Targeting HER2 Alterations in Non–Small-Cell Lung Cancer

Table 1.  The Prevalence of HER2 Alterations and the Impacts of on Treatment Outcome in NSCLC

Author/Country	Sample Size (No.)	HER2 Alterations	Key Results
Impact of HER2 alterations on survival of patients with NSCLC
Nakamura/Japan16	50	HER2 amplification: 1/50 (2%); HER2 overexpression: 13/50 (26%); HER2 gene DNA copy number ≥ 3: 22/50 (44%) NSCLCs	No significant correlation was observed between copy number increase and overexpression; neither gene copy number increase nor overexpression correlated with survival.
Suzuki/Japan17	1,275	HER2 mutation: 46/1,275 (3.6%); HER2 overexpression: 31/1,266 (2.4%); HER2 amplification: 222/1,170 (19.0%)	HER2 overexpression, HER2 amplification, and HER2 mutation did not affect patients' overall survival; there are statistically significant associations between HER2 overexpression and amplification and between HER2 overexpression and mutation.
Meert/Belgium18	129	HER2 overexpression: 24/106 (22.6%); HER2 amplification: 6/103 (6%)	HER2 amplification associated with shorter survival.
Kim/Korea24	321	HER2 overexpression: 25/321 (8.7%); HER2 amplification: 46/321 (14.3%); HER2 mutation: 7/104 (6.7%) in driver oncogene–negative adenocarcinomas	Patients with overexpression of HER2 showed significantly shorter OS and DFS rates; patients with HER2 amplification tended to have shorter OS rates
Gow/China Taiwan28	888	HER2 mutation: 40/888 (4.5%)	HER2 mutation patients had a better OS.
Li/China36	456	HER2 overexpression: 55/357 (15.4%); HER2 mutation: 22/456 (4.8%)	No correlation between HER2 mutation with DFS or OS.
Pillai/United States37	920	HER2 mutation: 24/900 (3%)	HER2 mutation patients had inferior survival.
Ninomiya/Japan38	1,126	HER2 overexpression: 227/1,126 (20.1%); HER2 amplification: 60/1,126 (5.3%); HER2 mutation: 21/724 (2.9%)	Patients with HER2-aberrant tumors had a worse prognosis than those with EGFR- and ALK-positive tumors; HER2 IHC+ and mutation tended to be independent prognostic factors in NSCLC.
Tan/United States40	140	HER2 overexpression: 25/131 (19%); HER2 amplification: 7/313 (5%); HER2 mutation: 21/724 (2.9%)	Patients with HER2 gene amplification and HER2 protein IHC 3+ showed a strong tendency of shorter survival.
Impact of HER2 alterations on chemotherapy outcomes
Calikusu/Turkey44	73	HER2 positive (IHC + approximately 3+): 21/73 (28.8%)	NSCLCs that express HER2 are resistant to cisplatin-based chemotherapies
Cappuzzo/Italy45	190	HER2 amplification: 53/184 (22.8%)	HER2 gene copy number is not associated with response to chemotherapy; HER2 FISH positive had longer TTP and OS with chemotherapy and higher RR, TTP, and OS with EGFR-TKIs.
Kuyama/Japan46	68	HER2 overexpression: 23/68 (34%); HER2 amplification: median ratio of HER2 to chromosome 17 copy numbers of 0.93 (range, 0.55–2.00)	Neither HER2 overexpression nor amplification was associated with objective response to the chemoradiotherapy; patients with HER2 amplification had a poorer outcome.
Graziano/United States47	160	HER2 overexpression: 67/103 (65%)	HER2 overexpression cannot predict the response to chemotherapy, combined chemotherapy/radiation, or for survival.
Li/China48	106	HER2 mutation: 32/106 (30.2%; EGFR/KRAS/BRAF/ALK/ROS1–negative patients)	HER2-mutant patients had greater ORR, DCR than HER2 negative when accepted first-line pemetrexed combined with platinum chemotherapy
Wang/China49	1,714	HER2 mutation: 29/1,714 (1.7%%)	HER2-mutant lung adenocarcinomas showed similar ORR, PFS of first-line pemetrexed-based chemotherapy compared with those with KRAS/EGFR-mutant and inferior to those with ALK/ROS1 rearrangements.
Impact of HER2 alterations on TKI treatment outcomes
Soh/Japan51	74	HER2 FISH-positive (HER2 high level of polysomy or gene amplification): 32/74 (43.2%)	High HER2 copy number was significantly associated with sensitivity to gefitinib and prolonged PFS in a univariate analysis, but not in a multivariate analysis.
Cappuzzo/Italy52	102	HER2 FISH-positive (HER2 high level of polysomy or gene amplification): 23/102 (22.8%); HER2 amplification: 10/102 (9.8%)	FISH-positive patients treated with gefitinib had significantly better ORR, DCR, TTP and a trend toward longer overall survival.
Varella-Garcia/Japan53	44	HER2 FISH positive (HER2 high level of polysomy or gene amplification): 23/44 (53%)	No difference in terms of TTP and OS for patients treated with gefitinib
Tiseo/Italy54	58	HER2 amplification: 11/58(19%)	No significant differences in terms of response or survival in patients treated with gefitinib. Concurrent EGFR and HER2 FISH positivity did not correlate with response to gefitinib.
Cappuzzo/Italy55	63	HER2 overexpression: 15/43 (34.9%)	No difference in TTP, OS, toxicity, and symptom outcome in patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2.
Kayatani/Japan57	1,126	HER2 overexpression in all patients: 227/1,126 (20.1%); HER2 overexpression in EGFR-mutant patients: 58/277 (20.9%)	In patients with EGFR-mutant NSCLC, HER2 overexpression was associated with significantly shorter TTP to EGFR-TKIs therapy.

