[Studies and Progress of EGFR exon 20 Insertion Mutation in Non-small Cell Lung Cancer].
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ABSTRACT:
SUBMITTER: Zhou W
PROVIDER: S-EPMC7049789 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
[Studies and Progress of EGFR exon 20 Insertion Mutation in Non-small Cell Lung Cancer].
Zhou Wensheng W Zhang Wei W Han Baohui B
Zhongguo fei ai za zhi = Chinese journal of lung cancer 20200201 2
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 positiv ...[more]
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Project description:Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) is one of the earliest driver gene activation mutations in non-small cell lung cancer (NSCLC). However, due to the unique structure of protein variation caused by this mutation, most patients with EGFR ex20ins mutation (except A763_Y764insFQEA) have poor response to the launched first/second/third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With the successive approval of new specific targeted drugs for EGFR ex20ins in Food and Drug Administration (FDA) and other national regulatory agencies, the development and clinical research of targeted drugs for EGFR ex20ins in China have also developed rapidly and Mobocertinib has been approved recently in China. It is worth noting that EGFR ex20ins is a variant type with strong molecular heterogeneity. How to detect it comprehensively and accurately in clinical practice, so as to enable more patients to benefit from targeted therapy, is a very important and urgent problem to be solved. This review introduces the molecular typing of EGFR ex20ins, then discusses the importance of EGFR ex20ins detection and the differences of various detection methods, and summarizes the research and development of new drugs progress of EGFR ex20ins, in order to optimize the diagnosis and treatment path of EGFR ex20ins patients by selecting accurate, rapid and appropriate detection methods, so as to improve the clinical benefits of the patients.
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Project description:Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor (EGFR) gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis. Here, we review the developments over the last 5 years in which pre-clinical studies, including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase, have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these EGFR mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit EGFR exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.
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Project description:BackgroundEpidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.MethodsTumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80?mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.ResultsEGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2?months (95% confidence interval 5.0-12.9?months; range 4.9-14.6?months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.ConclusionsThis study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.
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Project description:Epidermal Growth Factor Receptor (EGFR) exon 20 insertion alterations represent 4%-10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC) and result in resistance to standard EGFR-directed therapies. EGFR exon 20 insertions restrict the size of the kinase pocket, prohibiting the entry of approved EGFR kinase inhibitor drugs. Structural In Silico modeling also predicts that EGFR exon 20 insertion anomalies increase attractive electrostatic dimerization, hence stabilizing the activating dimer configuration. EGFR antibodies such as cetuximab that interfere with dimerization may lead to responses. We identified three non-smoking patients with NSCLC and EGFR exon 20 insertions treated with cetuximab-based therapy. All three patients demonstrated clinical benefit. A 58-year-old woman achieved prolonged stable disease lasting 9 months, while a 76-year-old woman and 38-year-old man maintained a partial response with progression-free survivals of 13 months and 32 months, respectively. In conclusion, cetuximab merits further investigation as it appears to be an additional promising therapy for overcoming EGFR exon 20 insertion-related resistance.
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Project description:Platinum-based chemotherapy was previously the first-choice treatment for lung cancer. The discovery of epidermal growth factor receptor (EGFR) gene mutations and the development of EGFR tyrosine kinase inhibitors (TKIs) marked the beginning of the targeted therapy era for non-small-cell lung cancer (NSCLC). Thirty percent of NSCLC patients carry EGFR gene mutations. For these advanced NSCLC patients, EGFR-TKIs are currently preferred for their superior activity and survival benefits over platinum-based chemotherapy. However, therapeutic efficacy is quite different in patients with EGFR exon 20 insertion (ex20ins) mutations versus common mutations. Patients with ex20ins mutations are insensitive to EGFR-TKIs and have poor prognosis. Some drugs targeting EGFR ex20ins mutations have been approved. Here, we systematically reviewed the recent clinical research of and treatments used for EGFR ex20ins mutations, summarized the latest data on emerging therapies, and discussed future prospects and treatments.
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Project description:Background and objectiveEpidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) are uncommon in non-small cell lung cancer (NSCLC). These mutations are generally resistant to first-generation EGFR tyrosine kinase inhibitors, unlike common EGFR mutations, including exon 19 deletions or exon 21 L858R point mutation. The development of effective targeted therapies for NSCLC harboring EGFR ex20ins has been eagerly anticipated over the years. Recently, the therapeutic landscape of this subgroup of EGFR-mutant NSCLC patients has rapidly evolved due to the emergence of new drugs. In 2021, several novel agents, such as amivantamab and mobocertinib, have been approved by the US Food and Drug Administration for patients with advanced platinum-resistant NSCLC harboring EGFR ex20ins. In this review, we mainly focus on emerging therapies targeting NSCLC with EGFR ex20ins, as well as important ongoing clinical trials.MethodsSearches were conducted in PubMed and supplemented with recent conference proceedings in November 30th, 2021.Key content and findingsSeveral novel emerging therapies showed favorable safety profile and promising anti-tumor activity in NSCLC patients with EGFR ex20ins in recent several clinical trials.ConclusionsThere is still room for improvement in the treatment results of NSCLC harboring EGFR ex20ins. Future research should focus on the molecular heterogeneity in the size and location of distinct EGFR ex20ins, the mechanisms of acquired resistance to novel EGFR inhibitors, effective treatment that have good central nervous system penetrance, and the potential role of combination strategy.
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Project description:Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC.
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Project description:BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion (EGFR ex20ins) is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR ex20ins generally respond poor to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR ex20ins are often co-occurring with EGFR amplification. However, the impact of EGFR amplification on the survival of patients with EGFR ex20ins mutations has not been determined.MethodsThis is an observational longitudinal cohort study. A prospectively managed database included consecutive treatment-naïve adult patients with advanced NSCLC and EGFR ex20ins confirmed by next-generation sequencing (NGS) at Guangdong Provincial People's Hospital between November 2017 and February 2019. The participants were enrolled from the database and extracted their clinical characteristics, treatment and clinical outcomes. NGS was used to establish whether EGFR amplification was present in tumor tissue. Overall survival (OS) and progression-free survival (PFS) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Subgroup analyses were performed based on the treatment used (EGFR-TKI or chemotherapy).ResultsFifteen different EGFR ex20ins mutation subtypes were identified in the 39 patients included in the analysis, and the most common subtypes were p.A767_D770dup (25.6%), p.S768_D770dup (23.1%) and p.N771_H773dup (10.3%). Among 31 patients with EGFR ex20ins mutations and NGS data for tumor tissue, EGFR amplification was identified in 12 patients (38.7%) and there were no significant differences in clinical characteristics. Among 26 patients, there were no significant differences between the EGFR amplification (n=11) and non-EGFR amplification (n=15) groups in median OS (715 vs. 452 days, P=0.912). Among 20 patients administered chemotherapy, there were no significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (206 vs. 112 days, P=0.425). Among 24 patients administered an EGFR-TKI, median PFS was longer in the non-EGFR amplification group than in the EGFR amplification group (110 vs. 31 days, P=0.030).ConclusionsThere is a tendency that EGFR amplification might be a poor predictor in EGFR ex20ins-positive NSCLC patients treated with EGFR-TKIs.
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Project description:Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.SignificanceWe report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.
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Project description:PurposeEpidermal 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 methodsBetween 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.ResultsOf 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 progressionfree 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.ConclusionThe 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 firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.
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