Targeting HER2 Alterations in Non–Small-Cell Lung Cancer

A Comprehensive Review

Jing Zhao, MD; Yang Xia, MD, PhD

Disclosures

JCO Precis Oncol. 2020;4:411-425. 

In This Article

HER2-targeted Therapy in HER2-aberrant NSCLC

A wealth of studies have been conducted to address HER2-targeted therapies in HER2-aberrant NSCLC (Table 2). However, in contrast to breast cancer, the role in lung cancer of HER2-targeted drugs as monotherapies or in combination with chemotherapy and other target drugs remains unclear. Although anti-HER2 antibodies, antibody-drug conjugates, and small-molecule TKIs are not yet standard treatments in NSCLC, certain patients may benefit from these therapies (Figure 1).

Figure 1.

Human epidermal growth factor 2 (HER2) alterations in, and anti-HER2 therapies for, non–small-cell lung cancer (NSCLC). HER2 is activated by homodimerization, or by heterodimerization with other members of the erbB family, leading to phosphorylation of intracellular tyrosine residues. This results in activation of the downstream PI3K/AKT or MEK/ERK pathways, thus facilitating cell proliferation and migration. HER2 mutations, gene amplification, and protein overexpression are common HER2 aberrations. The incidence of HER2 protein overexpression in patients with NSCLC is 2.4%-38%, and the incidence of HER2 gene amplification is 10%-20%. Tyrosine kinase inhibitors (TKIs) bind to the tyrosine domain of activated HER2 protein. Six pan-HER TKIs have been tested for NSCLC: afatinib, dacomitinib, pyrotinib, neratinib, poziotinib, and lapatinib. The efficacy of the monoclonal antibodies pertuzumab and trastuzumab has also been studied, alone or conjugated to cytotoxic drugs such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (DS-8201a). Considering the outcomes of HER2-targeting therapies, albeit not best, chemotherapy remains one of the reliable options for patients who harbor HER2 alterations.

Trastuzumab, a humanized IgG1 monoclonal antibody directed against HER2, is an approved treatment of breast cancer and gastric cancer showing HER2 overexpression or amplification.[59,60] However, trastuzumab has yielded disappointing results in NSCLC. A lack of response to trastuzumab has consistently been observed in NSCLC regardless of the HER2 status determined by IHC or FISH.[61–64] In contrast, Gatzemeier et al[63] conducted a phase II trial that showed that the benefit of trastuzumab was improved in 6 individuals harboring HER2 3+/FISH positive, but the sample size was too small to draw further conclusions. Another study by de Langen et al[58] attempted to evaluate the role of trastuzumab plus paclitaxel in overcoming EGFR-TKI resistance in 24 patients who harbored an EGFR mutation and were positive for HER2 (defined as HER2 IHC 1+ to 3+ or HER2 gene copy number > 1). The data showed that a higher ORR was achieved in 67% of 12 patients with an HER2 IHC status of 3+, and a higher ORR was achieved in 100% of 4 patients who had NSCLC with a HER2 copy number > 10.[58] This study implied that de novo and inducible HER2 pathway activation might contribute differently to the pathogenesis of lung cancer, and, in turn, HER2-targeted therapies can result in distinct outcomes.

In contrast, pertuzumab is a human EGFR2 dimerization inhibitor that shows tremendous therapeutic effects when combined with trastuzumab and chemotherapy in HER2-positive breast cancer.[65] However, pertuzumab was ineffective for patients with NSCLC as a monotherapy (no objective response observed in 43 patients)[66] as well as in combination with erlotinib (the response rate at day 56 was 19.5%).[67] These disappointing results might be due to nonselection for HER2 status or the EGFR mutation status. We are awaiting the outcome of an ongoing phase II trial aiming to evaluate the combination regimen of pertuzumab, trastuzumab, and docetaxel in pretreated patients who harbor a HER2 mutation (ClinicalTrials.gov identifier: NCT03845270).

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) designed to target HER2 and release a cytotoxic drug. A phase II basket trial of this therapy showed a therapeutic benefit for patients with NSCLC with HER2 mutations, with a median PFS (mPFS) of 5 months.[68] Therefore, the National Comprehensive Cancer Network Guideline has recommended T-DM1 as a targeted agent for HER2-mutant NSCLC. A subsequent phase II trial that enrolled 35 patients with a HER2 mutation confirmed the efficacy of T-DM1, with an ORR of 44%.[69] On the other hand, T-DM1 showed intricate efficacy in patients with NSCLC with HER2 amplification or overexpression. Peters et al[70] reported an ORR of 20% (4/20) in HER2 IHC3+ patients and 0% in HER2 IHC2+ patients. Interestingly, further analysis revealed that three out of four responders with IHC3+ had concomitant HER2 amplification. Li and colleagues[71] reported an ORR of 50% in 6 patients with NSCLC with HER2 amplification. In contrast, Hotta et al[72] showed no response in patients with IHC3+ or IHC2+/FISH-positive NSCLC. The divergent results might be explained by the distinct responses to T-DM1 in patients with de novo and acquired HER2 amplification. Thus, these two groups of patients are now stratified in clinical trials. For example, an ongoing phase II clinical trial is evaluating the role of combined T-DM1 plus osimertinib treatment of patients with NSCLC harboring EGFR mutations and who are resistant to EGFR-TKI because of acquired HER2 bypass activation (ClinicalTrials.gov identifier: NCT03784599). Another prospective ADC drug is DS-8201a, which consists of a HER2-targeting antibody conjugated with an exatecan derivative that is a topoisomerase I inhibitor. This agent exerted potent antitumor responses in HER2-positive breast cancer,[73] even in patients pretreated with T-DM1.[74] A phase I study using DS-8201a showed a promising ORR (62.5%) in patients with advanced NSCLC and who have HER2 overexpression or HER2 mutation.[75] A phase II trial is currently recruiting patients (ClinicalTrials.gov identifier: NCT03505710).