Abbreviations: DCR, disease control rate; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NSCLC, non–small-cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression.

Table 2.  Summary of Clinical Trials for HER2-Targeted Therapies in NSCLC

Agent	Combination Therapy	Study	HER2 Alterations	Sample Size (No.)	Clinical Efficacy
Transtuzumab58	Paclitaxel	Single-arm phase II study	HER2 IHC 1+ to 3+; HER2 gene number copy > 1 (with concurrent EGFR mutation and had progressed on EGFR TKI monotherapy)	24 (21 with HER2 overexpression)	ORR, 46% (11/24); DCR, 63% (15/24); mDOR, 5.6 months; mPFS 2.3 months
Transtuzumab61	Paclitaxel and carboplatin	Phase II study	HER2 IHC 1+ to 3+	56 (31 with HER2 overexpression)	mPFS, 3.3 months; median survival, 10.1 months; 1-year survival rate, 42%; median survival for 1+, 2+, and 3+ Her-2 expression was 14.6, 7.7 and 10.9 months
Transtuzumab62	Cisplatin and gemcitabine	Phase II study	HER2 IHC 1+ to 3+ or a serum Her2 shed ECD concentrations at least 15 ng/ml by ELISA)	21 (9 with HER2 overexpression)	ORR, 38% (8/21); DCR, 81% (17/21); 1-year survival rate, 62% (13/21); mTTP, 36 weeks
Transtuzumab63	Gemcitabine and cisplatin	Randomized phase II study	HER2 overexpression (IHC 2+ to 3+); HER2 amplification (FISH +); serum HER2 ECD positive	101 (only 5 with HER2 IHC3+; 7 with HER2 FISH+)	Efficacy was similar in the trastuzumab and control arms: ORR, 36% v 41%; DCR, 80% v 94%; mTTP, 6.3 v 7.2 months; mPFS, 6.1 v 7 months; 6 trastuzumab-treated patients with HER2 3+ or FISH+ had higher RR (83%) and mPFS (8.5 months)
Transtuzumab64	Docetaxel or paclitaxel	Randomized phase II study	Unselected by HER2 status	64 (20 with HER2 overexpression)	Efficacy was similar in the patients treated with docetaxel plus trastuzumab and the patients treated with paclitaxel plus trastuzumab: ORR was 23% (7/30) v 32% (11/34; P = .76); median survival, 16 v 14 months; 1-year survival, 57% v 55% (P = .998)
Pertuzumab66	No	Phase II study	Unknown	43	RR, 0/43 (0%); DCR rate at 6 and 12 weeks, 18/43 (41.9%) and 9/43 (20.9%); the median and 3-month PFS rates were 6.1 weeks and 28.4%
Pertuzumab and erlotinib67	No	Phase II study	Unselected by HER2 status	41 (9 mutated EGFR and 23 wild-type EGFR)	FDG-PET ORR, 19.5% in all patients (8/41) and 8.7% in patients with wild-type EGFR NSCLC (2/23); investigator-assessed CT ORR, 12.2% (5/41)
T-DM169	No	Phase II study	HER2 mutation	35	ORR, 44% (8/18) for RECIST cohort and 46% (6/13) for PERCIST cohort
T-DM170	No	Phase II study	HER2 overexpression	49	IHC 2+ cohort: ORR, 0/29; DCR, 28% (8/29); mPFS, 2.6 months; mOS, 12.2 months; IHC 3+ cohort: ORR, 20% (4/20); DCR, 40% (8/20); mPFS, 2.7 months; mOS, 15.3 months
