Prevalence and treatment of human epidermal growth factor receptor 2-altered non-small cell lung cancer: a retrospective analysis and systematic literature review
Ning Yi Yap1,2, Komathi Perumal1,3 and Pathmanathan Rajadurai1,2,4
1Laboratory, Subang Jaya Medical Centre, Subang Jaya 47500, Selangor, Malaysia
2Jeffrey Cheah School of Medicine & Health Sciences, Monash University, Bandar Sunway, Petaling Jaya 47500, Selangor, Malaysia
3ePink Health Sdn. Bhd., Shah Alam 40150, Selangor, Malaysia
4Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
Abstract
Human epidermal growth factor receptor 2 (HER2) is known for its oncogenic activities in diverse cancers, including non-small cell lung cancer (NSCLC). However, the prevalence of HER2 alterations in Malaysian NSCLC patients remains unreported. This study examined the prevalence and characteristics of HER2 mutations and amplification in a Malaysian cohort. Additionally, a systematic review was conducted to evaluate the global prevalence of HER2 alterations in NSCLC, as well as the efficacy of HER2-targeted therapies observed in clinical trials. NSCLC tumour samples received from October 2019 to December 2022 for next-generation sequencing diagnostics were included in the retrospective analysis. In this patient cohort, HER2 alteration was present in 5.8% of patients; 3.9% had HER2 mutations, 1.5% had HER2 amplifications and 0.4% were both HER2-mutated and amplified. HER2 exon 20 insertions were the most common HER2 variants, detected in 47/59 (79.7%) of HER2-mutated patients. Among cases with HER2 exon 20 insertions, the Y772_A775dup variant was found in 34 patient samples. HER2-mutated patients were significantly younger than non-HER2-mutants (61 versus 64 years old; p = 0.046) and were inclined to be female and never-smokers, albeit not statistically significant. Patients with HER2 amplification were more likely to have progressed post-tyrosine kinase inhibitor therapy (p = 0.015). The systematic review highlighted a global variation in the prevalence of HER2 alterations in NSCLC, ranging from 0.3% to 9.1% for mutations and 0.2% to 19% for amplification. Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies.
Keywords: HER2, Malaysia, next-generation sequencing, non-small cell lung cancer, Southeast Asia
Correspondence to: Pathmanathan Rajadurai
Email: drpathma@gmail.com
Published: 01/08/2024
Received: 28/05/2024
Publication costs for this article were supported by ecancer (UK Charity number 1176307).
Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a transmembrane glycoprotein receptor exhibiting intracellular tyrosine kinase activity [1]. It consists of extracellular, transmembrane and intracellular domains, and plays important roles in various cellular functions including adhesion, differentiation, growth, apoptosis and migration [2, 3]. HER2 has garnered considerable attention due to its role in tumorigenesis and potential as a therapeutic target [3, 4]. Its aberrations have been implicated in the development and progression of various cancers, including non-small cell lung cancer (NSCLC) [3].
Three types of HER2 oncogene activating mechanisms have been described in cancers, and they include gene mutation, gene amplification and protein overexpression [3]. These mechanisms of HER2 activation have significant implications on treatment strategies, and prognostic outcomes which may differ according to the cancer type. HER2 amplification and overexpression are well-established predictive markers for response to HER2-targeted monoclonal antibodies such as trastuzumab, in patients with breast and gastric cancers [2, 5]. However, HER2 protein overexpression has not demonstrated reliability in identifying NSCLC patients who may benefit from HER2-targeted therapies [6, 7]. In contrast, HER2 mutations have shown greater promise in selecting NSCLC patients who are likely to respond to HER2-targeted therapies [8].
Currently, standard chemotherapy or immunotherapy is administered to patients with HER2-mutant NSCLC, but their effectiveness as second- or later-line treatment is limited [9]. Nonselective tyrosine kinase inhibitors (TKIs) have shown limited benefit in NSCLC patients with HER2 mutation, with objective response rates (ORRs) ranging from 0% to 19% [10]. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone whereas selective HER2 TKIs (e.g., poziotinib and pyrotinib) showed better activity in pre-treated NSCLC patients with HER2 mutation [10]. More favourable data were reported in phase II studies evaluating antibody-drug conjugates (ADC) ado-trastuzumab emtansine and trastuzumab deruxtecan in HER2-mutated NSCLC patients [11, 12]. These agents bring hope to the management of HER2-altered NSCLC.
