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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 374-384

HER2 alterations in non-small-cell lung cancer – Druggable or undruggable?

1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Molecular Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission19-Apr-2021
Date of Decision24-May-2021
Date of Acceptance13-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Room No. 304, HBB, Tata Memorial Hospital, Parel East, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_81_21

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How to cite this article:
Bondili SK, Nandhana R, Noronha V, Pawar S, Menon N, Shetty O, Chougule A, Mahajan A, Kumar R, Patil VM, Joshi A, Prabhash K. HER2 alterations in non-small-cell lung cancer – Druggable or undruggable?. Cancer Res Stat Treat 2021;4:374-84

How to cite this URL:
Bondili SK, Nandhana R, Noronha V, Pawar S, Menon N, Shetty O, Chougule A, Mahajan A, Kumar R, Patil VM, Joshi A, Prabhash K. HER2 alterations in non-small-cell lung cancer – Druggable or undruggable?. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jul 4];4:374-84. Available from: https://www.crstonline.com/text.asp?2021/4/2/374/320207

  History and Examination Top

A 62-year-old man, with no history of smoking or other addictions and receiving oral hypoglycemic medications for the past 4 years for type 2 diabetes mellitus, presented to us with complaints of pain in the right foot that had persisted for 2 months. He had an Eastern Cooperative Oncology Group performance status of 1, and the physical examination was unremarkable, except for tenderness in the right mid-foot.

  Investigations Top

Plain radiography of the right foot revealed a lytic lesion in the body of the right second metatarsal bone. A positron emission tomography-contrast enhanced computed tomography (CECT) scan revealed a fluorodeoxyglucose-avid mass in the right upper lobe of the lung measuring 3 cm × 3.5 cm × 3.3 cm, with multiple tiny metastatic nodules bilaterally in the lungs and metabolically active multiple mediastinal nodes [Figure 1]a. Multiple osteolytic lesions were seen in the ninth dorsal vertebra, right iliac bone, right femoral shaft, left tibial tuberosity, and the right second metatarsal bone. A CT-guided biopsy from the right upper lobe lung mass as well as the lytic expansile lesion on the shaft of the second metatarsal bone was performed, which revealed adenocarcinoma with an acinar pattern. On immunohistochemistry (IHC), the cells were found to be positive for CK7 and HepPar-1 and negative for TTF-1, CK19, CK20, and napsin-A. The findings were suggestive of hepatoid adenocarcinoma of the lung [Figure 2]. The serum alpha-fetoprotein level was tested because of hepatoid adenocarcinoma histology and was found to be within the normal range.
Figure 1: Response to various lines of therapy as shown by computed tomography scans. (a) Baseline, (b) Partial response after four cycles of pemetrexed + carboplatin + atezolizumab, (c) Progression after four cycles of maintenance pemetrexed + atezolizumab, (d) Progression after six cycles of docetaxel, (e) Progression after three cycles of poziotinib

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Figure 2: Biopsy from the second metatarsal bone showed metastatic deposits of adenocarcinoma in a fibro-collagenous stroma (H and E; a: ×20, inset; ×40). Tumor cells were strongly and diffusely positive for CK-7 (b; DAB-×20, inset; ×40) and negative for TTF1 (with focal cytoplasmic expression, but no nuclear positivity [c; DAB × 20, inset; ×40]). In addition, the tumor cells also expressed HepPar-1 (d; DAB × 20, inset; ×40), confirming the diagnosis of a hepatoid adenocarcinoma

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  Molecular Testing Top

A TaqMan probe-based end point genotyping assay for the epidermal growth factor receptor (EGFR) was performed on the formalin-fixed paraffin-embedded tumor tissue by real-time polymerase chain reaction using the LC 480 II platform. The patient was found to have wild-type EGFR. The IHC for anaplastic lymphoma kinase 1 (ALK1) using the D5F3 antibody clone was negative. The programmed death-ligand 1 (PD-L1) expression was tested using the Ventana SP263 antibody and was found to be negative.

