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Biomarker Testing in NSCLC
Practical Insights for NPs and PAs: Biomarker Testing in NSCLC

Released: June 05, 2023

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Key Takeaways
  • Approximately 50% of patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) will have a driver mutation targetable by an FDA-approved targeted therapy.
  • Biomarker testing, preferably by next-generation sequencing (NGS), should be completed for all patients with advanced nonsquamous NSCLC, considered for patients with squamous NSCLC, and based on FDA approval in the adjuvant setting.
  • PD-L1 testing by immunohistochemistry should be done for all patients with advanced NSCLC.
  • Patients with advanced NSCLC will need to be counseled on the reasons why it is imperative to wait for the results of all biomarker testing, including both NGS and PD-L1, before treatment decisions are made.

In 2023, approximately 50% of patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) will have a driver mutation targetable by an FDA-approved therapy. The driver mutations with FDA-approved therapy include EGFR mutation (exon 19del, L858R, and exon 20 insertion), ALK rearrangement, ROS1 fusion, BRAF V600E mutation, NTRK fusion, RET fusion, MET mutation (exon 14 skipping), HER2 mutation, and KRAS mutation (G12C). Among these alterations, EGFR exon 20 insertion, HER2 mutation, and KRAS mutation (G12C) guide selection of FDA-approved targeted therapy in the second-line setting only. Based on the ADAURA trial, EGFR testing should be done in the adjuvant setting as well.

In addition, PD-L1 testing by immunohistochemistry (IHC) should be done for all patients with advanced NSCLC to guide application of immunotherapy-based treatment. Imunotherapy treatment is FDA-approved in the neoadjuvant and adjuvant settings based on the IMpower 010 trial for PD-L1–positive disease,  PEARLS/KEYNOTE-091, and CHECKMATE 816 regardless of PD-L1 expression. As the treatment landscape for NSCLC continues to evolve, understanding which biomarkers should be tested for, as well as their associated targeted treatment, is essential for today’s oncology advanced practice providers.

Guidelines for Biomarker Testing in NSCLC
To identify patients with advanced NSCLC appropriate for targeted therapy, experts and clinical guidelines recommend broad molecular testing, preferably with NGS, to detect actionable genomic alterations in all patients with nonsquamous disease and certain patients with squamous disease. In addition, all patients with advanced NSCLC should undergo PD-L1 expression testing by IHC to identify candidates for immunotherapy-based treatment approaches.

With the approval of neoadjuvant and adjuvant targeted therapy and immunotherapy approaches, the need for biomarker testing is moving into the setting of early-stage NSCLC. Testing for EGFR should be done for patients with resectable stage IB-IIIA NSCLC. Testing for PD-L1 expression should be done for those with resectable stage II-IIIA diease. Locally advanced disease, receiving definitive chemoradiation, currently has no indication for biomarker testing despite there being an indication of immunotherapy post definitive chemoradiation. Based on the PACIFIC trial the indication to proceed with immunotherapy was regardless of PD-L1 status.

Biopsy tissue from the primary tumor or a metastatic site is considered the “gold standard” for biomarker testing. However, liquid biopsies, which are a blood sample containing cell-free DNA from multiple sources including DNA shed from tumor, are increasingly being used for biomarker testing in the setting of lung cancer. Of importance, a negative test result with liquid biopsy is uninformative and should be confirmed with a tissue biopsy. Likewise, given the heterogeneity of the tumor, a negative biomarker result based on tissue should consider liquid biopsy.

Clinical Pearls for Counseling Patients With NSCLC About Biomarker Testing
Patients with a recent diagnosis of advanced NSCLC are often anxious to begin treatment, so will need to be counseled on the reasons why it is imperative to wait for the results of all biomarker testing, including both NGS and PD-L1, before treatment decisions are made. Of note, outcomes are improved for patients with NSCLC when they receive targeted therapy directed toward their specific cancer genotype as compared to chemotherapy with or without immunotherapy. Furthermore, giving immunotherapy upfront in a patient who is eligible for EGFR-directed therapy in the first-line setting may increase adverse effects if targeted therapy is subsequently given. Most tyrosine kinase inhibitors are now recommended as first-line therapy for patients with a specific targeted mutation. Even if PD-L1 results are high, molecular testing results need to be reviewed before initiating treatment. A high PD-L1 expression does not exclude the presence of a targeted mutation, and efficacy to immunotherapy is potentially reduced in the first-line setting in patients with a driver mutation. It is critical to get the right treatment to the right patient.

Your Thoughts?
What have been your biggest challenges with biomarker testing for patients with NSCLC? Join the discussion by leaving a comment.

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