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Jay M. Lee, MD, discusses the implications of the ADAURA trial in early-stage resectable NSCLC, the importance of molecular testing, and the need for a multidisciplinary approach in this population.
The substantial benefit reported with adjuvant osimertinib (Tagrisso) in patients with EGFR-mutated non–small cell lung cancer (NSCLC) in the phase 3 ADAURA trial (NCT02511106) has underscored the need for biomarker testing in the post-resection setting, according to Jay M. Lee, MD, who added that efforts are now focused on discovering biomarkers of response to targeted approaches and testing for these markers earlier on in the treatment journey.
“[We want to determine whether] we can use surrogate biomarkers to identify which patients are going to be responders [to osimertinib], but also who will not respond, so that we do not subject patients to up to 3 years [of treatment] in the adjuvant setting [if it is not necessary],” Lee said. “The real advantage in the neoadjuvant setting is that it is an ideal platform for biomarker discovery, and to assess whether a drug works and should be continued in the adjuvant setting.”
In an interview with OncLive®, Lee, chief of the Division of Thoracic Surgery; an associate professor of Surgery; surgical director of the UCLA Thoracic Oncology Program/Jonsson Comprehensive Cancer Center; surgical director of the UCLA Center for Esophageal Disorders; and member of the UCLA Sarcoma Program/Jonsson Comprehensive Cancer Center, discussed the implications of the ADAURA trial in early-stage resectable NSCLC, the importance of molecular testing, and the need for a multidisciplinary approach in this population.
Lee: The ADAURA trial [examined the efficacy of] osimertinib in patients with [stage IB to stage IIIA NSCLC] who underwent complete resection. In the adjuvant setting, patients then went on to [receive] chemotherapy or not, depending on the investigator, and then up to 3 years of osimertinib vs placebo. What was remarkable about this study is that the disease-free survival [DFS] outcomes were quite impressive with osimertinib, with hazard ratios [HRs] of 0.17 and 0.12 [in those with] stage II and IIIA disease, respectively. [We] really saw a profound DFS advantage in the osimertinib group.
Critics out there will want to see the overall survival [OS] data, but I cannot think of another trial where the HRs for DFS were in that range. Many of us feel that this [agent] will most likely portend a survival advantage, as well. [ADAURA] is practice changing because of these impressive data, and it changed the landscape in the sense that we now have the first study to identify a driver mutation that needs to be checked in the early-stage setting. We anticipate that EGFR testing will be a mandatory process in the post-resection setting.
Who orders the testing and at what point in the patient journey, in the resectable space, is a moving target. The only data we have so far is in looking at the presence or absence of driver mutations, and how that changes management. [Currently, that is] in the adjuvant setting, based on the ADAURA trial with adjuvant osimertinib, or the phase 3 IMpower010 trial [NCT02486718] with atezolizumab [Tecentriq] for up to 1 year in the adjuvant setting. Both studies showed a DFS advantage in the setting. For osimertinib to be effective, [patients] need to have an activating EGFR mutation, so we need to check for it. On the other hand, in IMpower010, patients who had a ALK or EGFR [driver mutation] did not benefit from the adjuvant atezolizumab. Because of this, it is important to test for at least EGFR and ALK in the adjuvant setting.
In the neoadjuvant setting, we currently have not seen a study that has been practice changing, but many phase 3 trials [have examined the] combination of chemotherapy and immunotherapy. The phase 3 CheckMate-816 trial [NCT02998528] was the first one to read out, and thus far, we have just seen data on pathologic complete response. Until there is a correlation to 1 of the clinical efficacy end points, like DFS or OS, it is not practice changing. Because of this, biomarker testing must occur in the post-resection setting at minimum, because that is really where it makes a difference. In most institutions, biomarker testing is not routinely performed in this early stage because [we had not seen] practice-changing [data]; however, with these adjuvant studies, [we have].
Who does the testing depends on the institution. We have reflexive testing done at the pathology level, or by diagnosticians. The diagnosis of lung cancer is commonly going to be done by a pulmonologist, thoracic surgeon, or interventional radiologists who do needle biopsies. [At any of those] levels, molecular testing can be ordered in the earlier-stage space.
The type of testing [done] depends on what is [available] to patients. Currently, the only studies that have read out are the 2 adjuvant studies, IMpower010 and ADAURA. [However], other studies have looked at either immunotherapy with chemotherapy or TKIs in the neoadjuvant setting.