The patient was started on first-line chemotherapy with pemetrexed, carboplatin, and atezolizumab. He tolerated the chemotherapy well with no grade 3/4 adverse events. Post four cycles of chemotherapy, a CECT scan revealed a partial response [Figure 1]b. Hence, he was continued on maintenance therapy with pemetrexed and atezolizumab. After four cycles of maintenance therapy, there was new onset of multiple bilateral metastatic lung nodules with stable disease at other sites of involvement [Figure 1]c. He received second-line chemotherapy with single-agent docetaxel (ramucirumab was not feasible), which he tolerated well. A CECT scan post three cycles of docetaxel revealed a partial response. Hence, three more cycles of docetaxel were administered. However, post six cycles of docetaxel, the patient had disease progression as detected by a CECT scan which showed an increase in the size of the lung mass and the number of lung nodules, new onset of right pleural deposits, and left adrenal gland nodule metastasis [Figure 1]d.

  Next-Generation Sequencing Top

Next-generation sequencing (NGS) analysis of the baseline lung biopsy was performed at the time of starting second-line chemotherapy using the miSeq for Illumina Focus panel for the detection of DNA alterations, including single-nucleotide variants and insertions/deletions in 42 genes, 139 RNA fusions, gene amplification events in 24 genes, and microsatellite instability status of 6 unique loci. DNA and RNA libraries were prepared using the Solid Tumour Plus library preparation kit and loaded on the Illumina MiSeq system for sequencing. The data were analyzed using the SOPHiA DDM, a platform for data analysis and clinical report generation. The patient was found to harbor an insertion mutation (pTyr772_Ala775dup; variant description: NM_004448: c. 2313_2324dup) in exon 20 of the human epidermal growth factor receptor 2 (HER2) gene with a variant allele frequency of 21.4%. The mutation was classified as a tier I pathogenic variant.[1]

  Excerpts from Discussion in the Molecular Tumor Board Top

Mutations in the tyrosine kinase domain of the HER2 (ERBB2) gene are observed in 2%–4% of the cases of non-small-cell lung cancer (NSCLC). The majority of these mutations occur in exon 20 as in-frame duplications or insertions.[2],[3] The in-frame insertion of 4 amino acids, tyrosine-valine-methionine-alanine (YVMA), between the alanine at position 775 and the glycine at position 776 in exon 20 (A775_G776insYVMA) accounts for more than 90% of all HER2 mutations.[4] Mutations in HER2 are mutually exclusive with other oncogenic driver mutations, such as those in the EGFR, ALK, ROS1, KRAS, BRAF, MET, and RET.[5] Preclinical and clinical studies on human lung adenocarcinomas with the HER2 exon 20 YVMA insertion have shown promising results with HER2-directed therapies such as trastuzumab plus chemotherapy, ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan, and tyrosine kinase inhibitors (TKIs) such as afatinib, pyrotinib, and poziotinib.[6],[7] As the patient had progressed on second-line chemotherapy, the Molecular Tumor Board recommended to procure poziotinib for the patient through an expanded access program.

  HER2-Directed Therapy Top

As recommended by the Molecular Tumor Board, the patient was started on poziotinib at a dose of 16 mg once daily. The patient experienced grade 2 dyspepsia, diarrhea, and fatigue after starting poziotinib, which did not subside with supportive care medications. Hence, the dose was decreased to 14 mg once daily on day 15 of the treatment. However, the patient continued to experience grade 2 dyspepsia and grade 1 diarrhea, with a weight loss of 4 kg. Therefore, the dose was further reduced to 12 mg once daily, which he tolerated well. The patient remained symptomatically stable thereafter. A response scan performed after 3 months of starting poziotinib revealed progressive disease as shown by an increase in the right pleural effusion and the size of the right upper lobe mass (25% increase as per the Response Evaluation Criteria in Solid Tumors [RECIST]) [Figure 1]e. Hence, poziotinib was stopped, and the patient was started subsequently on gemcitabine and bevacizumab.