T-DM172	No	Phase II study	HER2 overexpression/amplification/mutation (exon 20 mutation)	15 (5 with IHC 3+; 3 with IHC 2+/FISH +; 7 with mutation)	All patients: ORR, 6.7% (1/15); DCR, 53.3% (8/15); mPFS 2 months; median survival time, 10.9 months; HER2 mutation: ORR, 14.3%; DCR, 71.4%; HER2 IHC/FISH+: ORR, 0%; DCR, 37.5%
T-DM171	No	Phase II study	HER2 mutation/amplification	33	HER2 mutation: ORR, 8/18 (44%); PFS, 4 months; HER2 amplification: ORR, 3/6 (50%); HER2 IHC did not predict response
DS-8201a75	No	Phase I study	HER2 overexpression/mutation	12	ORR, 62.5% (5/8); ORR, 40% among subjects with HER2 overexpression (2/5); DCR, 75% (6/8); mDOR, 11.5 months
Lapatinib76	No	Randomized phase II multicenter study	Patients are unselected by HER2 status and 2 (3.5%) had increased HER2 gene copy number (2- and 6-fold);	131	ORR, 0/56; DCR, 25% (14/56)
Lapatinib77	Pemetrexed	Phase I study	Unknown	18	ORR, 22.2% (4/18); DCR, 77.8% (14/18)
Afatinib78	No	Single-arm phase II study	HER2 mutation (exon 20 mutation)	13	ORR, 7.7% (1/13); DCR, 53.8% (7/13); mPFS, 15.9 weeks; mOS, 56 weeks
Afatinib79	Paclitaxel/no	Phase II study	HER2 mutation	7	Afatinib monotherapy: ORR, 0/7; DCR, 71% (5/7); median duration of disease control, 16 weeks; mPFS, 17 weeks
Afatinib80	No	Retrospective study	HER2 mutation (ERBB2 exon 20 insertions)	171 (19 with afatinib monotherapy)	Patients harboring G778_P780dup (G778) had longer PFS and OS than other 20ins subtypes (mPFS, 10 v 3.3 months; mOS, 19.7 v 7 months); afatinib monotherapy: ORR, 15.8% (3/19); DCR, 68.4% (13/19)
Afatinib81	No	Retrospective study	HER2 mutation	16	Patients harboring G776delinsVC; Y772_A775dup; G778_P780dup had marginally higher ORR and longer PFS than those carrying other types of HER2 mutations (ORR, 50% v 0%; mPFS, 9.53 v 1.80 months)
Afatinib82	No	Phase II study	HER2 mutation	28	All patients: ORR, 19% (3/16); DCR, 69% (11/16); patients with p.A775_G776insYVMA in exon 20: ORR, 33% (2/6); DCR, 100% (6/6); mTTP, 9.6 months
Dacomitinib83	No	Phase II study	HER2 mutation/amplification	30 (26 with HER2 mutation; 4 with HER2 amplification)	HER2 exon 20 mutation: ORR, 12% (3/26); mPFS, 3 months; mOS, 9 months; 1-year survival, 44%; HER2 amplification: ORR, 0/4
Neratinib84	No	Phase II basket study	HER2 mutation	26	ORR, 3.8% (1/26); DCR, 42.3 (11/26); mPFS 5.5 months
Neratinib85	Temsirolimus	Phase I study	HER2 mutation	14 (6 with HER2 mutation)	ORR, 33% (2/6)
Neratinib86	Temsirolimus/no	Randomized phase II study	HER2 mutation	60	Neratinib: ORR, 0/17; DCR, 35% (6/17); mPFS, 3 months; mOS, 10 months; neratinib + temsirolimus: ORR, 19% (8/43); DCR, 51% (22/43); mPFS, 4.1 months; mOS, 15.8 months
Poziotinib or afatinib88	No	Retrospective study	HER2 mutation	7	Poziotinib: ORR, 33% (2/6); DCR, 83% (5/6); afatinib: ORR, 100% (1/1)
Poziotinib89	No	Phase II study	HER2 mutation	12	ORR, 50% (6/12); DCR, 83.3% (10/12) at 8 weeks
Pyrotinib90	No	Phase II study	HER2 mutation	15	ORR, 53.3% (8/15); DCR, 73.3% (11/15); mDOR 7.2 months; mPFS, 6.4 months

