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Associate Director of the Cancer Care Equity Program
The Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Narjust Florez, MD: consultant: AstraZeneca, Bristol-Myers Squibb, DSI, Merck, Mirati, Neogenomics, Pfizer.
In this commentary, Narjust Florez, MD, discusses the importance of biomarker testing for patients with non-small-cell lung cancer (NSCLC) using examples from her clinical practice. These key points and patient cases were discussed during a recent live Clinical Care Options satellite symposium held during the 2022 American Society of Clinical Oncology annual meeting.
Importance of Biomarker Testing for NSCLC
A 44-year-old, non-Hispanic White woman presented to my practice after developing shortness of breath on vacation. She has never smoked but did experience some second-hand smoke during childhood. She is a software engineer and is married with 2 healthy children. After 4 negative COVID-19 tests without improvement of symptoms, a CT scan revealed multiple small nodules bilaterally with a primary lung mass measuring 4 cm. Subsequent imaging showed the known, large primary mass as well as 1 liver lesion. The liver lesion could not be biopsied due to the depth and size of the lesion. A bronchoscopy-guided biopsy revealed a TTF1-positive adenocarcinoma of the lung with a PD-L1 of 90%. Tissue was sent for next-generation sequencing (NGS). Her diagnosis was stage IVB lung adenocarcinoma (T4N1M1c).
So, what should we do next for this patient? With 90% PD-L1 expression, do we start treatment with immunotherapy right away? Do we wait for the NGS results to come back? The answer is to wait, which can be difficult for the patient because the turnaround time is longer than for PD-L1 results but having good communication with patients about the importance of waiting for the NGS results is paramount. Waiting for NGS results is critical because this information can allow patients to be treated with targeted therapy, which helps them live longer and have an improved quality of life compared with standard therapy. When discussing this with my patients, I tell them to think of a lock and key: Their disease is like a lock and biomarker results can be like a key to treat their disease the best way possible. To have the right key, we need to wait for the results of biomarker testing. I acknowledge to my patients that this time waiting for results can be anxiety-provoking, but that I am here for them.
This patient’s NGS results showed an EGFR mutation. Proper testing and EGFR-targeted therapy allowed this patient to run the Boston Marathon, attend her children’s recitals, and maintain her quality of life. Most importantly, her NGS results allowed her to have more treatment options, not only for first-line therapy but, at the time of disease progression, clinical trials for novel EGFR-targeted therapy could be a treatment option for her. Biomarker testing not only provides treatment options at diagnosis but can also help guide therapy and/or clinical trial eligibility at the time of disease progression.
Another patient I saw was a 42-year-old woman with a remote smoking history in college (<100 packs in her lifetime). She was diagnosed with lung cancer at another practice and started therapy with carboplatin, pemetrexed, and pembrolizumab. When she came to see me in the clinic, I realized she, unfortunately, did not have NGS testing performed at the time of diagnosis. We decided to do a liquid biopsy during that same clinic encounter, and the report showed an ALK-positive mutation. The day I met her in clinic, I did a comprehensive metabolic panel, and her liver enzymes were greater than 500 U/L, which was an adverse event of the immunotherapy. I started her on steroids and stopped her immunotherapy to begin the washout period, hoping to be able to start ALK inhibitor therapy. Unfortunately, she was never able to initiate ALK-targeted therapy. Within 1 week, she developed severe toxicities secondary to immunotherapy and died in the hospital without ever receiving the appropriate therapy for her. Every year, her wife and I celebrate her because she left us too soon. Precision medicine starts with biomarker testing.
I share these cases with you to highlight the difference between when biomarker testing is or is not done. Biomarker testing allows us to identify the potential for using targeted therapy to improve patient outcomes. However, fewer than 50% of patients with advanced NSCLC who have a driver mutation are receiving appropriate therapy due to a lack of biomarker testing and awareness about the importance of biomarker testing. Furthermore, significant racial/ethnic disparities exist for biomarker testing; for example, Black patients are significantly less likely to get the appropriate biomarker testing compared to White patients.