  HER2 and Mechanism of Action Top

The HER family comprises four membrane-bound proteins, namely HER1 (EGFR or ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4).[8],[9] The HER2 gene is located on chromosome 17q2. The HER2 receptor does not have a ligand of its own, instead, it gets activated by homodimerization or heterodimerization with other members of the HER family.[10],[11] This leads to the activation of the downstream signaling pathways that cause cell proliferation and differentiation.[12] The PI3K/AKT/mTOR and MEK/ERK are the principal pathways that mediate the downstream effects of HER2 signaling.[13]

  HER2 Alterations in Cancers Top

HER2 alterations are frequently seen in several malignancies, including breast, ovarian, lung, stomach, gall bladder, oral, and salivary gland cancers.[14],[15],[16],[17],[18],[19] Of these, HER2 abnormalities have been extensively studied in breast cancers. HER2 amplification or overexpression is seen in about 15%–20% of the breast cancer cases, a major risk factor for distant recurrence, and is associated with an abysmal prognosis.[20],[21] The development of trastuzumab and other anti-HER2 agents has radically changed the treatment paradigm of breast cancers.[22]

HER2 alterations are commonly detected using IHC for protein expression and fluorescence in situ hybridization (FISH) for gene amplification [Figure 3]. Importantly, there is high concordance between these two detection methods in breast cancer. Hence, most of the centers across the world use IHC for the initial screening and dual-probe FISH for confirming the results in case of equivocal expression on IHC.[23] According to the American Society of Clinical Oncology/College of American Pathologist guidelines, an IHC score of 3+ indicates overexpression of the HER2 protein, a score of 2+ indicates equivocal expression, and the scores 1 and 0 indicate that the tumor is HER2-negative.[24] The possible results of dual-probe FISH are summarized in [Table 1]. Increased copy number of HER2 due to polysomy of chromosome 17 is not associated with response to anti-HER2 agents, and it can be differentiated from HER2 amplification by using dual-probe FISH (instead of single-probe FISH).[25]
Figure 3: A descriptive case of adenocarcinoma showing complete, strong membrane staining in almost all tumor cells for cErbB2 (score 3), and HER2 amplification was confirmed by fluorescence in situ hybridization as the ratio of the average HER-2 fluorescence in situ hybridization signals (green) to centromere 17 signals (red) per nucleus was more than 2

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Table 1: Interpretation of dual-probe fluorescence in situ hybridization result in breast cancer

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HER2 amplification or protein overexpression is seen in 12%–23% of gastric or gastroesophageal junction (GEJ) adenocarcinomas. However, the incidence differs according to the subtype. HER2 overexpression is more frequently observed in the intestinal and well-to-moderately differentiated types than in the diffuse or poorly differentiated types. Likewise, sex (more prevalent in men than women) and origin of the tumor (more prevalent in GEJ than in stomach cancers) have also been found to have an effect on the prevalence of HER2 overexpression.[26],[27] Testing for HER2 overexpression by IHC is recommended for all patients with metastatic gastric and GEJ adenocarcinomas, followed by confirmation with FISH in equivocal cases (IHC 2+). The ideal first-line therapy for HER2-overexpressing or metastatic gastric or GEJ adenocarcinomas is trastuzumab in combination with fluoropyrimidine and a platinum agent.[28] This recommendation was based on the results of the ToGA trial, which showed a significant improvement in the survival outcomes. The median overall survival (OS) was 13.8 months with trastuzumab plus chemotherapy and 11 months with chemotherapy alone (P = 0.046).[29] Recently, trastuzumab deruxtecan was approved by the United States Food and Drug Administration for patients with gastric or GEJ adenocarcinomas who have been previously treated with trastuzumab-based therapy, based on the results of the DESTINY-Gastric 01 trial. In this trial, the OS was 12.5 months with trastuzumab deruxtecan and 8.4 months with irinotecan or paclitaxel; hazard ratio (HR):0.59; 95% confidence interval (CI):0.39–0.88; P = 0.01.[30]

