Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer

Abstract

Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs. EGFR TKIs improve response rates, time to progression, and overall survival. Unfortunately, patients with EGFR mutant lung cancer develop disease progression after a median of 10 to 14 months on EGFR TKI. Different mechanisms of acquired resistance to first-generation and second-generation EGFR TKIs have been reported. Optimal treatment for the various mechanisms of acquired resistance is not yet clearly defined, except for the T790M mutation. Repeated tissue biopsy is important to explore resistance mechanisms, but it has limitations and risks. Liquid biopsy is a valid alternative to tissue re-biopsy. Osimertinib has been approved for patients with T790M-positive NSCLC with acquired resistance to EGFR TKI. For other TKI-resistant mechanisms, combination therapy may be considered. In addition, the use of immunotherapy in lung cancer treatment has evolved rapidly. Understanding and clarifying the biology of the resistance mechanisms of EGFR-mutant NSCLC could guide future drug development, leading to more precise therapy and advances in treatment.

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

“…In recent years, EGFR‐TKI have become the first‐line therapy for NSCLC patients with EGFR‐activating mutations . However, drug resistance becomes an obstacle to EGFR‐TKI treatment in the clinic . Thus, a variety of reports have focused on the mechanisms of resistance to EGFR‐TKI and have searched for strategies to overcome resistance based on these resistance mechanisms.…”

“…Although most EGFR mutant NSCLC initially respond to EGFR inhibitors, acquired resistance to targeted therapies inevitably occurs in most of these tumors. A number of studies have investigated mechanisms underlying EGFR‐TKI resistance, showing that acquired secondary EGFR mutations emerge in approximately 50% of EGFR‐mutated patients treated with EGFR‐TKI; activation of parallel signaling pathways, histological transformation, and activation of downstream signaling pathways as a result of acquired mutations also contribute to acquired resistance mechanisms …”

Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

“…Tumor sections were incubated with specific monoclonal antibodies against excision repair cross-complementation group 1 Finally, this proportion score was multiplied by the staining intensity score to obtain a final semi quantitative score, which was divided into 4 grades: −(0,1,2), + (3,4), ++ (6,8) and +++ (9,12). Tumors with a final score exceeding 3 were deemed IHC-positive.…”

“…For NSCLC patients with gene mutations, such as EGFR or ALK mutations, targeted therapy has already become the first line treatment . However, acquired resistance to targeted drugs is inevitable, and chemotherapeutic agents or immune checkpoint inhibitors will be used as alternative drugs after the failure of targeted therapy or combined drugs in the treatment . As genotyping becomes increasingly common, it is necessary to understand the sensitivity of patients with different mutation types to different chemotherapeutic agents or immune checkpoints inhibitors.…”

Salvage surgery for advanced non‐small cell lung cancer after targeted therapy: A case series

“…With the developments in molecular biology, targeted drugs are being constantly improved and updated to provide better therapeutic effect for lung cancer . However, tumor recurrence or residual tumor during targeted therapy has been commonly reported and there is a lack of high‐level evidence on which type of treatment should be employed for these patients . Conventionally, alternative medical treatment or radiotherapy may be administrated as second‐ or third‐line therapy, although the effect is usually unpredictable and poor .…”