Emerging Role of Targeted Therapies Combined With Radiotherapy in Inoperable Stages I to III NSCLC: A Review From the IASLC ART Subcommittee

Precision oncology has transformed the management of NSCLC by tailoring treatment to the specific genetic alterations driving oncogenesis. Targeted therapies, such as tyrosine kinase inhibitors, have been found to dramatically improve survival in patients with advanced-stage NSCLC. However, treatment options remain limited for patients with early or locally advanced stage (I-III) NSCLC harboring driver mutations, when the disease is not resectable, or the patient is unsuitable for surgery due to poor fitness or comorbidities. There is growing interest in combining targeted therapies with radiotherapy to optimize treatment outcomes for this patient group. Notably, a progression-free survival benefit has recently been reported with the third-generation tyrosine kinase inhibitor osimertinib in patients with inoperable, EGFR-mutated, stage III NSCLC after chemoradiotherapy. A narrative review of the literature was performed using PubMed, OVID (EMBASE), and ClinicalTrials.gov to identify studies evaluating the combination of targeted therapies and radiotherapy in inoperable stages I to III NSCLC. This review provides a comprehensive overview of the incidence of actionable driver alterations and emerging clinical evidence on combining targeted therapies with thoracic radiotherapy in patients with inoperable stages I to III NSCLC. The toxicity profile of combination treatments, optimal sequencing strategies, ongoing clinical trials, and future perspectives in this field are highlighted. In summary, a clear biological rationale supports the synergistic effects of combining targeted therapies with radiotherapy in the neoadjuvant, concurrent, and adjuvant settings. Advanced clinical trial methodologies may facilitate further research in this area, particularly for rare genetic alterations, to improve outcomes for these patients.