cancers

Review
HER2 in Non-Small Cell Lung Cancer: A Review of
Emerging Therapies
Natalie F. Uy , Cristina M. Merkhofer and Christina S. Baik *

Division of Medical Hematology and Oncology, Department of Medicine, University of Washington,

Seattle, WA 98195, USA
* Correspondence: cbaik2@uw.edu

Simple Summary: There are growing data on targeting HER2 alterations, which include gene mu-
tations, gene amplifications, and protein overexpression, for non-small cell lung cancer (NSCLC).
Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations,
and this remains an unmet clinical need. There has been an influx of research on antibody–drug con-
jugates, monoclonal antibodies, and tyrosine kinase inhibitors. This review discusses the diagnostic
challenges of HER2 alterations in NSCLC and summarizes recent progress in HER2 targeted drugs
for both clinicians and researchers treating this patient population.

Abstract: Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of
tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung
cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations,
gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now
a well clinically validated biomarker. Currently, there are limited targeted therapies approved for
NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations
are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of
EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs),
Citation: Uy, N.F.; Merkhofer, C.M.;
Baik, C.S. HER2 in Non-Small Cell
monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising
Lung Cancer: A Review of Emerging therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib,
Therapies. Cancers 2022, 14, 4155. mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated
https://doi.org/10.3390/ NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration
cancers14174155 to better select patients who will benefit, particularly for HER2 amplification and overexpression.
Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination
Academic Editors: Xiuning Le,
Jianjun Jay Zhang and Yasir Elamin
therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This
review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in
Received: 2 July 2022 novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of
Accepted: 22 August 2022
patients with HER2 altered NSCLC.
Published: 27 August 2022

Publisher’s Note: MDPI stays neutral Keywords: non-small-cell lung cancer; HER2 amplification; HER2 mutation; HER2 overexpression;
with regard to jurisdictional claims in exon 20 mutation; targeted therapies; driver mutation
published maps and institutional affil-
iations.

1. Introduction

Copyright: © 2022 by the authors.

Improved understanding of oncogenic driver alterations and targeted therapy develop-
Licensee MDPI, Basel, Switzerland.
ment has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC).
This article is an open access article Comprehensive molecular assessment has become a standard part of NSCLC management.
distributed under the terms and However, not all oncogenic driver alterations have effective targeted therapies, highlighting
conditions of the Creative Commons the need for novel therapeutic strategies.
Attribution (CC BY) license (https:// Human epidermal growth factor receptor 2/Erb-B2 receptor tyrosine kinase 2 (HER2/
creativecommons.org/licenses/by/ ERBB2), a tyrosine kinase receptor in the EGFR (epidermal growth factor receptor) family,
4.0/). is an emerging therapeutic target [1]. HER2 does not have a known soluble ligand and

Cancers 2022, 14, 4155. https://doi.org/10.3390/cancers14174155 https://www.mdpi.com/journal/cancers

 family, is an emerging therapeutic target [1]. HER2 does not have a known soluble ligand
and downstream signaling is triggered by dimerization with other ligand-bound HER
family members, which leads to phosphorylation and activation of downstream
Cancers 2022, 14, 4155 PI3K/AKT and MEK/ERK pathways. Alterations in the HER2 pathway drive oncogenesis 2 of 16
by increased dimerization and autophosphorylation, leading to uncontrolled cell growth.
Novel therapies are aimed at disrupting this pathway (Figure 1).
downstream signaling
In this review, is triggered
we aim by dimerization
to characterize with
the types of other
HER2ligand-bound HER
alterations in fam- dis-
NSCLC,
ily members, which leads to phosphorylation and activation of downstream PI3K/AKT
cuss the diagnostic challenges in identifying activating HER2 alterations, and review the
and MEK/ERK pathways. Alterations in the HER2 pathway drive oncogenesis by in-
application of HER2 targeted agents in patient care by discussing clinical trial data on
creased dimerization and autophosphorylation, leading to uncontrolled cell growth. Novel
HER2 agents.
therapies are aimed at disrupting this pathway (Figure 1).

