Continued Investigations are Pertinent for FDA Approvals in the Treatment of Patients With EGFR-mutated NSCLC

Jason Porter, MD

The supplemental new drug application requesting the approval for osimertinib (Tagrisso) in conjunction with chemotherapy for patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) was granted priority review by the FDA in 2023 based on recent data from the phase 3 FLAURA2 trial (NCT04035486), and Jason Porter, MD, noted that this potential approval will open the gates for other drugs to follow in osimertinib’s footsteps.

“Osimertinib plus chemotherapy is going to have a place but figuring out which patients are appropriate for this approach is going to be our responsibility,” Porter said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on lung cancers which he chaired. “It’s incumbent upon us to do that so that when patients will benefit, we give [the regimen] to them, and when they don’t need the toxicity, we avoid it for their quality of life.”

In the interview, Porter, who is a medical oncologist and hematologist, as well as the director of the Lung Cancer Disease Research Group at West Cancer Center and Research Institute in Memphis, Tennessee, discussed his colleagues’ presentations from the webinar. He highlighted the implications of recent data to emerge following the use of EGFR tyrosine kinase inhibitors (TKIs) in the adjuvant setting, the importance of the potential upcoming FDA approval of osimertinib with chemotherapy in EGFR-positive NSCLC, and considerations for the use of neoadjuvant radiation in combination with chemotherapy for patients with lung cancer.

OncLive: What are the implications of the positive overall survival data to come from the phase 3 ADAURA trial (NCT02511106) based on the presentation by Wade T. Iams, MD, MSCI, of Vanderbilt-Ingram Cancer Center, in Nashville, Tennessee?

Porter: We have tried to target EGFR in the adjuvant setting before and were not successful with those earlier-generation EGFR TKIs. However, we saw with ADAURA that when we targeted EGFR in the adjuvant setting, we changed the outcomes for patients. With or without chemotherapy, regardless of whether they have central nervous system [CNS] disease, we improved outcomes for all patients, and this was not only for stage 2 disease and above but even patients with stage 1b disease derived benefit. It is very hard to imagine not testing all patients for EGFR and other oncogenes now in an early setting where they may benefit from adjuvant treatment.

With neoadjuvant and adjuvant immune checkpoint inhibitors approved in early NSCLC as opposed to EGFR-targeted therapies, because of the ADAURA data we owe every patient a deep analysis to make sure that we don’t miss oncogenes that we can target in the adjuvant setting. Particularly, now approved [for the adjuvant treatment of patients with NSCLC and exon 19 deletions or exon 21 L858R mutations] based on the ADAURA trial, the use of osimertinib [is important], but other targeted therapies will come along and follow in the same pattern.

If approved by the FDA, what would the significance be of having osimertinib with chemotherapy available to treat EGFR-positive NSCLC?

With the use of osimertinib plus chemotherapy in metastatic EGFR-positive NSCLC when we look at the data from the clinical trial, we see a specific patient population—patients who have CNS involvement—seem to benefit more than others. Because osimertinib is such an effective therapy in the first-line already even as a monotherapy, it’s hard to imagine giving patients any additional toxicity.

The question that most people are asking is: When is it worth the toxicity? For patients who have CNS disease, this is a time where it may be worth it; based on the data from this trial adding chemotherapy to osimertinib in a first-line setting [may] improve outcomes when patients have CNS involvement. Also, for very young and fit patients, this may be a time to consider adding chemotherapy—you don’t have to worry as much about the toxicity and younger patients may tolerate it a bit better.

Another patient population who was not included in the clinical trial, but deserves some attention, are patients who possess nonclassical or non-typical EGFR mutations like exon 19 and exon 21. For those patients who have other non-typical mutations, it may be a time when you use osimertinib with chemotherapy to try to augment their response and increase the duration of response and outcomes.

Looking to the presentation on updates in SCLC from Nagla Abdel Karim, MD, of the University of Virginia, in Charlottesville, what’s the importance of starting to identify potential biomarkers in this space?

For SCLC we are in the dinosaur era. When we look at NSCLC, particularly non-squamous NSCLC or adenocarcinoma, I always talk about the pie charts of our oncogenes that we can target in NSCLC. These are very small percentages but cumulatively they make up a large percentage of the patients. However, I say that in SCLC we have pie chart envy where the pie chart is not even a thing. It’s all just 1 flavor right now and it is the way we’ve been treating SCLC for decades. Only recently have we started to subtype SCLC and look for drivers within the disease that we can target.