I am a big proponent of NGS for biomarker testing because it allows for less tissue use, and oncologists do not need to remember the exact genes they need to test for with these assays. In addition, guidelines are continuing to evolve as new targeted therapies are approved for treating lung cancer with specific mutations; we can often go back and find information on these new biomarkers in NGS reports and potentially offer patients the opportunity to enroll in a clinical trial for emerging biomarkers in lung cancer. However, the turnaround time for NGS results varies by institution, platform, and geographic location, so communication with the patient and with the care team while waiting for those results is very important.
Considerations for Biomarkers and Treatment Selection
Lung cancer is not the disease it used to be, with only chemotherapy and 2 targeted therapies to choose from. Now, I consider lung cancer to be many different diseases, with the prevalence of mutations changing by geographic location, race, and the ancestry of patients. This is pertinent to know as we are a very diverse community in the United States. EGFR mutations are common in Asian patients as well as Hispanic patients. KRAS mutations are higher in the non-Hispanic White population as well as Black patients. Regardless of who your patient is, we need to remember to find the key to unlock the best therapy for each of our patients to allow for the best outcomes with a better quality of life. In addition, smoking history should not impact whether a patient receives biomarker testing; patients with previous tobacco exposure can have genetic alterations, including ROS1, HER-2, MET, BRAF and KRAS mutations.
Two of the most common driver mutations for advanced NSCLC are EGFR and KRAS. EGFR mutations are present in approximately 20% of patients with NSCLC in the United States, and patients with EGFR mutations in exon 19 or 21 can be treated with osimertinib as a frontline therapy for metastatic disease. In countries where osimertinib is unavailable, afatinib or dacomitinib or erlotinib in combination with a VEGFR inhibitor can be used. Patients with uncommon EGFR mutations, including S768L, L861Q, and G719X, can consider therapy with afatinib or osimertinib. Patients with EGFR exon 20 insertions are generally unresponsive to the common EGFR TKIs, but they can be treated with mobocertinib and amivantamab for disease progression after platinum-doublet chemotherapy with or without immunotherapy.
KRAS mutations occur in 20% to 40% of nonsquamous NSCLCs. KRAS G12C mutations are the most common variant, accounting for approximately 40% to 50% of all KRAS mutations, and patients with KRAS G12C–mutated NSCLC can receive therapy with sotorasib after ≥1 previous therapy. Adagrasib is another small molecule inhibitor for KRAS G12C that is currently under investigation and has shown positive results from registrational trials.
Less common driver mutations for NSCLC include MET, RET, ALK, ROS, and NTRK. Although these biomarkers are less common in NSCLC, each has a highly effective targeted therapy available. Currently, capmatinib and tepotinib can be considered for the treatment of patients harboring MET exon 14 skipping mutations. Selpercatinib and pralsetinib are currently FDA-approved drugs for the treatment of patients with RET fusions. Crizotinib and entrectinib both have regulatory approval as first-line therapies for ROS1-positive metastatic NSCLC. Finally, TRK fusions, although incredibly rare, are targetable alterations in NTRK-positive lung cancer with entrectinib and larotrectinib.
The newest actionable biomarker in advanced NSCLC is HER2. Targeting HER2 is complex for NSCLC; however, activating HER2 mutations occur in 2% to 4% of nonsquamous NSCLC. Recently, the HER2-directed antibody, trastuzumab deruxtecan, was approved by the FDA for patients with NSCLC and activating HER2 mutations after a previous systemic therapy.
Although biomarker-guided therapy is critical to our patients with NSCLC, there are many challenges implementing this in clinical practice. Let me know some of the challenges you experience in your practice when it comes to biomarker testing for your patients with NSCLC. What questions do you have about selecting targeted therapy regimens for your patients with NSCLC? Answer the polling question and join the conversation in the discussion box below.