the targeted agent (95% CI, NC-NC) compared with 28.1 months (95% CI, 22.1-35.8) with placebo (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).
The trial has raised several questions in the lung cancer field, such as whether it is still too early to discuss this option with patients prior to more mature survival data, what testing should look like in those with early-stage disease, and what the role of adjuvant chemotherapy will be in light of these data.
“The ADAURA trial truly demonstrated the benefit of targeted therapy in this space. As such, one of the main take-home messages of this work is that molecular testing is of critical importance,” said Halmos. “We already routinely test patients with stage IV disease, but not just for EGFR mutations. We also use an ever-expanding panel that includes many actionable alterations. More will be added to the panel soon, such as KRAS.”
In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Halmos, director of the Multidisciplinary Thoracic Oncology Program and director of the Section of Thoracic Medical Oncology for Montefiore Health Systems, and first director of Clinical Cancer Genetics and professor of clinical medicine at Albert Einstein College of Medicine, highlighted the significance of the ADAURA trial in EGFR-positive NSCLC, questions raised by these data, and other efforts being made in the adjuvant setting.
Halmos: This was a highly awaited study for several reasons. First, in the adjuvant treatment of [patients with] lung cancer, we really haven't had any major successes over the past 25 years. Many ideas were [explored], but many failed. This included, for example, post-operative radiation therapy, which we received more information on during the 2020 ESMO Virtual Meeting, and some studies on vaccines and antiangiogenic therapies.
Outside of adjuvant chemotherapy, we haven't seen any validated approaches in the curative setting, following surgery. Notably, this is the setting where we want to make the biggest advances because it has the highest likelihood of cure. As such, everyone was eagerly waiting to see whether targeted therapies could make an impact. So many advances have been made in the management of stage IV disease. Could we translate those successes into earlier-stage disease? ADAURA came after a number of earlier attempts failed to provide clarity. Earlier studies were slightly positive or not positive at all, such as the RADIANT study.
We now have the phase 3 ADAURA study, which evaluated the best drug on the market: Osimertinib. This was a large, double-blind, randomized study with about 680 patients. Patients were randomized after the appropriate receipt of adjuvant chemotherapy, which was not mandated; this was one criticism of the study. Patients were randomized 1:1 to receive either osimertinib or placebo for 3 years.
The interim analysis showed such dramatic differences between the 2 arms, that the Independent Data Monitoring Committee decided to unblind the study, on the study level—not the patient level; this can be a source of some confusion. This means that patients continued on the study with the treatment they were assigned; however, on the study-level, the data were opened up to the rest of the world to help us understand the potential benefits [of this approach] and allow us to offer it to our patients in the meantime, as the study continues to mature.
The eye-opening results that led the committee to unblind the results so early and unexpectedly was the hazard ratio of 0.17 [that was seen] in [terms of] the primary end point, [which] was disease-free survival (DFS) in [patients with] stage II/IIIa [disease]. However, we have to remind ourselves that the study actually included [patients with] stages Ib, II, and IIIa [disease]. When looking entire group was looked at, the hazard ratio was a little less impressive, but still impressive at 0.21 or the overall study.
The toxicity was as expected; it was not very substantial. No patients died from treatment-related effects. However, at the same time, [osimertinib is] a very costly drug. The DFS benefit observed is very impressive, but also [somewhat] expected for a drug that treats EGFR-mutated stage IV lung cancer. Now the big question is, should we just wait until we see more data?
My take is that the study was quite well designed; it’s a very large, phase 3 study. Of course, there are some minor nuances, such as the fact that more patients could have received adjuvant chemotherapy. However, if you look at the subsets, both groups of patients seemed to benefit. Similarly, [patients with] stage IIIa [disease] who received placebo did extremely poorly. Almost 100% of them recurred within the timeframe of the study, thus far. That tells us these patients really need help.
The DFS benefit, at minimum, is extending cancer-free survival and allowing our patients to live their lives to the fullest. So, even if the overall survival (OS) benefit is ultimately not as robust, extending the healthy life of a patient before they suffer a major event such as brain metastases or spinal metastases, is significant enough [to discuss these data] with patients.
