D110-07 A Case Report of a Patient-derived Xenograft Model From a Lung Adenocarcinoma Patient With Wild-type EGFR Amplification

Abstract Introduction EGFR mutations, with or without concomitant amplification, constitute a substantial subset of lung adenocarcinoma. Patients harboring these alterations derive significant clinical benefit from EGFR tyrosine kinase inhibitors (TKIs). Wild-type EGFR amplification represents a rare yet biologically distinct subtype of lung cancer. The oncogenic driver role of this genetic alteration and its therapeutic implications remain subjects of ongoing debate, resulting in ill-defined clinical management strategies. This study employed a patient-derived xenograft (PDX) model to systematically evaluate the efficacy of diverse EGFR-targeting agents. Description of Case A 68-year-old male presented with a left lung mass and mediastinal lymph node enlargement, accompanied by profound cancer cachexia (20 kg weight loss over 4 months) and an ECOG performance status of 4. Comprehensive imaging evaluation confirmed widely metastatic disease involving bilateral lungs, adrenal glands, spleen, and brain. Histopathological diagnosis of lung adenocarcinoma was established via percutaneous biopsy, with complementary immunohistochemistry revealing exceptionally high PD-L1 expression (95%). Next-generation sequencing identified wild-type EGFR amplification (copy number 7.5) without other canonical driver mutations. Following patient demise with appropriate ethical consent, a PDX model was successfully established from subcutaneous metastatic tissue and rigorously validated to maintain the primary tumor’s molecular characteristics.Two distinct in vivo pharmacodynamic studies were conducted. The first study evaluated multiple EGFR-directed regimens, including erlotinib, afatinib, osimertinib, and cetuximab combined with pemetrexed. The second study specifically compared cetuximab monotherapy, pemetrexed monotherapy, and their combination. The cetuximab-pemetrexed combination demonstrated superior initial efficacy with 87.78% tumor inhibition, significantly surpassing all EGFR-TKI monotherapies (51.07%-53.12%, p 0.01). Cetuximab monotherapy subsequently achieved 92.03% inhibition, markedly outperforming pemetrexed monotherapy (15.40%) without demonstrating combinatorial synergy. Discussion This comprehensive investigation provides compelling evidence establishing wild-type EGFR amplification as an oncogenic driver in lung cancer. The marked superiority of cetuximab over multiple generations of EGFR-TKIs reveals a distinctive therapeutic vulnerability in amplification-only tumors, potentially attributable to differential mechanisms of target inhibition. These findings offer crucial preclinical rationale for prioritizing antibody-based EGFR targeting in this molecularly defined subset.Notable limitations include the unaddressed potential of immune checkpoint inhibition despite 95% PD-L1 expression, and the exclusion of emerging bispecific antibodies such as EGFR-MET bispecific antibodies. Future investigations addressing these therapeutic avenues are warranted to refine clinical strategies for this rare lung cancer variant. This abstract is funded by: None