Malaysia is a multi-ethnic Southeast Asian country, comprising an ethnic Malay majority, as well as significant Chinese, Indian and indigenous populations. Lung cancer survival is the worst among all cancers in Malaysia; the overall 5-year relative survival for lung, trachea and bronchus cancer among Malaysian patients was 11.0%, with a median survival time of 6.8 months [13]. The prevalence of HER2 mutation and amplification among NSCLC patients is not well-reported in the Southeast Asia region, and has not been reported in Malaysia. Therefore, we have performed a retrospective study to elucidate the prevalence of HER2 alterations and the characteristics of NSCLC patients with these alterations, based on diagnostic next-generation sequencing (NGS) performed at a tertiary private referral medical center in Malaysia. Additionally, a systematic literature review was conducted to offer a comprehensive overview of the existing evidence concerning the prevalence of HER2 mutation/amplification in NSCLC, as well as the efficacy of HER2-targeted therapies observed in prospective clinical trials involving NSCLC patients with HER2 alterations.
Methods
Determining prevalence of HER2 mutations and amplification among NSCLC patients in Malaysia.
Patient samples
Tumour samples from lung cancer patients from several medical centers in Malaysia were collected and sent to the Subang Jaya Medical Centre (SJMC) laboratory for NGS. We analyzed the NGS results of consecutive samples received from October 2019 to December 2022, to determine the prevalence of HER2 mutations and amplification. Ethical committee approval for the analysis of the retrospective NGS data was granted by the SJMC ethics committee (Ref: 201907.3 and Ref: 202109.3).
NGS testing
DNA from samples received from October 2019 to 2020 was sequenced using the Ion AmpliSeq Colon and Lung Cancer Research Panel v2 (Thermo Fisher Scientific, Waltham, MA, USA), while ribonucleic acid (RNA) was sequenced using the Ion AmpliSeq RNA Fusion Lung Cancer Research Panel or the Oncomine Focus Assay (Thermo Fisher Scientific, Waltham, MA, USA). DNA and RNA from samples received from November 2020 to December 2022 were sequenced using the Oncomine Precision Assay GX (Thermo Fisher Scientific, Waltham, MA, USA). The NGS testing process followed the method previously described by Rajadurai et al [14]. HER2 mutations and amplification were detected using the targeted NGS panels.
Table 1. Criteria for considering studies for systematic review, based on the population, intervention, comparator and PICOS structure.
Statistical analysis and data visualization
Statistical analysis was performed using the IBM SPSS Statistics Version 22.0 (IBM Corporation, Armonk, NY, USA). Patients’ demographic and clinical characteristics were evaluated using Pearson’s chi-square test or Fisher’s test for categorical variables, while the Mann-Whitney test was employed for comparing the patients’ age. The HER2 mutation lollipop diagram was generated using the MutationMapper visualization tools available at the cBioPortal site (https://www.cbioportal.org/) [15].
Systematic review of HER2 mutations and amplification in NSCLC
The systematic literature review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [16].
Search strategy
A systematic literature review was conducted to obtain (a) the prevalence of HER2 mutation/amplification in NSCLC, and (b) the efficacy of HER2-targeted therapies in NSCLC patients with HER2 alterations. A comprehensive database search was performed in PubMed and Web of Science to identify relevant studies published up to 31 December 2022. The Medical Subject Headings and text word search terms used were (‘HER2’ or ‘HER-2’ or ‘ERBB2’ or ‘ERBB-2’) AND (‘lung cancer’ or ‘NSCLC’). The studies were screened by two reviewers (NYY and KP) based on the article titles, abstracts and contents. The general inclusion criteria used to evaluate records include articles or abstracts published in the English language, and studies in which NSCLC patients were included. Studies involving only in vitro or in vivo samples, and review-type articles were excluded. The article selection criteria based on the populations, interventions and comparators, outcomes and study design (PICOS) are shown in Table 1.
Specific inclusion and exclusion criteria were also defined according to the two subtopics of the systematic literature review, as follows: (a) For systematic review on the prevalence of HER2 mutations and amplification, publications reporting the prevalence of HER2 mutations and amplification from a cohort of ≥ 200 NSCLC cases were included. Analyses involving only epidermal growth factor receptor (EGFR), Kirsten rat sarcoma 2 viral oncogene homologue (KRAS), anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) wild-type cases, analyses using liquid biopsy samples only and reports of HER2 protein overexpression were excluded. (b) For a systematic review of clinical trials evaluating the efficacy of treatment in NSCLC patients with HER2 mutations or amplification, prospective studies with ≥10 NSCLC subjects that were published from 2018 to 2022 were included. Retrospective studies and case series were excluded.
