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NSCLC: Experts Address FAQs
FAQs: New Directions in Biomarker Testing in the Management of NSCLC

Released: October 17, 2022

Expiration: October 16, 2023

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Key Takeaways

  • Testing for resistance mutations is important to guide the selection of next-line treatment for patients with progression of NSCLC on targeted therapy
  • Molecular testing in early-stage NSCLC helps to guide treatment decisions in both the neoadjuvant and adjuvant therapy settings

In this commentary adapted from a discussion between Matthew Gubens, MD, MS, a thoracic oncologist, and Craig Mackinnon MD, PhD, an anatomical and molecular pathologist, the experts address important clinical questions about the role of biomarker testing in guiding treatment selection for patients with non-small-cell lung cancer (NSCLC).

What is your definition of a “perfect” actionable biomarker?

Craig Mackinnon, MD, PhD:
A “perfect” actionable biomarker is one that is diagnostic, prognostic, and predictive. In other words, the identified biomarker is “perfect” if it is useful for making the diagnosis, provides information on the disease course or survival, and can be inhibited by targeted therapy. In most cases, targeting such biomarkers yields marked responses. At the present time, the targetable biomarkers in NSCLC are few. They are gene mutations or fusions/rearrangements in EGFR, ALK, ROS1, BRAF V600E, NTRK, RET, MET exon 14 skipping, and KRAS G12C, and now HER2 has been added to the list. In the absence of these gene mutations or fusions/rearrangements, however, the expression level of the PD-L1 protein also has utility as an actionable biomarker.

Matthew Gubens, MD, MS:
PD‑L1 expression is an imperfect biomarker in NSCLC, although it remains an important one, especially in the absence of the actionable gene mutations or fusions/rearrangements. My hope is that in the next 5-10 years, we will look back on PD-L1 expression as an archaic biomarker in NSCLC with advances in the field of immunotherapy biomarkers. 

Should rebiopsy for molecular testing be performed at the time of disease progression on first-line targeted therapy?

Matthew Gubens, MD, MS:
Assessing treatment resistance in NSCLC is an interesting and growing area of research, especially for targeted therapies. Important questions following disease progression on first-line targeted therapy include: What is driving the treatment resistance? Is it actionable? In my practice, I am increasingly asking these questions. Admittedly, the patients’ insurance companies do not always buy-in to performing next-generation sequencing (NGS)–based testing to answer these questions as the “actionable” findings may involve trials or off-label uses. If an actionable mutation can be identified at the first point of treatment resistance, the patient may be able to receive a targeted agent as second-line therapy if the identified mutation is actionable. If not, the patient may be eligible to receive targeted therapy on a clinical trial. For instance, if a patient with EGFR-mutant NSCLC experiences disease progression on first-line osimertinib, and at the time of progression, the disease is found to harbor high MET overexpression or a new MET exon 14 skipping mutation, I would consider adding a MET inhibitor to osimertinib if the patient is not eligible for any ongoing clinical trial. So, rebiopsy at the time of disease progression on targeted therapy is important for the identification of acquired resistance mechanisms driving tumor growth. Of note, there are many active fourth-generation targeted therapies in the pipeline, with some being very specific for acquired mutations such as the EGFR C797S resistance mutation, and others attempting to address multiple resistance pathways.

Should molecular testing be performed for patients with early-stage NSCLC?

Craig Mackinnon, MD, PhD:
Yes. At my institution, we perform molecular testing on specimens from patients with early-stage NSCLC. We have an in-house NGS-based test that we use to determine the presence or absence of alterations in the actionable genes found in NSCLC. This helps us to identify actionable variants in genes besides EGFR, which can open up opportunities for other therapies such as those being investigated in clinical trials. For the small gene panel that we use for samples from patients with early-stage NSCLC, the turnaround time is quite rapid, considering that we are only testing for a few genes.  

Matthew Gubens, MD, MS:
At the present time, testing for EGFR mutations in tissue specimens from patients with resected early-stage NSCLC is the standard of care because osimertinib is an FDA-approved targeted therapy in the adjuvant setting. However, if other gene mutations are identified in early-stage NSCLC, this also can be helpful clinically, and so we do comprehensive testing at my institution as well. The patient may be eligible to participate in ongoing trials of targeted adjuvant or neoadjuvant therapy, and it might also inform the choice about adjuvant or neoadjuvant immunotherapy, which is likely to be of lower benefit in the setting of some genetic alterations like EGFR mutations and ALK fusions/rearrangements and even with high PD-L1. In all, identifying the driver of tumor growth is crucial for the selection of the optimal treatment approach for each patient.

What is the role of neoadjuvant immunotherapy in early-stage NSCLC?

Matthew Gubens, MD, MS:
The recent FDA approval of 3 cycles of neoadjuvant platinum-based chemotherapy in combination with immunotherapy (nivolumab) for patients with resectable NSCLC based on the results of the CheckMate 816 trial has been practice changing. That pathologic complete response can be achieved with immunotherapy in some patients prior to surgery is remarkable. In general, however, patients with NSCLC harboring EGFR mutations or ALK rearrangements have poor responses to immunotherapy, and there is the possibility of increased toxicities for patients who receive immunotherapy prior to receiving osimertinib, for example. For these reasons, I am less inclined to recommend neoadjuvant chemoimmunotherapy compared with targeted therapy-based combinations for patients with early-stage NSCLC harboring EGFR or ALK alterations. Of importance, there are ongoing trials of targeted therapies in the neoadjuvant and adjuvant settings for which some patients with early-stage NSCLC may be eligible (eg, NCT02201992, NCT05015010).

Your Thoughts?
What are the challenges you experience in your practice when it comes to requesting NGS-based testing on rebiopsy samples for your patients with NSCLC at the time of disease progression on first-line targeted therapy? Answer the polling question and join the conversation in the discussion box below.

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In your current practice, how often do you consider NGS-based testing to identify potentially actionable mechanisms of resistance in your patients with advanced NSCLC and disease progression on a targeted therapy?
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