Targeted Therapy Treatment

This article reviews strategies for managing treatment resistance in advanced EGFR-mutated lung cancer, focusing on personalization, parsimony, and partnership.


The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

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.

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