Data extraction
Data were extracted from articles that met the defined inclusion and exclusion criteria by one independent reviewer, and verified by a second reviewer. Data extracted for two subtopics of the systematic literature review were as follows: (a) For systematic review on the prevalence of HER2 mutations or amplification, data extracted were on the prevalence of HER2 mutations and amplification. (b) For a systematic review on prospective clinical trials evaluating the efficacy of treatment in NSCLC patients with HER2 mutations or amplification, data extracted were the ORR, disease control rate (DCR), median progression-free survival (PFS) and median overall survival (OS).
Results
Prevalence of HER2 mutations and amplification in Malaysian NSCLC patients
Patient cohort
The demographic features of 1,373 NSCLC patients whose tumour samples were analyzed at the SJMC laboratory are shown in Table 2. Approximately half of the patients were male (52.7%), and the median patient age was 64 years old (range 16–93 years old). Most of the patients were of Chinese descent (76%), and nearly half of the patients were never smokers (44.8%). Most tumours (84.6%) were adenocarcinomas, and 88.1% of patients had advanced stage NSCLC (stage III or IV disease). Most patients (77.7%) were TKI-naïve.
Table 2. Clinical characteristics of Malaysian NSCLC patients whose tumour samples were analysed using NGS from October 2019 to December 2022.
NGS and HER2 profile of NSCLC patient cohort
Among the NSCLC specimens analysed at our centre, nearly half (n = 627, 45.7%) showed EGFR alteration, followed by KRAS alteration (174, 12.7%) and ALK alteration (85, 6.2%). HER2 alteration was present in 79 patients (5.8%); 54 (3.9%) of these were HER2 mutations only, 20 (1.5%) were HER2 amplification only and 5 (0.4%) were both HER2-mutated and amplified (Figure 1a). The HER2 mutation variants reported in the NSCLC patients are shown in Figure 1b. HER2 exon 20 insertions, found in the TKI domain, were the most common HER2 variants among these NSCLC patients, with 47 out of 59 (79.7%) patients having this form of HER2 alteration. The HER2 exon 20 insertion Y772_A775dup was the most frequent HER2 variant, found in 34 patient samples. Other HER2 mutations are found in the extracellular ligand binding domain (S310S/Y, 7 patients) and transmembrane domain (V659E, 2 patients).
HER2 exon 20 insertions were mutually exclusive with ALK, BRAF, EGFR, RET, ROS1 and MET genetic alterations. Two patients with HER2 Y772_A775dup harboured KRAS alterations, one with KRAS amplification and the other KRAS K117N. EGFR sensitising mutations were detected in four patients with HER2 S310S/Y variants; of these, two patients were post-TKI progression cases. In addition, 11 patients with HER2 amplification had EGFR sensitising mutation; of these, 5 patients were post-TKI progression. TP53 mutations were the most common co-mutations seen with HER2 mutation (14 patients) and HER2 amplification (9 patients).
Figure 1. (a): Prevalence of genetic alterations in a cohort of NSCLC patients in Malaysia (N = 1,373). The breakdown of prevalence of HER2 mutation, amplification, as well as mutation and amplification are shown in color. (b): HER2 mutation variants reported in NSCLC patients in Malaysia (n = 59). The number of patients showing the specific mutations are indicated in brackets. HER2 exon 20 insertions were the most common HER2 variant in the NSCLC patients. BRAF: B-Raf proto-oncogene; MET: mesenchymal-epithelial transition; RET: RET proto-oncogene.
Characteristics of patients with HER2 mutations and amplification
Patients with HER2 mutations were significantly younger than non-HER2-mutants (median age 61 versus 64 years old; p = 0.046), and were inclined to be female and never-smokers (not statistically significant; p = 0.111 and 0.204, respectively) (Table 3). On the other hand, patients with HER2 amplification were inclined to be male, and ex- or current smokers (not statistically significant; p = 0.157 and p = 0.159, respectively). Patients with HER2 amplification were more likely to have progressed post-TKI (p = 0.015). All five patients with HER2 amplification who progressed post-TKI also had EGFR sensitising mutations.
