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Head,Thoracic Oncology Unit
Vall d'Hebron University Hospital
Enriqueta Felip, MD, has disclosed that she has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Puma, Roche, Sanofi Genzyme, Takeda; fees for Non-CME/CE services from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; funds for research support from Fundación Merck Salud; and other financial or material support from Grifols (independent member of the board).
University of California, San Francisco
San Francisco, California
Matthew Gubens, MD, MS, has disclosed that he has received funds for research support paid to his institution from Celgene, Merck, Novartis, OncoMed, and Roche and consulting fees from AstraZeneca, Beyond Spring, Boehringer Ingelheim, Bristol-Myers Squibb, Inivata, and Takeda.
The treatment landscape for patients with non-small-cell lung cancer (NSCLC) and actionable mutations continues to evolve. In this commentary, Enriqueta Felip, MD, and Matthew Gubens, MD, MS, explore regional differences in biomarker testing and management between the European Union (EU) and the United States, respectively. An overview of current best practices for treating metastatic EGFR-mutated NSCLC can be found here.
Biomarker Testing in NSCLC: Perspectives From the EU and US
The key to implementing optimal therapy for newly diagnosed advanced NSCLC is to first identify patients with actionable mutations, including EGFR mutations. Now that approximately 35% of these patients will harbor a driver mutation that is targetable with an FDA-approved therapy (ie, alterations in EGFR, ALK, ROS1, BRAF, RET, MET, or NTRK), the optimal molecular testing approach for all patients with advanced NSCLC is broad panel testing with next-generation sequencing (NGS). Using an NGS approach serves to provide more information using less tissue. Furthermore, RNA NGS techniques might offer better identification of targetable gene fusions.
In the United States, the testing paradigm is rapidly changing. Although uptake of DNA NGS is improving, many practices still start with sequential testing of specific mutations, which takes longer and could lead to running out of tissue. With more targetable mutations known, it is now considered more efficient to do multiplex testing from the start. Given the recent FDA approval of osimertinib for adjuvant therapy after resection for early-stage disease, we are increasingly testing our patients with early-stage disease. However, the question remains whether to perform broad panel testing in this setting or to test only for EGFR exon 19 deletions or exon 21 L858R mutations per the indications for adjuvant osimertinib.
In Europe, NGS is increasingly being performed but currently is limited mainly to academic centers. Osimertinib is not currently approved by the European Medicines Agency (EMA) for adjuvant therapy, so we rarely test nonmetastatic patients for mutations, but that should change if approval is granted. Although the number of patients who have NGS testing on their tumor is increasing in Spain, we still see many sequential single gene tests being performed.
In both the United States and the EU, the turnaround time for NGS is 2-3 weeks. However, some patients who have a high burden of disease, have quick progression, or are very symptomatic need to be treated quickly. Liquid biopsies can play a role in these cases and are increasingly being performed in the United States. In the EU, liquid biopsies are used in patients with EGFR-mutated NSCLC at disease progression on an earlier-generation EGFR tyrosine kinase inhibitor (TKI) to identify resistance mutations as well as at diagnosis when there is not enough tumor material for molecular tests. However, reimbursement strategies for molecular alteration tests are unclear and differ across countries.
Regional Perspectives on Frontline Therapy for Advanced EGFR-Mutated NSCLC
Globally, osimertinib is the preferred therapy for newly diagnosed, advanced EGFR-mutated NSCLC with the canonical EGFR mutations del19 and L858R based on clinical evidence, current indications, and guideline recommendations. Although physicians in the EU support the use of osimertinib first line, the reimbursement policies are not uniform across EU countries, so cost might force some healthcare professionals to treat newly diagnosed disease with an earlier-generation EGFR TKI.
In Spain, we use afatinib to treat patients with noncanonical EGFR-activating mutations such as those in exon 18. Afatinib is also approved in the United States for uncommon activating EGFR mutations (ie, EGFR G719X in exon 18, S768I in exon 20, and L861Q in exon 21). However, for patients with newly diagnosed disease and an exon 18 G719X mutation, we will often use osimertinib based on data from a single-arm phase II trial showing an overall response rate of 52.6%, along with its better tolerability as compared with afatinib, but this will depend on a discussion with insurance.