However, I presume [the OS benefit] will be significant.
We're not mandating patients to take the drug, but we should discuss the pros and the cons [of this treatment]. It wouldn't feel appropriate to not share this information with our patients; I believe we should offer it to [those with] stage II/IIIa [disease]. I’m less convinced about the patients stage Ib disease, because [the] hazard ratio [in these patients was] a lot less. The value is also probably less relevant; as such, it would be a very costly drug with fewer benefits.
The update showed that these benefits translated to central nervous system events, as well. Although this was anticipated, it was reassuring to see a hazard ratio of 0.18. Notably, within such a short timeframe, already 10% of the patients developed brain metastases on the placebo arm, versus 1% or 2% [of those] on the osimertinib arm. This is important because we don’t want our patients to develop brain metastases; the treatment for this could be detrimental. I was definitely very impressed, and look forward to, hopefully, a favorable decision by the FDA so that we can discuss this option even more with our patients.
Molecular testing is definitely a routine in the metastatic setting, and the ADAURA trial reconfirms that. However, we should also be testing our patients in the early-stage setting, as well. As such, testing should be routine.
The question is, does this need to include next-generation sequencing testing or could we get away with single-gene testing in the surgical setting? That’s an open question. Of course, each institution must think about their own practices and how they can set this up. However, single-gene testing is not that difficult—especially in 2020. This should be looked into further.
I think that's a reasonable concern. The study didn't mandate adjuvant chemotherapy. The trial included patients with stage Ib disease and we know that adjuvant chemotherapy is not a standard recommendation [for those patients]; it’s more so a consideration. Personally, I don't have any issue about the study not mandating it.
Ultimately, about 55% of the patients received it and there seemed to be benefits in both groups. Of course, the study seems positive, but it doesn't provide any answers as to whether adjuvant chemotherapy is needed or not. For the time being, I believe we should offer adjuvant chemotherapy, just like we've done so far, to all eligible patients. For [patients with] node-positive disease, we should consider targeted therapy afterward.
I also believe it’s time for us to rethink some trials, such as those evaluating the need for adjuvant chemotherapy in the context of adjuvant targeted therapy. Some may be beneficial, but quite toxic for our patients.
The Lung ART trial is one that we have been waiting for, for quite some time now. As I mentioned earlier, adjuvant radiation has been debated for many years and there hasn't been any high-level data to suggest that it leads to survival benefit. However, we know that it does reduce local recurrences in patients, and it's been [used routinely] in the United States, despite not having high-level data.
We have struggled with the appropriateness of that recommendation, how to select patients for [the approach], and the potential toxicity. Radiation is definitely very effective in terms of reducing recurrences, but there are some toxicities that come with that. This study finally provides very high-level randomized data, mostly from France. It looked at patients with node-positive disease and about some had N2disease. In half of those, before surgery, there was no indication of nodal involvement. A pathologist found nodal involvement after surgery.
What the study showed was very striking. Results showed that the outcomes were identical in the 2 groups. The DFS was favoring radiation slightly, but not to a statistically significant degree. Additionally, the OS was identical between both arms. The local recurrence rate was drastically reduced by radiation, [dropping] from around 46% to about 20%. You would think that this would translate to some overall benefit, but it didn't because it added a substantial amount of toxicity. In fact, the non-cancer death rate was increased by 10%, demonstrating how much sicker patients can be after surgery.
The treatment modality that we typically view is not very morbid, but it can add very substantial morbidity in this particular context. So, that increased complication rate could not be outweighed by the benefit in terms of local recurrences. This was a negative study, but I'm sure there will be many subsequent analyses and discussions [on this topic]. However, right now, post-operative radiation is no longer the standard of care in patients with node-positive disease. We would have to come up with smart arguments to justify this [approach].
However, we should learn from this and implement new designs. Whether these designs should include radiation is another question, but if it does require radiation, the radiation technology has to be delivered in a way that is much less morbid. Nowadays, technology has improved so this could be possible.
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