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Management of Treatment Resistance in Patients With Advanced Epidermal Growth Factor Receptor–Mutated Lung Cancer: Personalization, Parsimony, and Partnership

*February 2024*


Patients with epidermal growth factor receptor (EGFR)–mutated advanced non–small-cell lung cancer represent a distinct subgroup of individuals who can experience initially tolerable and durable effects with first-line EGFR-directed tyrosine kinase inhibitors. Unfortunately, acquired treatment resistance and cancer progression within the CNS are inevitable during the disease course and present a challenging transition in the care continuum. Next-line therapies generally require combinations of drugs and afford nuanced differences in clinical outcomes relative to the treatment experience, toxicity profile, and quality of life. Therapeutic stratification and modulation thus require further personalization and partnership with patients to identify key clinical, molecular, and human-specific factors to best guide optimal care.

Case Presentation

A patient with a 20-pack-year history of tobacco use presents with several months of weight loss and hip pain. Diagnostic imaging demonstrates a left upper lobe mass with metastases to the intrathoracic lymph nodes, skeleton, and brain (Fig 1). Bone biopsy shows lung adenocarcinoma. The patient undergoes palliative radiotherapy to brain and symptomatic skeletal metastases. Comprehensive tumor molecular profiling demonstrates an epidermal growth factor receptor (EGFR) exon 19 deletion mutation (E746_A750) and coalteration in TP53; the PD-L1 22C3 immunohistochemistry tumor proportion score is 1%. The Eastern Cooperative Oncology Group performance status (ECOG PS) is 2. The patient begins first-line palliative osimertinib with tumor response, but 17 months later, the patient has symptomatic progression. Rebiopsy confirms adenocarcinoma of the lung; tumor molecular reprofiling yields identical results as before. The ECOG PS is 1. The patient is here to discuss ongoing treatment options, including chemotherapy, immunotherapy, targeted therapy, or symptom-focused care.

Clinical Challenges in Evaluation and Management

Comprehensive Histopathologic and Molecular Characterization is Mandatory for Patients With Advanced Non–Small-Cell Lung Cancer

Among patients with actionable oncogene-addicted tumors, EGFR-mutated (EGFRm) non–small-cell lung cancer (NSCLC) is the most common and disproportionately affects young women and those with limited/no tobacco use. Canonical EGFR mutations—exon 19 deletions (del19) and point mutations in exon 21 (L858R)—account for 80%-85% of EGFR mutations,1 with less common recurring alterations in exons 18-21 seen in the other 10%-15% and representing a cohort in whom outcomes remain suboptimal.2

For patients with advanced EGFRm NSCLC and either del19 or L858R, first-line therapy with an EGFR-directed tyrosine kinase inhibitor (TKI) is the standard of care. The third-generation TKI osimertinib is preferred, owing to better outcomes—median progression-free survival (PFS) 18.9 months, median overall survival (OS) 38.6 months, intracranial response/disease control rate, and toxicity profile—compared with first-generation TKIs (erlotinib, gefitinib).3 Recent trials exploring up-front combination therapy strategies may afford even better outcomes than TKI monotherapy, including chemotherapy-TKI and combinations of novel EGFR-directed therapies.4,5 Despite these therapeutic successes, acquired treatment resistance and CNS progression are inevitable realities and a challenging transition in the cancer care continuum.

Acquired Osimertinib Resistance Is Inevitable and Heterogeneous

Mechanisms of acquired TKI resistance include (1) acquisition of a second site EGFR alteration, (2) upregulation of a bypass pathway that promotes oncogenic signaling in an EGFR-independent manner, (3) histologic transformation to small-cell lung cancer, or (4) suboptimal drug penetration at a sanctuary site such as the CNS. While resistance to first-generation EGFR TKIs is commonly due to the EGFR T790M mutation,6 a variety of mechanisms cause resistance to third-generation EGFR TKIs (Fig 2). Actionable resistance mechanisms are uncommon, making empiric platinum-doublet chemotherapy the standard second-line option for most patients.713 Several trials have been designed to address the majority of patients who experience disease progression on osimertinib and lack an identifiable or actionable mechanism of treatment resistance (Table 1). Examples include trials targeting EGFR/MET in combination with chemotherapy and studies using immune checkpoint inhibitors (ICIs) in combination with chemotherapy and vascular endothelial growth factor (VEGF) inhibitors (VEGFi). Read more.