  HER2 Alterations in Non-Small-Cell Lung Cancer Top

Three types of HER2 abnormalities are seen in NSCLC. These are HER2 gene amplification, HER2 protein overexpression, and point mutations [Table 2].[31],[32] The majority of the HER2 mutations occur in the tyrosine kinase domain, leading to the constitutive activation of the receptor and downstream signal transduction pathways.[33] The most common HER2 mutation, present in about 80%–90% of the NSCLC cases, is the in-frame insertion of the YVMA amino acids at codon 776 in exon 20.[34] Activating mutations in the transmembrane and juxtamembrane domains (exon 18–21) are rare.[34] NGS is the most commonly used method for detecting HER2 mutations, as it allows for the simultaneous detection of several other genetic abnormalities from a limited amount of the tumor tissue, at a significantly lower cost and within a short span of time. However, its ability to identify copy number variations depends upon the platform used. In addition, NGS can also be used for the detection of HER2 amplification. Whether alterations in HER2 mediate resistance to standard chemotherapeutic agents is debatable, as there are a limited number of studies with conflicting results.[35],[36],[37],[38],[39],[40],[41],[42],[43] In contrast to breast and gastric cancers, anti-HER2 drugs have failed to show a durable benefit in NSCLCs with HER2 overexpression or amplification.[10],[44] However, these studies used a different cutoff for a positive signal on IHC (score 1+ to 3+). Moreover, a significant proportion of these patients had concurrent HER2 mutations.[10],[45],[46] Recent studies have suggested that in NSCLCs, HER2 mutations might be of greater relevance than HER2 protein overexpression and HER2 amplification. Several drugs have shown promising activity in this subgroup of patients, and clinical trials are underway in this direction.[47]
Table 2: Types of human epidermal growth factor receptor 2 alterations in lung cancer

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  Correlation Between Various HER2 Alterations Top

In breast cancers, a strong expression of the HER2 protein (IHC score 3+) is often found to be associated with HER2 amplification as detected by FISH.[48],[49],[50] However, the scenario is different in NSCLC, as numerous studies have failed to demonstrate a clear correlation between HER2 amplification, mutation, and protein expression.[51],[52],[53] In NSCLC, HER2 protein expression is not always associated with HER2 amplification and vice versa. This is because overexpression of the HER2 protein may not always be due to the upregulation of HER2 transcription, and mechanisms such as polysomy or post-transcriptional modification of proteins may also play a role. Furthermore, HER2 amplification or protein overexpression may coexist with a HER2 mutation in some patients.[54],[55]

  HER2 Alterations as a Resistance Mechanism Top

HER2 alterations are an important mechanism of acquired resistance to EGFR TKIs.[56],[57],[58] HER2 amplification is seen in 13% of the patients who acquire resistance to EGFR TKIs[59] and has been reported as a resistance mechanism in the FLAURA trial, which investigated the role of first-line osimertinib in NSCLC with sensitizing EGFR mutations.[60] Case reports of other HER2 alterations, such as mutations and gene amplification, leading to TKI resistance have also been described in the literature.[55],[61]

  HER2-Targeted Therapy Top

Monoclonal antibodies

Monoclonal antibodies such as trastuzumab and pertuzumab have good clinical activity in HER2-overexpressing breast cancers. Single-agent trastuzumab has been associated with poor outcomes in NSCLC, regardless of the type of HER2 alteration, as detected by IHC or FISH. Trastuzumab with chemotherapy has also been proven to be ineffective in small phase II trials in HER2-overexpressing NSCLCs [Table 3].[44],[62] However, there is evidence of some activity in HER2-positive tumors with an IHC score of 3+ or a positive signal on FISH. In HER2-mutant NSCLCs, Mazieres et al. have reported a disease control rate (DCR) of 93% (n = 15) for trastuzumab-based chemotherapy. The EUHER2 study reported an objective response rate (ORR) of 50%, DCR of 75%, and progression-free survival (PFS) of 5.1 months for trastuzumab-based chemotherapy. However, these were retrospective studies, and the benefit of trastuzumab in HER2-mutant NSCLCs remains to be proven in prospective, randomized studies.[70]
Table 3: Outline of studies using anti-human epidermal growth factor receptor 2 therapy for non-small-cell lung cancers with human epidermal growth factor receptor 2 overexpression

