Neoadjuvant Targeted Therapy in Resectable NSCLC: Current and Future Perspectives

The standard of care (SoC) for medically operable patients with early-stage (stages I-IIIB) NSCLC is surgery combined with (neo)adjuvant systemic therapy for patients with stages II to IIIB disease and some stage IB or, rarely, che-moradiation (stage III disease with mediastinal lymph node metastases). Despite these treatments, metastatic recur-rence is common and associated with poor survival, high-lighting the need for systemic therapies that are more effective than the current SoC. After the success of targeted therapy (TT) in patients with advanced NSCLC harboring oncogenic drivers, these agents are being investigated for the perioperative (neoadjuvant and adjuvant) treatment of patients with early-stage NSCLC. Adjuvant osimertinib is the only TT approved for use in the early-stage setting, and there are no approved neoadjuvant TTs. We discuss the importance of comprehensive biomarker testing at diag-nosis to identify individuals who may benefit from neo-adjuvant targeted treatments and review emerging data from neoadjuvant TT trials. We also address the potential challenges for establishing neoadjuvant TTs as SoC in the early-stage setting, including the identification and valida-tion of early response markers to guide care and accelerate drug development, and discuss safety considerations in the perioperative setting. Initial data indicate that neoadjuvant TTs are effective and well tolerated in patients with EGFR- or ALK-positive early-stage NSCLC. Data from ongoing trials will determine whether neoadjuvant targeted agents will become a new SoC for individuals with oncogene-addicted resectable NSCLC. (c) 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

For medically operable early-stage NSCLC patients, surgery combined with systemic therapy is the standard of care. However, metastatic recurrence is common, highlighting the need for more effective systemic therapies. Targeted therapy has been investigated for perioperative treatment in early-stage NSCLC patients, and initial data show promising results. However, establishing neoadjuvant targeted therapy as the standard of care in the early-stage setting still faces challenges.