# Neoadjuvant, Adjuvant and Perioperative Treatment in Early-Stage Non-Small Cell Lung Cancer (NSCLC) with Actionable Genomic Alterations: Current Landscape and Future Perspectives

## TL;DR

This paper reviews current and future treatment strategies for early-stage non-small cell lung cancer with specific genetic mutations.

## Contribution

The paper provides a comprehensive overview of current and emerging targeted therapies in the perioperative management of oncogene-driven non-small cell lung cancer.

## Key findings

- Adjuvant osimertinib and alectinib improve survival in EGFR-mutant and ALK-rearranged NSCLC.
- Neoadjuvant immunotherapy improves outcomes in non-oncogene addicted NSCLC.
- Future directions include perioperative use of targeted therapies for actionable molecular alterations.

## Abstract

Non-small-cell lung cancer is a leading cause of morbidity and mortality worldwide. The landscape of early non-small-cell lung cancer treatment is currently undergoing a massive paradigm shift. Chemoimmunotherapy has revolutionized perioperative management of non-oncogene addicted early disease. Concerning oncogene-driven early non-small-cell lung cancer, adjuvant treatment with osimertinib in EGFR-mutant disease and alectinib in ALK-rearranged disease is considered a standard of care option for patients after complete resection. Ongoing studies—at different stages—evaluate targeted approaches in the perioperative setting of EGFR-mutant, ALK-rearranged, and other actionable molecular alterations. This comprehensive review aims to summarize the major breakthroughs in the perioperative management of oncogene-driven non-small-cell lung cancer and give an overview of promising ongoing efforts.

Surgical resection remains the cornerstone of curative-intent treatment for both oncogene and non-oncogene addicted early-stage non-small cell lung cancer, with neoadjuvant/adjuvant chemotherapy providing only a modest benefit in terms of disease-free survival and overall survival. Currently, in non-small-cell lung cancer without actionable molecular alterations, the addition of neoadjuvant or perioperative immunotherapy to chemotherapy has become the standard of care for resectable disease, with significant improvements in the rates of complete pathological response, major pathological response, and event-free survival. In terms of oncogene-addicted non-small-cell lung cancer, adjuvant treatment of completely resected disease with the third-generation EGFR inhibitor osimertinib in patients harboring activating EGFR mutations or the second-generation ALK inhibitor alectinib in patients with an ALK fusion/translocation has brought about a paradigm shift by significantly improving event-free survival and, in the case of osimertinib, overall survival. A glimpse into the future management of patients with early-stage disease and a common EGFR mutation or an ALK fusion/translocation may reveal a perioperative use of the respective targeted treatment. Data for the rest of the actionable molecular alterations remain limited, and those tumors are usually treated with algorithms used for non-oncogene-addicted non-small-cell lung cancer. This review aims to summarize all existing evidence about the current management of patients with early-stage non-small-cell lung cancer and actionable molecular alterations and to examine the future directions in this rapidly evolving field.