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HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

ABSTRACT: HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four different subtypes of HER2 exon 20 insertions were identified, including a rare subtype G778_S779insCPG never reported before with a partial response (PR) to pyrotinib and progression-free survival (PFS) of 12.8 months. Our findings reveal that HER2 exon 20 insertion mutations were detected in a small subset of lung adenocarcinomas. Given the different drug sensitivities, determining the mutation subtype by next-generation sequencing at the time of diagnosis might make sense.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7411254 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

Zhang Xinyong X Lv Jialin J Wu Yuhua Y Qin Na N Ma Li L Li Xi X Nong Jingying J Zhang Hui H Zhang Quan Q Yang Xinjie X Shi Huibo H Wang Jinghui J Zhang Shucai S

Frontiers in oncology 20200731

HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four dif ...[more]

PMID: 32850330

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Project description:No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Project description:BackgroundEpidermal growth factor receptor exon 20 insertions (EGFR ex20ins) occur in about 4-14% of lung adenocarcinoma (LUAD) patients with EGFR mutations. Recently some targeted drugs have been approved for the treatment of LUAD patients with EGFR ex20ins. However, the heterogeneity of EGFR ex20ins mutations and resultant challenges in identifying them have led to the underestimation of their frequency.MethodsWe investigated the molecular and clinicopathologic features of EGFR ex20ins in 3,892 Chinese LUAD patients using next-generation sequencing (NGS). The frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients were also compared by integrating the data of this study and the data of previous studies.ResultsA total of 23 unique EGFR ex20ins were identified in 77 LUAD patients, accounting for 1.98% of all LUAD patients and 3.49% of EGFR mutant LUDA patients. The 2 most common EGFR ex20ins subtypes were S768_D770dup and A767_V769dup, which together accounted for 55.84% of the EGFR ex20ins cases. About 61% (14/23) of the EGFR ex20ins subtypes occurred only once. Additionally, 8 of the EGFR ex20ins subtypes were not recorded in the COSMIC database. These results showed that the EGFR ex20ins mutations were highly heterogeneous. There was no significant difference in the frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients, but the frequency of EGFR ex20ins mutations was significantly lower in EGFR-mutant Chinese LUAD patients than Western LUAD patients. The co-mutation analysis showed that EGFR ex20ins occurred significantly and exclusively with certain driver genes in LUAD, including ALK fusion (χ2=7.133, P=0.008), KRAS (χ2=8.468, P=0.004), and PIK3CA (χ2=5.792, P=0.016). No gene was observed to be significantly co-mutated with EGFR ex20ins. In general, patients with EGFR ex20ins shared a similar age and gender to patients with other EGFR mutations or without EGFR ex20ins.ConclusionsOverall, our results revealed the molecular and clinicopathologic features of EGFR ex20ins in Chinese LUAD patients, which will be helpful for drug development and in clinical trials targeting EGFR ex20ins.

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.

Dataset Information

HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

Publications

HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

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