Table 3. Characteristics of Malaysian NSCLC patients with HER2 mutations and amplification compared with patients without the HER2 alterations.
Systematic review of HER2 mutations and amplification in NSCLC
Study selection
The database search performed on PubMed and Web of Science yielded 5,828 unique records for screening. Of these, 295 records were retrieved for full text screening; most records were excluded due to non-relevance, unsuitable article type (review articles and case reports), non-English abstract or article, unsuitable studies (in vitro or in vivo studies, and immunohistochemistry (IHC) results) or clinical trials performed before 2018. Upon applying the PICOS criteria, 94 articles were included; of these, 76 articles reported the prevalence of HER2 mutation and/or amplification, and 18 articles were prospective clinical trials evaluating the efficacy of treatment in NSCLC patients with HER2 mutations or amplification (Figure 2).
Figure 2. PRISMA diagram for inclusion of systematic review.
Prevalence of HER2 mutations and amplification
The prevalence of HER2 mutations and amplification reported in global studies are shown in Table 4. HER2 mutations in the studies were detected using various methods including Sanger sequencing, reverse transcription polymerase chain reaction (RT-PCR), NGS and matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry (Supplementary Table S1 shows the full list of studies reporting the prevalence of HER2 mutations and amplification). The prevalence of HER2 mutations in NSCLC ranged from 0.3% to 9.1%. In some studies, the prevalence of HER2 exon 20 insertions were specifically reported, ranging from 0.4% among African-American populations in North America, to 4% in North America and East Asia. HER2 amplification was detected using fluorescent in situ hybridisation (FISH), silver in situ hybridisation (SISH), dual in situ hybridisation (DISH), multiplex ligation-dependent probe amplification (MLPA) or NGS. The prevalence of HER2 amplification varied widely, from 0.2% reported in China, up to 19% reported in Japan [17, 18]. Two studies which reported relatively high prevalence of HER2 amplification (14% and 19%) used the SISH or DISH method of detection [17, 19].
Efficacy of HER2-targeted therapies in NSCLC patients with HER2 mutations and amplification
Prospective clinical trials of various treatments for NSCLC patients with HER2 mutations and amplification are shown in Table 5.
Two phase II trials of afatinib in NSCLC patients with HER2 mutations were performed in post-progression patients; these trials revealed modest clinical benefits, i.e., ORR of 0%–7.7%, DCR of 53.9%–61.1%, median PFS of 2.8–4.0 months and median OS of 10–14 months. However, both studies did not compare the efficacy of afatinib in different HER2 exon 20 insertion variants [20, 21].
Poziotinib achieved a higher ORR (27.8%–27.9%), DCR (70%–73%) and PFS (5.5 months) compared to afatinib in patients on subsequent lines of therapy [22, 23]. Poziotinib’s DCR and PFS at subsequent lines of therapy were comparable to its use in the first line setting (ORR of 41%, DCR of 73% and PFS of 5.6 months) [22–24]. However, poziotinib did not receive United States Food and Drug Administration approval due to its modest efficacy, yet significant gastrointestinal and dermal toxicities [25].
Table 4. Prevalence of HER2 mutations and amplification in NSCLC reported in global studies.
Treatment of lung cancer patients with trastuzumab emtansine at various lines of therapy yielded an overall ORR of 38.1%–51.0%, DCR of 52.4%–83.3% and PFS 2.8–5.0 months [8, 11, 26]. Li et al [8] reported comparable responses to trastuzumab emtansine among patients when stratified according to HER2 status (mutation, amplification or combination of both). Although these trials recruited patients with central nervous system (CNS) metastasis, no subgroup analysis data were presented.
Pyrotinib has been investigated as a monotherapy, and in combination with apatinib for patients with HER2 mutation or amplification [27–31]. The ORR, DCR and PFS were generally lower with pyrotinib monotherapy at 19.2%–30.0%, 74.4%–85.0% and 5.6–6.9 months, respectively, compared to 35.7%–51.5%, 93.9%–100% and 6.9–8.0 months seen in pyrotinib + apatinib [27–31]. In a subgroup analysis of pyrotinib monotherapy, the ORR were comparable between patients with and without brain metastases (25.0% versus 31.3%).
