Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Chinese Expert Consensus on Non-small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (2023 Edition) / 中国肺癌杂志

With the development of precision diagnosis and treatment for non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, as a rare subset of EGFR mutaions, have gradually attracted attention recently. The heterogeneity of EGFR ex20ins mutations is very high, different variants have different clinical benefits, and the prognosis is extremely poor. The available traditional treatment outcomes are poor in patients with EGFR ex20ins positive NSCLC and polymerase chain reaction (PCR) tests would miss aprocimately 50% of the variants. Therefore, high attention should be paid to EGFR ex20ins positive NSCLC during the clinical practice. The expert panel has formed a consensus on the standardized clinical diagnosis and treatment of EGFR ex20ins mutation NSCLC through reference to literature and clinical data, and combined with the experts' own clinical experience, the consensus recommendations including clinicopathologic characteristics, therapies, testing methods and recent relevant clinical trials for NSCLC patients with EGFR ex20ins mutation, in order to provide medication reference for clinical physicians at all levels.

Advances in the Treatment of EGFR Exon 20ins Mutant NSCLC / 中国肺癌杂志

Lung cancer has become one of the most dangerous cancers to human health and the mortality rate is the highest among all the causes of cancer death. Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of lung cancer. Chemotherapy is the main treatment for advanced NSCLC, but the 5-year survival rate is low. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in lung cancer, but EGFR exon 20 insertions (EGFR ex20ins) mutation belongs to one of the rare mutations, accounting for about 4%-10% of overall EGFR mutations, thus around 1.8% of advanced NSCLC patients. In recent years, targeted therapies represented by EGFR tyrosine kinase inhibitors (TKIs) have become an important treatment option for patients with advanced NSCLC, however, NSCLC patients with EGFR ex20ins mutation are not sensitive to most of EGFR-TKIs treatments. Currently, some of the targeted drugs for EGFR ex20ins mutation have achieved significant efficacy, while some of them are still under clinical investigation. In this article, we will describe various treatment methods for EGFR ex20ins mutation and their efficacy.
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Advances in Treatment of Non-small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations / 中国肺癌杂志

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are the third most prevalent activating EGFR mutation in non-small cell lung cancer (NSCLC), accounting for 5%-12% of all EGFR mutations in NSCLC cases. Patients harboring EGFR exon 20 insertion mutations exhibit similar clinical characteristics except for worse prognosis as compared to those with 'classic' EGFR mutations. EGFR exon 20 insertion mutations are considered as a heterogeneous class of alterations that cause different conformational changes in EGFR. The majority of mutations (almost 90% of cases) is positioned in the loop that immediately follows the C-terminal of the C-helix, and the most widely reported subtype of insertion mutations is D770_N771>ASVDN(A767_V769dupASV) with frequency of 21%-28%. NSCLC patients with EGFR exon 20 insertion mutations show primary drug resistance to previously approved EGFR tyrosine kinase inhibitors and are generally insensitive to conventional chemotherapy and immunotherapy. The recently approved targeted drugs Amivantamab and Mobocertinib shift the treatment paradigm for NSCLC patients harboring EGFR exon 20 insertion mutations. There are also several new compounds targeting NSCLC EGFR exon 20 insertion mutations are in development. In this article, we provide a through overview on the treatment development in EGFR exon 20 insertion mutant NSCLC.
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EGFR exon 20 insertion mutation in non-small cell lung cancer: classification and clinical treatment research / 药学学报

In recent years, targeted therapy has become the standard treatment for advanced non-small cell lung cancer (NSCLC), but this treatment method has very limited effect on patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation. This insertion mutation is the third most common mutation in EGFR. It shrinks the drug binding pocket and gives tumors inherent resistance to available EGFR tyrosine kinase inhibitors (TKIs), resulting in the limited efficiency of the first and second generation of EGFR tyrosine. So far, no targeted therapy has been approved for NSCLC patients with EGFR exon 20 insertion mutations, and there are still no drugs that have met clinical needs. In this case, new treatment strategies using new EGFR TKIs or bispecific antibodies may establish new treatment standards for these patients in the future. In this review, we will summarize all relevant exon 20 insertions reported so far on the structure of EGFR and its influence on EGFR inhibitor sensitivity, as well as the treatment strategies of exon 20 insertions in NSCLC patients, hoping to be a clinical treatment for reference.

The research status and development trend of EGFR gene exon 20 insertion mutant non-small cell lung cancer / 中华肿瘤杂志

The successful application of tyrosine kinase inhibitor (TKI) has kicked off the targeted therapy of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) since the discovery of EGFR gene mutations. Patients harboring the two most classic representative mutations of EGFR gene including exon 19 in-frame deletion or exon 21 L858R mutation could get significant clinical benefits from EGFR-TKIs compared to traditional chemotherapy. Among other approximately 10% of EGFR gene mutation type, exon 20 insertion occupies the first place. Available research had demonstrated that EGFR exon 20 insertion in NSCLC was highly malignant and most insertion variants showed de novo drug resistance towards current approved 1st to 3rd generation EGFR-TKIs, with much poorer clinical prognosis. Currently, there is a lack of comprehensive research and clinical guideline on the treatment of this specific mutation. In this article, we review the pathogenesis, amino acid sequence variants and current management of EGFR exon 20 insertion mutant NSCLC. Moreover, we come up with the emphasis on the treatment challenges and further development of this rigid mutation in NSCLC.

Studies and Progress of EGFR exon 20 Insertion Mutation in Non-small Cell Lung Cancer / 中国肺癌杂志

Lung cancer has the highest morbidity and mortality among malignant tumors worldwidely. Targeted therapy related to non-small cell lung cancer (NSCLC) is the research hotspot in recent year. The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has brought a huge change in the treatment of patients with EGFR mutation. The patients with EGFR exon20 insertion are specific cohort in NSCLC. Reviewing the clinical researches to EGFR exon20 insertion mutation positive NSCLC, as well as summarizing character, testing methods and treatment, will provide a help for clinical application, bringing more benefits for patients at the same time.

Clinical Outcomes of EGFR Exon 20 Insertion Mutations in Advanced Non-small Cell Lung Cancer in Korea / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. MATERIALS AND METHODS: Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. RESULTS: Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progression-free survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response. CONCLUSION: The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to first- or second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.