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In patients with a HER2 alteration as a secondary driver (HER2 overexpression in patients who have developed resistance to EGFR TKIs), trastuzumab plus paclitaxel showed the highest ORR in patients with an IHC score of 3+ (ORR 67%, n = 12) and HER2 copy number ≥10 (ORR 100%, n = 4).[61] This suggests that the response to anti-HER2 therapy for those with a de novo HER2 alteration may be different for those with secondary HER2 alterations. In our patient, as the NGS was performed on the baseline tissue biopsy specimen, the HER2 alteration was likely to be present de novo.

Single-agent pertuzumab has been found to be ineffective in patients with NSCLC-harboring HER2 alteration.[63],[64] Trials assessing various combination therapies are ongoing. Studies that evaluated HER2-directed therapies in patients with HER2 amplification are summarized in [Table 4].
Table 4: Clinical trials for anti-human epidermal growth factor receptor 2 treatment in nonsmall cell lung cancers with human epidermal growth factor receptor 2 amplification

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Antibody–drug conjugates

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate, in which the anti-HER2 agent, trastuzumab, is coupled with a potent antimicrotubule cytotoxic drug, emtansine. In a phase II trial on 18 patients with metastatic, heavily pretreated NSCLC harboring HER2 mutations, the ORR with T-DM1 was found to be 44% (95% CI, 22%–69%) and the median PFS was 5 months (95% CI, 3–9 months). Moreover, T-DM1 was tolerated well, with the majority of the adverse events having a severity of grade 1 or 2, including infusion reactions, anemia, thrombocytopenia, and transaminitis [Table 5].[65] Based on the results of this study, the National Comprehensive Cancer Network (NCCN) guidelines now recommend the use of T-DM1 for HER2-mutant NSCLCs (category 2A).
Table 5: Summary of clinical trials for anti-human epidermal growth factor receptor 2 monoclonal antibodies and antibody-drug conjugates for nonsmall cell lung cancers with human epidermal growth factor receptor 2 mutation

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Trastuzumab deruxtecan, an antibody–drug conjugate comprising trastuzumab and a topoisomerase I inhibitor, was studied in a phase II trial (DESTINY-Lung 01) in pretreated patients with NSCLC-harboring HER2 mutations. The ORR was 61.9% (95% CI, 45.6%–76.4%), median DOR was not reached at the time of reporting, DCR was 90.5% (95% CI, 77.4%–97.3%), median PFS was 14 months (95% CI, 6.1–14 months), and median OS was not reached. About 64.3% of all treatment-related adverse effects had a severity of grade ≥3, and 5 patients developed drug-related interstitial lung disease.[66] The latest NCCN guidelines recommend trastuzumab deruxtecan as a treatment option for HER2-mutant NSCLCs (category 2A). T-DM1 and trastuzumab deruxtecan have been tested in small phase II studies on patients with NSCLC with HER2 overexpression and have shown limited benefits [Table 3].

  Small-Molecule Tyrosine Kinase Inhibitors Top

There are several small-molecule TKIs with activity against the HER2 receptor. They differ in their structure, affinity, and binding site, resulting in differences in their clinical efficacies [Table 6]. Lapatinib is a reversible HER1/HER2 inhibitor; afatinib is an irreversible HER1/HER2 inhibitor, while tucatinib causes selective irreversible inhibition of HER2. Other TKIs such as neratinib, pyrotinib, poziotinib, and mobocertinib cause irreversible pan-HER inhibition.[67] The benefit from TKIs depends on their binding affinity for the kinase domain, the precise nature of the mutation, the binding pocket conformation, and the class of inhibitor (type 1 or 2).
Table 6: Summary of clinical trials for anti-human epidermal growth factor receptor 2 small-molecule tyrosine kinase inhibitors for in human epidermal growth factor receptor 2-mutant nonsmall cell lung cancer