Treatment of post-progression patients with trastuzumab deruxtecan (at a dose of either 5.4 or 6.4 mg/kg) in DESTINY-Lung01 and DESTINY-Lung02 yielded an encouraging ORR of 42.9%–54.9% and DCR of 90.4%–92.9% [12, 32]. In addition, trastuzumab deruxtecan at 6.4 mg/kg also yielded a more prolonged PFS of 8.2 months and OS of 18.6 months [12]. Trastuzumab deruxtecan seemed to achieve better treatment outcomes in post-progression lung cancer patients, compared to other HER2-targeted therapies (pyrotinib, afatinib, poziotinib and trastuzumab emtansine) (Table 5). In the DESTINY-Lung01 trial, comparable responses were observed with trastuzumab deruxtecan between patients with CNS metastasis and those without [12]. Safety-wise, although the DESTINY-Lung02 trial demonstrated similar efficacy of trastuzumab deruxtecan at both 5.4 and 6.4 mg/kg, a lower incidence of toxicities was observed with the 5.4 mg/kg dosage.
In the Drug Rediscovery Protocol (DRUP) trial, trastuzumab + pertuzumab demonstrated limited activity in patients with heavily pre-treated HER2-positive NSCLC (ORR 8.3%; DCR 38.0%; PFS 4.0 months; OS 10.0 months) [33]. Comparatively, trastuzumab + pertuzumab + docetaxel achieved improved outcomes in the IFCT 1703-R2D2 trial (ORR 29.0%; DCR 87.0%; PFS 4.0 months; OS 10.0 months) [34]. However, the IFCT 1703-R2D2 trial only included patients with stage III disease, while the DRUP trial recruited patients with metastatic disease.
Table 5. Summary of phase II clinical trials of HER2-targeted therapies for NSCLC patients with HER2 mutations and amplification.
Finally, neratinib as monotherapy as well as in combination with temsirolimus or trastuzumab in NSCLC patients with HER2 alteration produced inferior ORR (0%–14%) and DCR (28%–49%) compared with poziotinib, pyrotinib, trastuzumab emtansine and trastuzumab deruxtecan.
Discussion
This article aims to elucidate the prevalence of HER2 mutations and amplification in NSCLC, as well as the clinical characteristics and mutational profiles of patients with these alterations, based on retrospective analysis of diagnostic NGS performed at a referral center in Malaysia. To the best of our knowledge, this article reports the first known statistics on HER2 alterations among lung cancer patients in Malaysia. We also performed a systematic literature review to summarise the available evidence on the prevalence of HER2 alteration in NSCLC and the treatment outcomes in these patients.
It is important to note that the frequency of HER2 alterations may vary depending on the detection modalities used, target region of test assay, tumour heterogeneity, NSCLC subtype and sample type. Our systematic review on the prevalence of HER2 mutations and amplification in NSCLC was analysed from a total of 76 articles; most articles described studies originated from East Asia, North America or Europe, with variations in the testing method used. The prevalence of HER2 mutations reported may be higher in studies using NGS for testing, as more variants can be detected using this modality. In contrast, Sanger sequencing demonstrates lower sensitivity compared to NGS or RT-PCR. The assessment of HER2 amplifications can be carried out utilising techniques such as FISH, SISH, DISH or NGS but currently, there is no standardised criteria for determining HER2 amplification in NSCLC [1]. Finally, HER2 expression can be evaluated using IHC. The current testing recommendation is to include HER2 mutation testing upfront as part of broad molecular profiling for NSCLC patients with advanced or metastatic disease, in particular, if approved therapies are available [1, 35].
