The HER Project: HRD in EGFR-mutated NSCLC

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. Interestingly, emerging evidence suggests that a higher Genomic Scarring Score (GSS), a surrogate for HRD, may predict PARPi sensitivity better than the traditional assessment of the mutational status of homologous recombination repair (HRR) genes. In this study, the administration of PARPi significantly delayed tumour growth in patient-derived xenograft (PDXs) with high GSS, half of which carried pathogenic/likely pathogenic somatic HRR mutations. Importantly, favourable responses to the PARPi-olaparib were observed regardless of HRR gene mutation status, underscoring the potential of GSS as a robust biomarker to more effectively select patients for PARPi-based therapies. HRD in EGFR mutated NSCLC In a Chinese cohort of HRD-positive NSCLC, EGFR-mutated tumours are associated with poor TKI response, which might be explained by gene amplifications like MET, a common resistance mechanism that can be promoted by HRD. Studies also showed the co-occurrence of biallelic TP53 mutations and high HRD score in poor-risk EGFRm NSCLC, suggesting a link between this tumour genotype and TKI-resistance. In preclinical models of NSCLC, osimertinib-resistant EGFRm cell lines exhibited sensitivity to olaparib, leading to increased DNA damage and cell death via a pro-oxidant state. Moreover, combining osimertinib with a PARPi in vivo significantly improved tumour regression compared to osimertinib alone. Altogether, these findings lead to hypothesize that the HRD positive score/GSS may define a patient subgroup that could benefit from PARPi-based combination therapy. Clinical trials evaluating EGFR-TKIs with PARPi failed to achieve their primary endpoint of PFS, possibly due to a lack of patient selection based on HRD score or other molecular criteria. However, subsequent analyses of the GOAL trial found a stronger synergy between gefitinib (a 1st generation TKI) and olaparib in tumours with higher BRCA1 expression, supporting a predictive role for targeting DNA damage repair pathways. In operable NSCLCs, the percentage of HRD positive tumours is \~20-30%, suggesting that the acquisition of HRD status could be an early event. Importantly, a similar incidence was observed in a Chinese cohort of any-stage EGFRm or ALK-rearranged NSCLC patients in which the cases with high HRD score are \~33% of the total. The sensitivity of EGFRm tumours to platinum-based doublets, which is a known characteristic of HRD-positive tumours, and a larger compendium evidence of chromosomal instability further support exploring the role of HRD in EGFR-mutated lung cancer, paving the way for new targeted therapeutic approaches. The HER Project With the HER project, we will investigate the role of HRD and genomic instability (GSS) in EGFRm NSCLC by i) defining the fraction of metastatic EGFRm tumours with HRD positive score, ii) correlating HRD score with patient outcomes, and iii) assessing the synergic efficacy of EGFR-TKIs plus PARPi based on the HRD score in different preclinical settings, ranging from cell lines to a murine model of spontaneous EGFRm lung cancer. We expect that this drug combination will be effective in a specific subset of EGFR tumors. However, even if we won't observe any relevant findings by targeting this pathway, our work will increase our knowledge about DNA damage repair and drug resistance in EGFRm tumours.