Neoadjuvant Targeted Therapy in Resectable NSCLC: Current and Future Perspectives

Abstract

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, chemoradiation (stage III disease with mediastinal lymph node metastases). Despite these treatments, metastatic recurrence is common and associated with poor survival, highlighting 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 diagnosis to identify individuals who may benefit from neoadjuvant 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 validation 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.

Keywords: Early-stage NSCLC; NGS testing; Neoadjuvant treatment; Resectable NSCLC; Targeted therapy.

Figure 1.

PRISMA flow diagram for systematic search of ClinicalTrials.gov. Other reasons for exclusion include diagnostic clinical trial (n = 3), alternative treatments (vitamin A and leucoselect phytosome, n = 1 each), bifunctional fusion protein (bintrafusp alfa, n = 1), proteasome inhibitor (bortezomib, n = 1), unknown drug (n = 1). CIT, cancer immunotherapy; CT, chemotherapy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RT, radiotherapy.

Figure 2.

LCMC leader study schema. Figure from: Sepesi et al. [presented at ASCO 2022]. amp, amplification; cfDNA, cell-free DNA; CLIA, Clinical Laboratory Improvement Amendments; CT, computed tomography; LCMC, Lung Cancer Mutation Consortium; MET, c-MET; MPR, major pathologic response; mut, mutation; NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; pCR, pathologic complete response; PD-L1, programmed death-ligand 1; PET, positron emission tomography.

Figure 3.

NAUTIKA1 study schema. Figure adapted from: Lee et al. [data presented at WCLC 2022]. *Unless contraindicated or patient refusal. AJCC, American Joint Committee on Cancer; BID, twice daily; CLIA, Clinical Laboratory Improvement Amendments; ECOG PS, Eastern Cooperative Oncology Group performance status; LCMC, Lung Cancer Mutation Consortium; PD-L1, programmed death-ligand 1; Q3W, every 3 weeks; QD, once daily; SBRT, stereotactic body radiotherapy; SoC, standard of care; TKI, tyrosine kinase inhibitor.