With the continuous exploration and revelation of the biological nature of non-small cell lung cancer, precision treatment of NSCLC is booming. In addition to common targets such as EGFR and ALK, HER2 has also become a hot spot and focus of researchers around the world. Currently

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With the continuous exploration and revelation of the biological nature of non-small cell lung cancer (NSCLC), precision treatment of NSCLC is booming. In addition to common targets such as EGFR and ALK, HER2 has also become a hot spot and focus of researchers around the world. Currently, it has There are several drugs in development that target HER2. The annual American Society of Clinical Oncology (ASCO) annual meeting was held from June 3 to 7, bringing a cutting-edge and authoritative academic feast to doctors and practitioners in the field of cancer diagnosis and treatment around the world. This article excerpts some of the NSCLC research related to HER2 targets at this ASCO conference for the benefit of readers.

HER2 mutations and characteristics in Chinese NSCLC patients "revealed"

HER2 mutations have become a therapeutic target for NSCLC, but their clinical pathological characteristics have not yet been elucidated in detail. In this retrospective study, we used next-generation sequencing (NGS) to detect HER2 activating mutations (abstract number: 8546) ^[1].

found a total of 686 HER2 activating mutations in 21,745 NSCLC patients, and 12 patients carried double HER2 activating mutations. Of the 12 patients, the mean age was 58 years (range 13-90 years), 59.6% of patients were female, and 88.2% were diagnosed with lung adenocarcinoma . 47 HER2 activations were detected in 674 patients Mutation subtypes, the most common activating mutation is Y772\U A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778\U P780dup ( 5.6%, 38/674) and V659E (4.1%, 28/674).

HER2 activating mutations most commonly occur in the tyrosine kinase domain (TKD) (80.1%), including exon (76.2%), exon 19 (3.0%) and exon 21 ( 1.2%) mutation. In addition, 13.2% of HER2 activating mutations occur in the extracellular domain and 5.5% occur in the transmembrane domain.

Figure 1 Mutation characteristics of HER2 activating mutations in Chinese NSCLC patients

23.1% (156/674) Patients with HER2 activating mutations can be evaluated for concurrent mutations, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Among these patients, HER2 activating mutations were most commonly co-mutated with TP53 (54/156) and EGFR (21/156). The frequency of EGFR mutations in patients with non-TKD mutations was much higher than that in patients with TKD mutations (56.7% vs 3.2%, P0.001), but there was no difference in TP53. All these patients were microsatellite stable (MSS) and had low tumor mutation burden (TMB).

HER2 Real-world frequency of exon 20 insertion mutations in NSCLC

HER2 Exon 20 insertion mutations are in-frame insertions or duplications clustered around two critical regions of exon 20: the α-C helix [amino acids (AA) 770-774 ], the loop after the α-C helix [amino acid (AA) 775-783]. This study used real haplotype genome data from NSCLC patients to determine the frequency of HER2 exon 20 insertion mutations by insertion sites (abstract number: e15026) ^[2].

From the haploid genome data, 284 (1.56%) of 18,205 NSCLC patients had HER2 exon 20 insertion mutations: 72.2% were located in the helix and 27.8% were located in the loop. The three most common insertion sites are Y772\U A775dup (71.5%), G776delinsVC (11.3%) and G778\U P780dup (6.0%).

Table 1 Types of HER2 exon 20 insertion mutations

HER2 mutated NSCLC patients have poor response to immunotherapy

The efficacy of immune checkpoint inhibitors (ICIs) in NSCLC patients with HER2 mutations (including HER2 exon 20 insertions) Not good. The purpose of this study was to explore the efficacy and immune characteristics of ICIs in NSCLC patients carrying HER2 exon 20 insertions and those without HER2 exon 20 insertion mutations (Abstract No.: 2591) ^[3]. A total of 117 eligible patients were included in the

study, 37 of whom received subsequent ICIs treatment. Compared with NSCLC patients who did not carry HER2 exon 20 insertion mutations, the PD-L1 TPS scores of patients with HER2 exon 20 insertion mutations were not significantly different, but the number of mutations was significantly lower (3.0 vs. 6.2 muts/person, p0.01).