The 2 targeted therapy phase 2 trials that come to mind are Geometry Mono-1 [NCT02414139] and NAUTIKA1 [NCT04302025]. Geometry Mono-1 examined neoadjuvant capmatinib [Tabrecta] in [patients with] MET exon 14 skipping mutations, and NAUTIKA1 evaluated 5 different targets, including some of the rarer mutations like NTRK, ROS1, BRAF, ALK, and RET. Other trials [are also being conducted]. For example, we are now looking at [targeting] KRAS with sotorasib [Lumakras], which was [evaluated in] the phase 1/2 CodeBreaK 100 trial [NCT03600883]. As such, other targeted therapies for driver mutations are currently being moved to the neoadjuvant setting.
If an institution offers these studies, it is important to check for the driver mutations, and the platform needed is NGS. There are other ways to rapidly test for EGFR, including therascreen. However, if an institution offers these trials, and that is really where the field is moving, then we are really looking at NGS as the future for testing for these driver mutations. Ideally, whole-exome sequencing would be better, but given the time constraints in the neoadjuvant setting, we need a quick turnaround because we want to reduce the time from study screening, to enrollment, to giving the drug, to resection. We want a fast turnaround with the NGS testing platform; that is really going to be the challenge moving forward as we roll out these studies.
Surgeons are usually involved quite early in the process, but that also depends on the institution. At some institutions where we have a strong interventional pulmonologist, both the interventional pulmonologist and thoracic surgeon are going to be in the forefront of staging patients and getting a diagnosis. A lot of the mediastinal staging performed by endobronchial ultrasound is going to be done by interventional pulmonologists and thoracic surgeons.
There are a multitude of ways to get a diagnosis, including computed tomography–guided needle biopsies [that are done] by radiologists, robotic or transbronchial biopsy [done] by interventional pulmonologist and thoracic surgeons, and in some cases, we just have to resect to find out what it is. Surgeons usually get involved very early in the resectable space, and early in what we perceive to be early-stage lung cancer. [We are] involved both in the diagnostic phase, the ordering of the molecular studies, and then also in providing staging information and resection, ultimately.
One of the questions that comes up when we are looking at the ADAURA trial, [for example], where patients are getting an adjuvant TKI for 3 years, is: Does everyone need to be on that drug for 3 years? How do we measure efficacy? Even though the grade 3 and higher toxicities [occur in] approximately 20% [of those who receive] osimertinib, the fact is that they are still adverse effects. [The drug is] costly, and 3 years is a bit arbitrary. Does everyone need to be on the agent for 3 years? Can we identify patients that do not need to be on it at all, and who are going to be cured by surgery alone, or with chemotherapy?
One of the advantages of a neoadjuvant approach is to identify who the responders and non-responders are. Right now, the field is focused on looking at pathologic regression, whether that is major pathologic response, or complete pathologic response, and looking at the number of viable tumor cells that are present. Other platforms can identify efficacy, such as circulating tumor DNA, or circulating tumor cells.
Multidisciplinary conferences and clinics are important. We have a wide variety of surgeons who are contributing to lung cancer care, nationally and internationally. Not every surgeon is going to be a thoracic surgical oncologist who is aware of the breadth of data that are out there, or the new data coming out. Because of this, it is important to engage in multidisciplinary discussions to know who should be getting neoadjuvant therapies, or who should be getting definitive chemoradiation plus durvalumab [Imfinzi] based on the phase 3 PACIFIC trial [ NCT02125461], or who should receive adjuvant TKIs or immunotherapy.
Emerging data [show that] multidisciplinary clinics, discussions, conferences, and tumor boards do increase survival in patients. That is largely because there is adherence to guidelines, such as National Comprehensive Cancer Network [NCCN] guidelines in the United States, and more patients are getting appropriately staged. Based on that, we are making decisions that lead to perioperative systemic therapy.
When we look at NCCN data on [patients with] resected stage II and stage III disease, all of whom should be getting chemotherapy in either the preoperative or postoperative setting, only approximately 50% are receiving this. When we look at NCCN guidelines, and international consensus statements, these patients should all be receiving chemotherapy. Multidisciplinary discussions will help to have better adherence and compliance with set guidelines, both domestically and internationally.