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Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease.

ABSTRACT: EGFR exon 20 insertion mutations (Ex20ins) and HER2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients' prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody-drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2-mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations.

SUBMITTER: Metro G

PROVIDER: S-EPMC9354707 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease.

Metro Giulio G De Giglio Andrea A Ricciuti Biagio B Siringo Marco M Marinelli Daniele D Gelibter Alain A Pecci Federica F Berardi Rossana R Cantini Luca L Di Federico Alessandro A Andrini Elisa E Mosca Mirta M Lamberti Giuseppe G Brambilla Marta M Mountzios Giannis G

Drugs in context 20220729

EGFR exon 20 insertion mutations (Ex20ins) and HER2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identificat ...[more]

PMID: 35975031

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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.

Project description:BackgroundDue to less sensitivity to classic tyrosine kinase inhibitors, effective first-line treatment is limited in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) exon 20 insertion (ex20ins) mutations. Meanwhile, the impact of driver genes on the efficacy of PD-1 inhibitors is discrepant. Our study aimed to assess the clinical response to immunotherapy in NSCLC patients with EGFR or HER2 ex20ins mutations. In parallel, patients treated with chemotherapy but without immunotherapy were included as controls.MethodsWe retrospectively reviewed patients harboring ex20ins mutations treated with immune checkpoint inhibitors (ICIs) and/or chemotherapy in the real world. The clinical response was assessed by progression-free survival (PFS) and the objective response rate (ORR). Propensity score matching (PSM) was performed to control for confounding factors between immunotherapy and chemotherapy.ResultsOf 72 patients enrolled, 38 had been treated with one line of single-agent immunotherapy or combined therapy including immunotherapy, and 34 had received conventional chemotherapy without immunotherapy. Among patients treated with immunotherapy, the median PFS was 10.7 months [95% confidence interval (CI): 8.2-13.2 months] in the first-line setting, with an ORR of 50% (8/16). The median PFS was significantly longer in the first-line immunotherapy group than in the chemotherapy group (10.7 vs. 4.6 months, P<0.001). A trend of an increased ORR in patients who received ICIs was observed compared with chemotherapy, but there was no statistical difference (50% vs. 21.9%, P=0.096). After PSM, the median PFS with first-line immunotherapy was still longer than that with chemotherapy (10.7 vs. 4.6 months, P=0.028). Grade 3-4 adverse events (AEs) were observed in 13.2% (5/38) of patients, with the majority developing granulocytopenia (40%, 2/5). One patient discontinued treatment due to a grade 3 rash after three cycles of ICI plus anlotinib treatment.ConclusionsThe results showed that immunotherapy combined with chemotherapy may play a role in the first-line treatment of NSCLC patients with ex20ins mutations. This finding requires further investigation for application.

Project description:BackgroundFor patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients.MethodsWe reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS).ResultsOf the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016).ConclusionFor patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

Dataset Information

Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease.

Publications

Advanced non-small-cell lung cancer: how to manage <i>EGFR</i> and <i>HER2</i> exon 20 insertion mutation-positive disease.

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