In our retrospective analysis, HER2 alteration was seen in 5.8% of Malaysian NSCLC patients. Of these, 3.9% had HER2 mutations only and 1.5% had HER2 amplifications only, and a small subset (0.4%) of our patient cohort were both HER2-mutated and amplified. Our prevalence findings fall within the range reported in global studies (0.3%–9.1% for HER2 mutation and 0.2%–19% for HER2 amplification) (Table 4). Specifically, the prevalence of HER2 mutations (4.3%) was within the range reported by studies from East Asia (Table 4), with marginally lower overall prevalence from North America and Europe. The prevalence in this study was also slightly above Singapore (3.1%), the other Southeast Asian country with available published data. HER2 exon 20 insertions were the most common HER2 variants in our patient cohort. Similarly, available literature reported that most HER2 mutations (90%) occur in the form of HER2 exon 20 insertions, with Y772_A775dup (also referred to as A775_G776insYVMA, E770_A771insAYVM or A771_M774dup in scientific literature) being the most common subtype [3, 36]. Furthermore, in our patient cohort, HER2 exon 20 insertions were mostly mutually exclusive to other driver mutations, with only the S310S/Y mutation found in the extracellular ligand binding domain co-occurring with EGFR sensitising mutations. This finding is also mirrored in another retrospective study, which found only eight patients (out of 12946 NSCLC patients) who had both EGFR and HER2 mutations; of these eight patients, six patients had sensitising EGFR mutations and exon eight HER2 mutation (S310F/Y) [37]. However, it is unclear whether if a concurrent HER2 S310X mutation will affect response to EGFR TKIs.
In our patient cohort, those with HER2 mutations tend to be younger than non-HER2-mutants (median age 61 versus 64 years old; p = 0.046) and were inclined to be female and never-smokers (not statistically significant; p = 0.111 and 0.204, respectively) (Table 3). HER2 mutations have been reported to be significantly associated with never-smokers, patients of Asian origin and female patients [38, 39]. There may be a higher prevalence of HER2 mutations in NSCLC patients from East Asia, although this could be attributed to the greater number of studies conducted in this region. HER2 amplifications, on the other hand, have also been described as a potential mechanism of acquired resistance to EGFR TKI, as FISH analysis has revealed that HER2 was amplified in 12% of tumours with acquired resistance, versus only 1% of untreated lung adenocarcinomas [40]. Other gene amplifications (e.g., EGFR and MET) are also known to act as resistance drivers against targeted therapy [41, 42]. These gene amplifications may occur de novo, or develop post-progression. In our patient cohort, all five patients with HER2 amplification who progressed post-TKI also had EGFR sensitising co-mutations. These patients likely developed HER2 amplification as acquired resistance to EGFR TKI. For these patients, therapies that target both EGFR and HER2 may confer clinical benefit [43]. Future studies of the Malaysian NSCLC patient cohort with HER2 alterations could benefit from analysis of treatment modalities and their impact on survival outcomes.
Our analysis of 18 prospective phase II clinical trials of various treatments for NSCLC patients with HER2 alterations revealed promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. Both HER2 mutation and amplification in lung cancer may be indicators of benefit with HER2-targeted therapy. HER2 mutations particularly in the extracellular domain or kinase domain, as well as amplification, lead to HER2 hyperactivation of downstream signalling cascades such as the PI3K and MAPK pathways [8]. Emerging therapeutic agents such as ADCs work by the selective binding of the monoclonal antibody component to the receptor’s extracellular domain, and delivery of the cytotoxic payload to arrest malignant cell growth. Anti-HER2 ADCs have generally demonstrated clinical activity in lung cancers with HER2-activating mutations, irrespective of the level of protein expression [8].
A phase II trial investigating treatment with trastuzumab emtansine in NSCLC characterised by HER2 overexpression or mutation was stopped early due to limited efficacy [44]. The authors noted that IHC 3+ or IHC 2+/FISH-positive tumours showed limited response to the investigational agent in the study [44]. In the phase II DESTINY-Lung01 study, trastuzumab deruxtecan was also evaluated in HER2-overexpressed metastatic NSCLC (IHC 2+ and 3+) at two dose levels: 6.4 and 5.4 mg/kg. The ORR was 26.5% and 34.1%, DCR was 69.4% and 78.0%, PFS was 5.7 and 6.7 months and OS was 12.4 and 11.2 months at 6.4 and 5.4 mg/kg, respectively. Both trastuzumab deruxtecan doses showed consistent antitumor activity in heavily pre-treated patients with HER2-overexpressed NSCLC [45]. This is in contrast with trastuzumab emtansine, which demonstrated limited efficacy in HER2-overexpressed NSCLC; DCR were only 7% and 30% in IHC 2+ and 3+ cohorts, respectively [7, 44]. Trastuzumab deruxtecan has an 8:4 8:1 chemotherapy drug-to-antibody ratio, compared with trastuzumab emtansine’s 3.5:1 chemotherapy drug-to-antibody ratio, which may explain the improved efficacy of trastuzumab deruxtecan [46]. Additionally, the membrane permeability of the cytotoxic payload of trastuzumab deruxtecan contributes to the bystander effect of inducing apoptosis in neighbouring tumour cells [12, 46]. Nonetheless, this higher drug-to-antibody ratio also leads to increased toxicities associated with trastuzumab deruxtecan treatment, in particular interstitial lung disease. Likewise, the DESTINY-Breast03 trial demonstrated that trastuzumab deruxtecan conferred better clinical benefit compared to trastuzumab emtansine in HER2-positive breast cancer [5]. The incidence of interstitial lung disease was reported to be higher in breast cancer patients treated with trastuzumab deruxtecan (15%) compared with trastuzumab emtansine (3%), although no grade 4/5 event was seen with either treatment [5].
