CE / CME
Pharmacists: 1.25 contact hours (0.125 CEUs)
Nurses: 1.25 Nursing contact hours
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 30, 2022
Expiration: September 29, 2023
Edward B. Garon, MD, MS:
We will begin our discussion by taking a look at how HCPs are identifying patients with NSCLC and EGFR mutations. The 77 HCPs from around the world who responded to our survey were asked, “In your practice, when are you first testing for EGFR mutations in your patients with NSCLC?”
As can be seen in this table of survey results, slightly more than 60% of HCPs reported that they are testing at diagnosis regardless of disease stage, whereas approximately 30% are testing only in patients with advanced NSCLC (stage III/IV disease). Fewer than 10% report that they do not test for EGFR mutations.
Table 1. In your practice, when are you first testing for EGFR mutations in your patients with NSCLC?
Let’s turn now to our expert panel to discuss how these survey results compare with their current approach to testing for EGFR mutations in patients with newly diagnosed NSCLC.
Edward B. Garon, MD, MS:
Dr. Yu, at what stage of NSCLC are you testing for EGFR mutations?
Helena A. Yu, MD:
My practice is to test for EGFR mutations in all patients with newly diagnosed NSCLC regardless of disease stage. At my institution, we have reflex EGFR testing of the tumor biopsy that happens without a physician order—meaning that the pathologist automatically tests for EGFR mutations (and other actionable biomarkers) when NSCLC is diagnosed without having to wait on the oncologist to order biomarker testing.
Testing in the earlier stages to identify candidates for adjuvant osimertinib after adjuvant chemotherapy is supported by positive data from the ADAURA trial that led to the FDA approval of osimertinib as an adjuvant treatment. As we will discuss more later, the phase III ADAURA trial demonstrated significantly improved disease-free survival (DFS) rates with osimertinib (a third-generation EGFR TKI) compared with placebo when used in the adjuvant setting for patients with stages IB-IIIA EGFR-mutant NSCLC, with or without postoperative adjuvant chemotherapy.1
I expect that the timing of community testing for EGFR mutations will continue to expand to earlier stages of NSCLC.
Edward B. Garon, MD, MS:
Thank you, Dr. Yu. I would like to hear how you would approach EGFR mutation testing in the setting of very early disease.
Let’s envision a hypothetical patient who presents with stage IA NSCLC based on lung cancer screening. The tumor was resected and there is no evidence of disease anywhere else. The patient is concerned about the cost of performing NGS on their tumor biopsy. What reasons would you offer to this patient to support testing?
Helena A. Yu, MD:
I want to first note that molecular testing orders are often submitted at the time of resection when pathologic staging is not yet available. Regardless, in this hypothetical case, I would not offer adjuvant osimertinib. That being said, this case does raise the important issue of cost for testing. Now that most patients with early-stage NSCLC harboring EGFR mutations are eligible for adjuvant osimertinib, I expect that I could appropriately respond to a patient’s insurance company if there were billing issues.
Edward B. Garon, MD, MS:
I agree.
Edward B. Garon, MD, MS:
An important related issue is the use of liquid biopsy for molecular testing at diagnosis of NSCLC. In our survey, we asked, “When are you using liquid biopsy to test for EGFR mutations in your patients with NSCLC?”
As can be seen in this table of survey results, the largest percentage of our 77 responding HCPs (38%) reported using liquid biopsy testing at progression, which we will discuss more later. Another 31% said they use it at both diagnosis and progression, whereas 6% said they use it at diagnosis only. Of interest, 25% of the respondents reported they do not use liquid biopsy testing at all, which may be explained by some regional variation.
Table 2. When are you using liquid biopsy to test for EGFR mutations in your patients with NSCLC?
Edward B. Garon, MD, MS:
Dr. Socinski, do you use liquid biopsy when doing molecular testing in your patients with newly diagnosed advanced NSCLC?
Mark A. Socinski, MD:
I test both plasma and tissue biopsies at diagnosis of advanced NSCLC. Finding an oncogenic driver is such a game changer for patients that you want to leave no stone unturned to identify them.