Small-molecule TKIs are another promising therapeutic strategy. Notably, different TKIs target distinct ERBB family members. Lapatinib and afatinib are dual EGFR/HER2 TKIs, and dacomitinib, neratinib, poziotinib, pyrotinib, and TAK-788 are irreversible pan-ErbB receptor TKIs against EGFR/HER1, HER2, and HER4. The differences in structure, binding site, and affinity of these agents resulted in contradictory results regarding clinical efficacy in HER2-mutant NSCLC. Lapatinib interacts by reverse binding to the cytoplasmic ATP binding site of the tyrosine kinase domain, which has been widely used in HER2-positive metastatic breast cancer. However, lapatinib as a single agent or combined with pemetrexed did not result in a sufficient antitumor response in NSCLC (although the HER2 status was not selected in these trials).[76,77] Afatinib is an irreversible EGFR/HER2 dual inhibitor and has been approved as first-line treatment of metastatic EGFR-mutant NSCLC; however, it showed limited efficacy in HER2-mutant NSCLC. Preclinical in vitro studies have shown a potent antitumor activity of afatinib in NSCLC cell lines that have HER2 exon 20 insertions [half-inhibitory concentration (IC50), 0.001 μM], moderate activity for HER2 amplification (IC50, approximately 0.1 μM), and blunted activity for HER2 wild-type (IC50, 2–5 μM). In a recent phase II trial involving 13 previously treated patients, afatinib treatment resulted in a DCR of 53.8% at 12 weeks, with an mPFS of 12 weeks.[78] In another trial, 5 of 7 patients showed stable disease, but none of the patients exhibited partial response.[79] Nonetheless, several retrospective studies demonstrated that patients harboring certain mutations, including G778_P780dup (G778),[80,81] p.A775_G776ins/YVMA,[82] p.G776delinsVC, and p.Y772_A775dup[81] benefitted more from afatinib than those with other HER2 mutations. In a phase II trial, dacomitinib also produced limited objective responses in patients who had lung cancers with HER2 exon 20 insertions (3/26, ORR 12%) but not HER2 amplification.[83] Similarly, neratinib, as a single agent, demonstrated only a 3.8% overall response rate in patients with NSCLC with a HER2 mutation in a phase II clinical trial.[84] Furthermore, the combination of neratinib and temsirolimus (mTOR inhibition) resulted in a response rate of 33% (2 of 6 patients) in a phase I trial[85] but only a 19% (8 of 43 patients) response rate in a phase II trial.[86] Poziotinib has been reported to exhibit six times more potent antitumor activity than afatinib and dacomitinib in cell lines with HER2 exon 20 mutants in vitro.[87] Poziotinib appeared to have encouraging antitumor activity in a retrospective cohort study. A partial response was observed in 2 of 6 (33%) patients with NSCLC harboring HER2 exon 20 insertion.[88] Three ongoing phase II clinical trials are assessing the efficacy of poziotinib in this setting (ClinicalTrials.gov identifiers: NCT03318939, NCT04044170, and NCT03066206). The preliminary data from trial NCT03066206 showed that 6 of 12 (50%) patients harboring HER2 exon 20 insertion had a radiologically confirmed objective partial response.[89]

Pyrotinib is another emerging irreversible pan-HER inhibitor. In a patient-derived tumor xenograft model, pyrotinib showed a superior antitumor effect compared with afatinib and T-DM1. A phase II trial also revealed a promising response in previously treated patients with HER2-mutant adenocarcinomas, providing a 53.3% (8/15) ORR and an mPFS of 6.4 months.[90] These encouraging results warrant validation in large multicenter clinical trials. A recent study comparing the efficacy of poziotinib against HER2 mutations to that of other TKIs, including erlotinib, afatinib, dacomitinib, neratinib, osimertinib, AZ5104, pyrotinib, lapatinib, and ibrutinib, showed that the most common HER2 exon 20 insertion (A775_G776insYVMA) exhibited resistance to all of the drugs tested, except neratinib, poziotinib, and pyrotinib; importantly, poziotinib demonstrated the highest efficacy.[91] TAK-788 is a novel TKI that has shown potent and selective activity in preclinical studies in cells harboring activating EGFR and HER2 mutations, including exon 20 insertions. An early phase clinical trial is currently assessing the efficacy of TAK-788 in patients with NSCLC who have HER2 mutations (ClinicalTrials.gov identifier: NCT02716116).

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