Among 37 patients who received ICIs, the median progression-free survival (PFS) of patients without HER2 exon 20 insertion mutations was 13.5 vs. 4.4 months compared with patients with HER2 exon 20 insertion mutations. , HR: 0.31, 95%CI: 0.14-0.71) and median survival (OS) were longer (27.5 vs. 8.1 months, HR: 0.47, 95%CI: 0.20-1.14) (as shown below).

Figure 2 Results of the PFSOS study

In addition, the density of CD4+T cells in the tumor stroma of patients carrying HER2 exon 20 insertion mutations seems to be lower than that of patients without HER2 exon 20 insertion mutations (300.5 vs. 1288.0/mm², p=0.08).

Another study evaluated the effectiveness of ICIs in patients with HER2-amplified NSCLC. Eighteen patients with metastatic HER2-amplified NSCLC received ICI alone as first-line treatment or subsequent treatment after progression, with histological subtypes including adenocarcinoma (78%) and squamous cell carcinoma (22%). The median TMB was 9.2muts/Mb, and the median OS was 11 months (95%CI: 4-37); the 6-month and 12-month survival rates were 67% (95%CI: 40%-83%) respectively. and 49% (95% CI: 25%-70%); median PFS was 2 months (95% CI: 1-7) (Abstract number: e21098) ^[4]. In conclusion, patients with HER2-amplified NSCLC respond poorly to ICIs treatment.

ctDNA level monitoring may be used to predict the efficacy of poziotinib

Circulating tumor DNA (ctDNA) levels in plasma samples can provide real-time assessment of tumor mutational status and tumor burden during patient treatment. Poziotinib is an oral HER2-TKI used to treat patients with NSCLC harboring HER2 exon 20 insertion mutations.

In this study, the researchers evaluated HER2 exon 20 insertion mutations and other driver gene changes in plasma samples from a series of NSCLC patients treated with poziotinib in the first and second lines, and compared the clinical efficacy assessed according to RECIST1.1 criteria. The investigators collected plasma samples from enrolled patients at baseline, C3D1 (day 1 of cycle 3), and every other cycle day 1 until disease progression (abstract number: 3051) ^[5]. The

study enrolled a total of 23 NSCLC patients (including first-line and second-line), and the consistency between plasma samples and tissue-based next-generation sequencing (NGS) was 95%. Seven patients underwent serial testing via C7D1 (day 1 of cycle 7) to evaluate and compare dynamic changes in ctDNA and clinical efficacy. Five (71%) of seven consecutive patients taking 16 mg of poziotinib once daily had an undetectable HER2 exon 20 insertion mutation at C3D1, which was associated with tumor response. Tumor escape (PD) was observed in 2 of 5 patients, which was associated with an increase in HER2 exon 20 insertion variant allele frequency (VAF) in the plasma of the remaining 3 patients with ≥ partial response (PR) . It is worth noting that the increased VAF of HER2 exon 20 insertion mutations in ctDNA occurs before tumor escape .

Therefore, continuous monitoring of ctDNA is a potential biomarker for predicting treatment response and disease progression, which still needs to be evaluated in a larger population in the future.

The updated HER2-related research at this ASCO conference has given clinicians new ideas. It is hoped that with the continuous progress of research, there will be further breakthroughs in HER2-mutated NSCLC, and patients with HER2-mutated NSCLC will have more treatment options.

Reference:

[1] Fan Xu, et al. Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC. J Clin Oncol 40, 2022 (suppl 16; abstr 8546)

[2] Li Yang, et al. Real-world frequency of non-small cell lung cancer with ERBB2 exon 20 insertion (Exon20ins) mutations by site of insertion. J Clin Oncol 40, 2022 (suppl 16; abstr e15026)

[3]Hai-Yan Tu, et al. Efficacy of immune checkpoint inhibitors in patients with non–small cell lung cancer harboring ERBB2 exon 20 insertions and non-ERBB2 exon 20 insertions. J Clin Oncol 40, 2022 (suppl 16; abstr 2591)

[4]Raymond DeMatteo, et al. Clinical outcomes of immune checkpoint inhibitors in HER2-amplified non-small cell lung cancers. J Clin Oncol 40, 2022 (suppl 16; abstr e21098)

[5]Arunthi Thiagalingam, et al. Circulating tumor DNA (ctDNA) in HER2 exon 20 Insertion mutations and responses in NSCLC HER2 exon 20 insertion treated with poziotinib. J Clin Oncol 40, 2022 (suppl 16; abstr 3051)

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