Regarding the clinical utility of liquid vs tissue biopsy, the NILE trial greatly influenced my practice. The NILE trial evaluated the identification of relevant biomarkers with a validated cell-free DNA (cfDNA) test compared with tissue genotyping in 282 patients with newly diagnosed metastatic NSCLC.2 The trial met its goal of demonstrating noninferiority of biomarker identification in cfDNA from plasma relative to physician discretion standard-of-care (SoC) tissue testing (27.3% vs 21.3%, respectively; P <.0001 for noninferiority), with a high rate of concordance for FDA-approved targets (>98.2%).
Of more importance, NILE showed that testing of plasma may allow the identification of more biomarkers compared with a tissue biopsy specimen. With a cfDNA-first approach, 1 of 8 guideline-recommended biomarkers would have been identified in 87% of 89 patients vs 67% when tissue testing was the primary modality for molecular testing. This is a great finding considering that tissue is often inadequate for all necessary testing or may even be lacking. Finally, the trial also demonstrated that liquid and tissue testing are complementary: Adding a cfDNA test to tissue testing increased the detection of an identifiable guideline-recommended biomarker by 48%.
I think finding a driver mutation is the best thing we can do for our patients with advanced NSCLC, and that is why I advocate testing with both tissue and plasma at the time of diagnosis.
Edward B. Garon, MD, MS:
In our survey, approximately 20% of HCPs reported requesting EGFR mutation testing only at the diagnosis of stage III or IV NSCLC. Dr. Socinski, how would you counsel a patient diagnosed with stage III disease who was expressing concerns about the cost of EGFR mutation testing?
Mark A. Socinski, MD:
Before I begin, I’d like to mention that at my institution, any adenocarcinoma resected by a surgeon is reflexively tested, meaning we automatically receive the EGFR mutation status for all of our patients with early-stage disease who have undergone surgery. However, here is what I would discuss with patients as the rationale for testing if that were not the case.
For resectable stage III disease, I would talk to patients about the benefit of adjuvant osimertinib observed in the ADAURA trial for patients with resectable stage IIIA EGFR-mutated NSCLC,1,3 which we will discuss further in the next section as the reason for testing. I will note that my most recent couple of patients with EGFR-mutated NSCLC that was stage III or earlier declined adjuvant osimertinib because of uncertainty around the benefit in these early-disease settings.
For unresectable stage III disease, I would discuss the nuances around the use of consolidation immunotherapy with durvalumab—which was established as an SoC for patients with unresectable stage III NSCLC without progression following concurrent chemoradiation based on the progression-free survival (PFS) benefit seen in the phase III PACIFIC trial—and that we now know it also achieves improved PFS and overall survival (OS) all the way out to 5 years.4-7
First, if the patient were to be found positive for an EGFR mutation, we might not want to use immunotherapy considering evidence of its lack of benefit in this population in the advanced disease setting. For example, a phase II study of first‑line pembrolizumab in EGFR‑mutated, PD-L1–positive lung cancer was closed due to futility.8
Edward B. Garon, MD, MS:
Yes. I was involved in that trial, and we did not see any responses, even in patients with high PD‑L1 tumor expression.
Mark A. Socinski, MD:
That said, a small subgroup of 43 patients enrolled on PACIFIC who had an EGFR mutation had an unstratified HR for disease progression or death of 0.76 (95% CI: 0.35-1.64) compared with 0.47 (95% CI: 0.36-0.60) in the patients who were negative for an EGFR mutation.
Second, if we did decide to proceed with the PACIFIC regimen, it still stands that slightly over 50% of patients with unresectable stage III NSCLC experienced disease progression on PACIFIC, either during or following consolidation durvalumab, as shown with an extended follow-up of PFS.7 Thus, it is clear that many of these patients will need a subsequent line of therapy because immunotherapy has not cured their disease. If we have upfront testing results showing that the patient has an EGFR mutation, we will be poised to start them on first-line osimertinib for metastatic disease if they progress, which we will also explore further below. I explain to them, “We have a really good plan should you be one of the patients who experiences disease progression either during or following consolidation therapy with durvalumab.”
Edward B. Garon, MD, MS:
Thank you.
Edward B. Garon, MD, MS:
Returning to our survey results, an additional point of interest is that we compared the responses to this question from academic vs community practitioners. In general, the practice patterns associated with testing for EGFR mutations were similar across the 2 groups. Fortunately, there were only a very few community HCPs who indicated that they were either not testing for EGFR mutations or testing only after progression on first-line therapy, which is clearly not recommended.
Table 3. In your practice, when are you first testing for EGFR mutations in your patients with NSCLC?
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