The HER Project: Homologous Recombination Deficiency in EGFR-Mutated NSCLC, a Retrospective and Prospective Translational Single-center Study

Introduction

Lung cancer is the most common diagnosed cancer, with almost 2.5 million new cases per year, and the leading cause of cancer-related death (18.7%), according to GLOBOCAN (2022). Non-small cell lung cancer (NSCLC) is the most prevalent subtype, accounting for 85% of lung cancers. Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that regulates survival, proliferation and differentiation in mammalian cells. EGFR mutations occur in around 30% of patients affected by NSCLC, representing the second most frequent targetable oncogenic driver in NSCLC.

The treatment landscape for metastatic EGFR-mutated (EGFRm) NSCLC has significantly evolved since the introduction of 1st generation tyrosine kinase inhibitors (TKIs) in 2010. While osimertinib (a 3rd generation TKI) is currently the standard first-line treatment worldwide in the advanced setting, emerging combination strategies, such as osimertinib plus chemotherapy (FLAURA2 trial) or lazertinib plus amivantamab (MARIPOSA trial), improved progression-free survival (PFS) and overall survival (OS) compared to TKI alone. However, these drug combinations often cause increased treatment-related toxicities, impacting both patients' quality of life and healthcare costs. For this reason, it becomes crucial to identify predictive biomarkers to guide patient selection for combination therapies. For example, post-hoc analyses of FLAURA2 were conducted on poor-risk populations, such as EGFRm patients with high tumour burden or TP53 co-mutations. Despite better outcomes of chemotherapy plus osimertinib across all patient subgroups, only 1 out of 4 patients had baseline tissue samples available for wider genome sequencing. Therefore, understanding the role of co-alterations in EGFRm tumours remains to be explored, particularly those associated with shorter OS and/or more aggressive clinical presentations.

Targeting HRD pathway with PARP-inhibitors in Non-small cell lung cancer

Homologous recombination deficiency (HRD) is a condition linked to an impaired DNA repair mechanism that contributes to genomic instability in several cancers, including NSCLC. PARP-inhibitors (PARPi), drugs targeting a key protein involved in DNA repair, are already available in clinical practice for the treatment of other HRD-positive subgroups of solid tumours (e.g. breast, ovarian, prostate cancer). In NSCLC, however, their clinical benefit remains unclear. Previous studies evaluating PARPi in NSCLC, including combinations with chemotherapy or immunotherapy, have shown modest or non-significant improvements in PFS and OS. However, a significant limitation of these studies is the lack of HRD status assessment, which may have diluted the expected benefits in HRD-positive patients.