The common HER2 mutation, HER2 Y772_A775dup / A775_G776insYVMA, was identified to confer increased resistance to afatinib and chemotherapy treatments in patients with NSCLC [47–49]. However, it is unclear if this resistance extends to treatment with other HER2 TKIs and ADCs. NSCLC patients with HER2 mutations have a higher incidence of brain metastases compared with patients with EGFR or KRAS mutations [50]. Moreover, HER2 exon 20 YVMA insertion is also associated with a higher lifetime incidence of brain metastasis in advanced NSCLC, compared to non-YVMA cases [51]. This higher propensity for brain metastasis might contribute to the challenges faced in achieving effective responses to afatinib and chemotherapy treatments due to poor penetration of the blood-brain barrier. In the phase II trials for NSCLC patients with HER2 mutations, sub-group analyses revealed comparable outcomes in patients with CNS metastasis who were treated with trastuzumab deruxtecan or pyrotinib. This finding is encouraging as it indicates that these treatment approaches could be effective in managing patients with CNS metastasis. TP53 is a common co-mutation that may also affect treatment efficacy. Co-mutations in the TP53 pathway have been shown to confer additional resistance to afatinib therapy in lung cancer [52]. In breast cancer, TP53-mutated patients tended to have a worse prognosis with anti-HER2 TKI treatment compared to TP53-wild-type patients [53]. Given the frequent occurrence of TP53 co-mutations in NSCLC patients, further investigation is warranted to better understand its implications for HER2-targeted therapies.
Conclusion
In conclusion, in this retrospective analysis of diagnostic NGS performed at a referral center in Malaysia, HER2 alteration was present in 5.8% of Malaysian NSCLC patients. Of these, 3.9% had HER2 mutation, 1.5% had HER2 amplification and 0.4% had both HER2 mutation and amplification. Most (79.7%) of Malaysian NSCLC patients with HER2 mutation had HER2 exon 20 insertions, with Y772_A775dup being the most frequent HER2 mutation variant. These findings fall within the range reported in global studies; the prevalence of HER2 mutations in NSCLC reported in global studies ranged from 0.3% to 9.1%, whereas the prevalence of HER2 amplification ranged from 0.2% to 19%. A systematic review of prospective phase II clinical trials of various treatments for NSCLC patients with HER2 alterations revealed promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. Malaysian NSCLC patients with HER2 alteration are anticipated to similarly benefit from the abovementioned HER2-targeted therapies.
Acknowledgments
This study received grant support from AstraZeneca; however, the funder had no role in the study’s design, analysis or manuscript drafting. Medical writing assistance for this article was provided by Mediconnexions Consulting Sdn Bhd. The authors also extend their gratitude to the SJMC laboratory staff for their valuable contributions to the NGS testing process.
Conflicts of interest
PR declares consultancies and receipt of speaker fees from AstraZeneca and Thermo Fisher, as well as research grants from AstraZeneca and Roche. NYY declares conference travel support from AstraZeneca. KP declares no conflict of interest regarding the publication of this article.
Funding
This study received grant support from AstraZeneca.
Author contributions
Conceptualisation, NYY and PR; Supervision, PR; Funding Acquisition, PR; Data Curation, NYY and KP; Formal Analysis, NYY; Writing – Original Draft Preparation, NYY and PR; Writing – Review & Editing, NYY, KP and PR.
Data availability
Data supporting the findings of this study are available from the corresponding author upon request.
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Supplementary materials
Supplementary Table S1 provides the list of studies reporting the prevalence of HER2 mutations and amplification.
Supplementary Table S1. Studies reporting the prevalence of HER2 mutations and amplification.
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