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Lapatinib did not show a clinical benefit in the limited number of studies on patients with NSCLC. However, patients in these studies were not selected based on the HER2 expression of their tumors.[68],[69] A retrospective analysis of five patients treated with lapatinib from the EUHER2 cohort reported that all patients had progressive disease at the time of initial response assessment.[70] Afatinib demonstrated potent antitumor activity in the preclinical studies, but the outcomes in clinical studies were mixed. Greve et al. conducted an exploratory phase II study of afatinib in five patients with NSCLC-harboring HER2 mutations. Response evaluation could be performed in three out of five patients, all of whom showed an objective response to afatinib.[71] In another study on 28 previously treated patients with NSCLC-harboring HER2 mutations, the ORR was 19%, and the time to treatment failure was more than 1 year for 8 patients. In this study, 4 out of 10 patients who had an exon 20 YVMA insertion continued to receive afatinib for more than a year, suggesting that this subgroup of patients responds better to afatinib.[72] Retrospective studies have shown that patients harboring certain other mutations in HER2 such as G778_P780dup (G778),[73] p.G776delinsVC, and p.Y772_A775dup may also benefit from afatinib.[6],[74] However, a few other studies have reported a dismal response to afatinib in these patients.[70],[75],[76] The poor overall response of afatinib in HER2-mutant NSCLCs can be attributed to the fact that the drug concentration required to inhibit the HER2 receptor is 100-fold higher than that required to inhibit mutant-EGFR in in vitro models. Such a high dosage can lead to severe drug-related toxicities in the patients.[77] Costa et al. investigated a pulse afatinib regimen (280 mg once weekly) in 3 patients with HER2-mutant NSCLC, of which one had a partial response for 5 months and another had stable disease for 11 months.[77]

Wang et al. studied the efficacy of afatinib, pyrotinib, and T-DM1 in patient-derived organoids and xenograft models with HER2-A775_G776YVMA insertions. They found that high-dose pyrotinib (80 mg/kg once daily) had the greatest tumor inhibitory activity, with a 52.2% reduction in tumor burden, while T-DM1 and afatinib failed to show a significant decline in the tumor burden. The authors conducted a phase II trial with pyrotinib in patients with HER2 mutations and reported an ORR of 53.3% and a median PFS of 6.4 months [Table 6].[78]

Dacomitinib and neratinib have also shown limited efficacy in phase II studies [Table 5].[79],[80]

Of all the TKIs, poziotinib has been shown to have the highest potency against HER2 mutations. In vitro studies suggest that it is about six times more potent than afatinib at inhibiting cell growth.[81] In cohort 2 of the phase II trial, ZENITH20-2, poziotinib demonstrated an ORR of 27.8% (95% CI, 18.9%–38.2%), median DOR of 5.1 months (range, 1 to >12.3), DCR of 70%, and a median PFS of 5.5 months; these data look promising and further studies are ongoing [Table 6]. The adverse effects of poziotinib are similar to those of other second-generation EGFR-TKIs. The most common adverse effects of grade ≥3 include rash (30%), diarrhea (26%), and mucositis (14%).[82]

Mobocertinib, a selective HER2 and EGFR exon 20 inhibitor, is an emerging drug that has shown significant antitumor activity in patients with EGFR and HER2 exon 20 insertions and is currently being tested in larger studies. Tarloxitinib, a hypoxia activated prodrug, is a pan-HER TKI, which is being studied in a multi-arm phase II study (RAIN-701). A preliminary analysis showed that 4 (44%) out of 9 patients with HER2-mutant NSCLCs had tumor reduction as per RECIST.[83]

  Role of Immune Checkpoint Inhibitors in HER2-Altered Non-Small-Cell Lung Cancer Top