For patients with EGFR exon 20 insertions, where our available EGFR TKIs at standard doses, including osimertinib, have not shown a benefit, enrollment on a clinical trial is the best option for managing their disease, and several agents including osimertinib at the higher dose of 160 mg/day, poziotinib, mobocertinib, and amivantamab, are being examined. In the absence of a clinical trial, these patients can be managed with first-line platinum-doublet chemotherapy.
Finally, due to its demonstrated efficacy against central nervous system (CNS) metastases, frontline osimertinib can also now be used at diagnosis for the management of most patients with EGFR-mutated NSCLC and CNS metastases before invoking treatment with radiation. Because patients with oncogenic driver alterations who are treated with targeted therapies are experiencing longer-term survival, we want to delay radiotherapy and its associated adverse events for as long as safely possible to preserve brain function and quality of life. In Spain, we sometimes consider stereotactic body radiation therapy, which although tolerable, is still associated with adverse events; we try to avoid whole-brain radiotherapy, known for its extensive, long-term effects on cognition. In general, we are now comfortable starting osimertinib alone in these patients. This shift away from using radiation to treat brain metastases, in particular those that are not causing symptoms or are causing only low-grade symptoms, for patients with NSCLC and actionable mutations where we now have CNS-penetrant targeted therapies has also occurred in the United States. Monitoring in these patients can be intensified, including obtaining a baseline brain MRI and then following up on a more frequent schedule to confirm that the CNS disease is being controlled by the systemic therapy.
Regional Perspectives on Therapy After Progression
Upon systemic progression on a first-line EGFR TKI, determining the mechanism of resistance via rebiopsy, whether tissue or liquid, can inform the choice of subsequent therapy. In the United States, especially at academic centers, we will try to at least do a liquid biopsy to identify if there is an actionable resistance mutation that we can target, whether on a clinical trial or by lobbying insurance to allow us to add an available therapy directed against the targetable resistance mutation (eg, a MET inhibitor for bypass MET amplification) to osimertinib. However, in the absence of an actionable resistance mutation, platinum plus pemetrexed with or without bevacizumab is the only FDA-approved option in the post-osimertinib setting. Tissue biopsies on progression are also important to determine whether histologic transformation to small-cell lung cancer (SCLC) or squamous cell carcinoma has occurred, which may affect which subsequent chemotherapy regimen is used (eg, platinum plus etoposide for transformation to SCLC).
In Spain, for those patients treated with first-generation and second- generation EGFR TKIs, rebiopsy, often by liquid biopsy, is mandatory to detect a T790M mutation and direct subsequent treatment with osimertinib. For patients who received frontline osimertinib, knowing the mechanism of resistance could direct their enrollment on a clinical trial, but the standard of care for these patients is platinum plus pemetrexed. In the third line, we will then use docetaxel, possibly with nintedanib, an antiangiogenic agent that is approved in combination with docetaxel in the EU.
Of note, the recent phase III IMpower150 trial demonstrated significantly improved progression-free survival and overall survival with atezolizumab plus carboplatin/paclitaxel and bevacizumab in patients with nonsquamous NSCLC, including a small subset of patients with EGFR mutations who progressed on or were intolerant to first-line EGFR TKI therapy. Although it is worth having a discussion with patients about these data, this combination is not approved by the EMA or the FDA for patients with EGFR mutations who progressed on an EGFR TKI. And notably, the KEYNOTE-189, -024 and -042 trials did not allow patients with EGFR mutations.
For a discussion of how to approach indolent or oligometastatic progression on first-line EGFR TKI therapy, please see here.
Patient advocacy groups have emerged globally as strong partners in research and advocating for changes in clinical care. In the United States, it is often our patients with EGFR mutations and other actionable alterations who are pushing for increased research funding, improved access to clinical trials, and early approvals of drugs by the FDA (eg, EGFResisters). The fact that the epidemiology for some of these alterations skews younger means an even greater proportion of these patients are web-savvy and engaged. In the EU, we have Lung Cancer Europe (LuCE), which supports the establishment of national lung cancer groups in different EU countries. Overall, we need to work together with our patients, who have become more informed and more engaged in their care, in all our initiatives, from lung cancer trials to reimbursement issues and how to improve upfront molecular testing.
Despite rapid advances in the field of EGFR-mutated NSCLC, additional therapeutic options are needed for patients who develop resistance to first-line therapy, and numerous clinical trials are underway to address this question. How often do you discuss clinical trials with your patients who progress on osimertinib? Answer the polling question and join the conversation by posting a comment in the discussion section.