Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.

Keywords: Chemotherapy; EGFR-TKIs; Immunotherapy; NSCLC; Osimertinib; Precise medicine; Resistance mechanisms; Targeted therapy; Therapeutic strategy.

Fig. 1

The development of EGFR-TKIs. a Timeline of approval of all three generations of EGFR-TKIs in EGFR-mutated NSCLC. The chemical structures and the first approval time of EGFR-TKIs are presented. b The coverage of common EGFR mutations of four generations of EGFR-TKIs. EGFR mutations are comprised of single mutant, double mutant and triple mutant, which are targeted by corresponding EGFR-TKIs. FDA, US Food and Drug Administration; NMPA, China National Medical Products Administration; KFDA, Korea Food and Drug Administration

Fig. 2

Mechanisms of resistance to osimertinib. a Resistance mechanisms of osimertinib occur in first-line (left) and second-line therapy (right), and incidences of each class of resistance mechanisms are also presented. b Resistance mechanisms to osimertinib are broadly divided into EGFR-dependent and EGFR-independent resistance mechanisms. The latter include bypass signaling activation, oncogenic fusions, downstream pathway alterations, histologic transformations and cell cycle gene alterations. Abbreviations: act, activation; amp, amplification; mut, mutation

Fig. 3

The procedures after osimertinib resistance. Before osimertinib treatment, patients should be examined via tissue biopsy and/or liquid biopsy to confirm whether EGFR mutations exist. Liquid biopsy can be used as a noninvasive and practical method for dynamic monitoring to evaluate genomic status in the period of osimertinib treatment. When patients progress on osimertinib, tissue biopsy and/or liquid biopsy should be conducted to determine the mechanisms of resistance to osimertinib to guide treatment. A corresponding treatment regimen will be applied to treat patients if effective approaches currently exist; in the case of a lack of valid targets, preclinical studies and clinical trials are warranted to be taken into consideration for the acquisition of valuable evidence to further explore viable therapeutic strategies

Fig. 4

Targeted therapy for osimertinib resistance. a Different treatment regimens targeting on-target resistance mechanisms (mainly EGFR tertiary mutations). C797S/T790M in cis: osimertinib-resistant NSCLC responds to brigatinib in combination with cetuximab, and such a regimen has been proven in several case reports. C797S/T790M in trans: NSCLC patients become sensitive to combination therapy of osimertinib and first-generation EGFR-TKIs. C797S alone and the other tertiary EGFR mutations: patients may resensitize to early-generation EGFR-TKIs. Novel EGFR inhibitors are under way to overcome C797S-mediated resistance to osimertinib, regardless of the C797S/T790M allelic context. b Targeting common off-target resistance mechanisms. Based on current available preclinical and clinical evidence, combination treatments of osimertinib plus inhibitors of corresponding targets are the major therapeutic strategies.

Fig. 5

The core mechanism of action of antibody–drug conjugates (ADCs). ADCs contain three parts: monoclonal antibody targeting tumor antigen, cytotoxic drugs and a linker that combines antibody with drugs. ADC binds to specific antigens expressed on tumor cells, followed by internalization via endocytosis. The ADCs enter endosomes and subsequently degrade in lysosomes, resulting in the release of cytotoxic drugs. Cytotoxic drugs contribute to DNA breakage and microtubule disruption, ultimately inducing the death of tumor cells

Fig. 6

Summary of therapeutic strategies for osimertinib resistance. Therapeutic strategies are comprised of targeted therapy, chemotherapy and immunotherapy; in addition, combination regimens will be considered depending on the individual characteristics of patients