Retrospective data suggest that the response rate of HER2-altered NSCLCs to immune checkpoint inhibitors (ICIs) ranges from 7.4% to 27%.[84] In a study on 122 patients by Lai et al., PD-L1 expression was found to be lower in patients with HER2-altered NSCLCs when compared with an unselected cohort (PD-L1 expression was found to be <1% in 77% of the patients). However, the median tumor mutational burden of these patients was found to be similar to that of the unselected cohort (5.8 mutations per megabase). In this study, 26 patients received ICIs, and the ORR was 12%. Interestingly, none of the responders had the HER2-A775_G776YVMA insertion, and 66% of the patients had PD-L1 expression ≥50%.[85] As per the retrospective data from the IMMUNOTARGET registry, the ORR to ICIs in HER2-mutant NSCLCs (n = 29) was 7%, with a median PFS of 2.5 months and median OS of 20.3 months.[86] In another study (n = 23), the ORR with ICIs in HER2-mutant NSCLCs was 27%, and patients with higher PD-L1 expression had longer PFS and OS.[87] The apparent discrepancy in the ORR reported by the various studies suggests that certain types of HER2 mutations could be responsive to ICIs.[84] However, in the absence of prospective data, chemo-immunotherapy combination should be used as standard upfront therapy.

  Putting the Data of HER2 Alterations in Lung Cancer into Perspective Top

Although HER2 alterations are well-known oncogenic drivers, their role in lung cancers is ambiguous. Most of the studies are inconclusive, and this could be due to several reasons. First, the lack of precise definitions for the various HER2 alterations led to enrollment of a heterogeneous patient population. Second, some patients harbor more than one HER2 alteration; for instance, HER2 mutations may coexist with HER2 protein overexpression or gene amplification in some patients. Third, there are alternate mechanisms of downstream signaling, which may not be completely inhibited by single-agent anti-HER2 therapy; for instance, temsirolimus in combination with neratinib has been shown to have a better response rate than neratinib alone in HER2-mutant NSCLCs.[88],[89] Fourth, HER2 mutations might play a dominant role in lung tumorigenesis, whereas HER2 overexpression and gene amplification might play an important role in breast and stomach cancers.[90],[91] This is exemplified by the fact that trastuzumab and other anti-HER2 agents are associated with a greater response in carcinomas of the breast than in NSCLCs. Limited knowledge of the primary and secondary resistance mechanisms to anti-HER2 therapy, tumor heterogeneity, and clonal evolution of the tumor are other possible reasons behind the inconclusive results in NSCLCs.[92],[93] Thus, increasing the enrollment of patients in clinical trials on drugs targeting HER2 or its downstream signaling pathways is the way forward for improving the outcomes for this subgroup of patients with NSCLC.

Currently, the relationship between the various types of HER2 alterations is not clear, and there are no standard guidelines for HER2 testing. NGS can be used to detect HER2 mutations, with the advantages of a parallel analysis of several other oncogenic drivers, smaller amount of tissue required, and lower costs.

In conclusion, with regard to HER2 overexpression, the studies with anti-HER2 therapies are divergent. Trastuzumab in combination with chemotherapy may have some activity in patients who are strongly HER2 positive (IHC score of 3+). T-DM1 is another drug that has shown promising activity in a phase I study but requires further validation in larger studies. The role of HER2-directed therapy in tumors with HER2 amplification is ambiguous due to the paucity of studies. In view of the absence of clear data, patients with HER2 amplification and overexpression should be considered for standard-of-care chemotherapy or immunotherapy. Nevertheless, targeting HER2 mutations with newer drugs such as pyrotinib, poziotinib, T-DM1, and trastuzumab deruxtecan appears to be promising as they have shown evidence of activity in small phase-II trials. HER2 mutations might be an emerging biomarker for anti-HER2 therapy in patients with NSCLCs. Currently, T-DM1 and trastuzumab deruxtecan are the only two drugs recommended by the NCCN guidelines for patients with NSCLC-harboring HER2 mutations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.[108]

  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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