Abbreviations: CT, computed tomography; DCR, disease control rate; FDG, fluorodeoxyglucose; ECD, extracellular domain; ELISA, enzyme-linked immunosorbent assay; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; mTTP, median time to progression; NSCLC, non–small-cell lung cancer; ORR, overall response rate; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; RR, response rate.

Authors and Disclosures

Jing Zhao, MD¹ and Yang Xia, MD, PhD<sup>2

1</sup>Department of Medical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Corresponding Author
Yang Xia, MD, PhD, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, Zhejiang, 310009, China. E-mail: yxia@zju.edu.cn

Author Contributions
Conception and design: Yang Xia
Financial support: Yang Xia
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors

Authors' Disclosures of Potential Conflicts of Interest
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst =My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
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No potential conflicts of interest were reported.

Sidebar

Context

Key Objective. To characterize the HER2 aberrations seen in non–small-cell lung cancer (NSCLC), and the efficacy of HER2-targeted therapies in patients with NSCLC.

Knowledge Generated. The relevance of HER2 gene amplification, overexpression, and point mutations to NSCLC remains unclear. The impact of de novo and acquired HER2 aberrations on the outcomes of chemotherapy and epidermal growth factor receptor–tyrosine kinase inhibitor therapies is a matter of debate. Multiple HER2-targeted therapies have been tested in patients with HER2-aberrant NSCLC. Trastuzumab is ineffective as a monotherapy for HER2-overexpressing NSCLC, and HER2 point mutations are susceptible to ado-trastuzumab emtansine treatment. Emerging pan-HER inhibitors, such as poziotinib and pyrotinib, have shown potent antitumor activity in patients with NSCLC harboring HER2 mutations. Several novel anti-HER2 therapeutic approaches are currently under investigation, as monotherapies or in combination.

Relevance. De novo and recurrent HER2 pathway alterations must be managed using distinct approaches. HER2 mutations, especially mutations in exon 20, are likely to be the most clinically relevant HER2 aberrations in HER2-directed therapies for NSCLC.