Over the next decade, we can start to see targets like SLFN11 and look at the different subtypes of SCLC to try to parse out which patients would benefit most from the addition of immune checkpoint inhibitors to their chemotherapy platinum doublet up front. Then we’ll be able to avoid immune checkpoint inhibitor mediated toxicities when we know that patients are not likely to respond. A very small population of our patients end up with long-term survival benefit when we add checkpoint inhibitors to therapy and the toxicities are real and potentially lifelong. It’s exciting to see the development of an actual pie chart of potential targets in SCLC. Dr Karim did a great job of showing some of those and the approaches that we may use when nuancing therapy in SCLC in her talk.

What are some of the current considerations for the use of neoadjuvant radiation in combination with chemotherapy for select patients per the presentation by Daniel V. Wakefield, MD, MPH?

It is always a difficult decision when using therapies like radiation for patients. However, when we look at clinical trials that consider what we have known for a long time, try to describe this abscopal effect and what kind of immune modulation radiation may have on tumors, and when [we] change the actual tumor microenvironment, radiation is very important to consider.

In early-stage disease, we look at chemotherapy and radiation as a preoperative approach for NSCLC particularly for patients who may not be candidates for immune checkpoint inhibitors or for patients who have oncogenes where our clinical trials using neoadjuvant targeted therapies are not completely developed or ready for application in clinical use. For those patients, it may be a relevant approach to continue our old approach of chemotherapy and radiation before surgery. We did that before and it’s not new.

It is important to remember that the approach for patients who aren’t candidates for immunotherapy plus chemotherapy is neoadjuvant; they’re patients whom treatment with chemotherapy alone would result in a substandard response and lower response rates. We see complete response [CR] rates in the ranges of 18% to 25% for patients who get neoadjuvant chemo-immunotherapy, but chemotherapy alone doesn’t offer that so the addition of radiation may help to improve responses for those patients.

Therefore, radiation still has a very important role in the cure of early-stage disease. We have to remember that and keep multidisciplinary review and [these] considerations [in mind] when we’re deciding on cure plans for patients.

Lastly, Erin A. Gillaspie, MD, MPH, FACS, of Vanderbilt-Ingram Cancer Center, discussed updates on neoadjuvant and adjuvant therapy. How has the emergence of more treatment options in these settings affected the role of surgery?

With the phase 3 PACIFIC [NCT02125461] data from several years ago, we had a shift towards chemo-radiation and immunotherapy for patients because this data looked good, and patients were suddenly having improvements in long-term survival even in stage 3b disease. With that, surgery became a bit questionable. Even some of the surgeons would say, ‘We’re not going to do as well as PACIFIC for this stage 3 NSCLC with subcarinal adenopathy’; single station [N2] for sure, but those patients were being pushed towards chemotherapy/radiation.

With the neoadjuvant and perioperative approaches from the phase 3 KEYNOTE-671 [NCT03425643] and CheckMate-816 [NCT02998528] trials, we’re using chemotherapy plus immunotherapy before surgery with or without adjuvant immunotherapy to continue for those patients. We’re starting to see patients who would have for the last few years gone on to chemoradiation [and] surgery instead after a neoadjuvant therapy—that includes those with stage 3 disease who have non-bulky subcarinal adenopathy who are going to surgery again. Even those patients with advanced disease can experience complete pathologic responses from the use of chemotherapy and immunotherapy.

This means that we need to do a few things before a patient’s care plans are decided. We need to have a multidisciplinary discussion. The surgeon needs to declare if this patient is operative or a surgical candidate before we initiate any therapy. We also need molecular testing because we need to know if they have EGFR or ALK mutations including ROS1 and so many other oncogenes that we know don’t respond well to immune checkpoint therapy before we put them on neoadjuvant chemotherapy and immunotherapy.

The KEYNOTE-671 trial did include some patients with EGFR-positive disease, but specialists who treat thoracic oncology or thoracic diseases of NSCLC are not very excited about putting those patients on a regimen like KEYNOTE-671. We want to do what’s going to be safest for those patients.

There were small numbers of EGFR-positive patients who were included in those trials, so it’s hard to make a lot of inferences from that data and clinical application is going to be limited for that reason. Overall, patients who were chemoradiation candidates are now being shifted back to surgery with the use of neoadjuvant chemotherapy and immunotherapy.