Figure 1. Non–small cell lung cancer HER2 tumorigenesis pathways and targeted therapy mecha-
Figure 1. Non–small cell lung cancer HER2 tumorigenesis pathways and targeted therapy mech-
nisms. The HER2 extracellular domain does not have a known soluble ligand and is activated by
anisms. The HER2 extracellular domain does not have a known soluble ligand and is activated
forming homo or heterodimers, which leads to phosphorylation and activation of downstream
by forming homo or heterodimers, which leads to phosphorylation and activation of downstream
PI3K/AKT and MEK/ERK pathways. (1) Tyrosine kinase inhibitors block phosphorylation of the
PI3K/AKT and MEK/ERK pathways. (1) Tyrosine kinase inhibitors block phosphorylation of the
tyrosine kinase residues, inhibiting cell proliferation. (2) Monoclonal antibodies bind to the extra-
tyrosine kinase residues, inhibiting cell proliferation. (2) Monoclonal antibodies bind to the extracel-
cellular domain of HER2 to block homo and heterodimerization. (3) Antibody–drug conjugates
lular domain of HER2 to block homo and heterodimerization. (3) Antibody–drug conjugates (ADC)
(ADC) incorporate the HER2 targeted actions of trastuzumab with a cytotoxic component
incorporate the HER2 targeted actions of trastuzumab with a cytotoxic component (microtubule
(microtubule inhibitor or topoisomerase I inhibitor) connected by a cleavable tetrapeptide-based
inhibitor or topoisomerase I inhibitor) connected by a cleavable tetrapeptide-based linker. Upon
linker. Upon degradation of the HER2-ADC complex in endosomes/lysosomes, the cytotoxic
degradation of the HER2-ADC complex in endosomes/lysosomes, the cytotoxic component is re-
component is released. This allows for selective delivery into HER2 overexpressing cells, resulting
leased. This allows for selective delivery into HER2 overexpressing cells, resulting in cell cycle arrest
in cell cycle arrest and apoptosis.
and apoptosis.
Cancers 2022, 14, 4155 3 of 16

In this review, we aim to characterize the types of HER2 alterations in NSCLC, dis-
cuss the diagnostic challenges in identifying activating HER2 alterations, and review the
application of HER2 targeted agents in patient care by discussing clinical trial data on
HER2 agents.

2. Types of HER2 Alterations

Three main HER2 activating mechanisms have been described: gene mutations, gene
amplification, and protein overexpression [2].
Oncogenic mutations in HER2 are present in 2–4% of NSCLC and can be identified by
genetic sequencing, often by next generation sequencing (NGS) in clinical settings. These
mutations are predominantly found in females, never-smokers, and patients with lung
adenocarcinomas [3]. The most frequent mutations are HER2 exon 20 insertions, which have
emerged as a particular area of therapeutic interest [1]. HER2 mutations are almost always
mutually exclusive with activating mutations in other oncogenic drivers such as EGFR,
KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT, as well as with ALK rearrangements [1].
HER2 mutations are heterogeneous, which has made developing therapeutics challenging.
The majority are insertions or duplications between amino acids 772 and 780, but point
mutations and other insertions have also been reported [1,4]. In addition, to select HER2
mutations serving as a primary oncogenic driver in NSCLC, these may also present as an ac-
quired mechanism of resistance to EGFR tyrosine kinase inhibitor (TKI) treatment [5,6]. The
prognostic value of HER2 mutations remains unclear. Higher rates of brain metastases have
been noted in HER2 mutant lung cancers compared with other driver mutations [7]. No-
tably, the exon 20 YVMA insertion is associated with a higher incidence of brain metastases
and inferior outcomes with chemotherapy [8].
HER2 amplification occurs in 3% of NSCLC cases without prior EGFR TKI treatment
and may account for up to 10% of acquired resistance to EGFR TKI therapy [9]. In contrast
to HER2 mutations, a higher proportion of HER2 amplified patients are male smokers [10].
Amplification can be detected with fluorescence in situ hybridization (FISH). There is no
standardized definition of HER2 amplification. However, a commonly accepted defini-
tion is a ratio of ≥ 2 of the HER2 gene copy number to centromeres [HER2/chromosome
enumeration probe 17 (CEP17)] [11]. The prognostic value of HER2 amplification is unclear,
although one observational study in resected NSCLC found that high levels of HER2 am-
plification (defined as HER2/CEP17 ratio ≥ 5 or copy number ≥ 10) in resected NSCLC
were associated with shorter overall and disease-free survival compared to lower levels [9].
HER2 protein overexpression is found in 2–20% of NSCLC, with the frequency varying
depending on the level of overexpression. Overexpression is commonly assessed using
immunohistochemistry (IHC). There is no consensus on the definition of HER2 protein
overexpression in lung cancer, but clinical studies frequently use a score of 2+ (“weak to
moderate complete membrane staining observed in >10% of tumor cells”) or 3+ (“circum-
ferential membrane staining that is complete, intense and in >10% of tumor cells”) as per
the American Society of Clinical Oncology/College of American Pathologists breast cancer
guidelines [11]. HER2 overexpression is also associated with a poor prognosis, with some
suggesting that this may be the case for women but not men [12,13].
Contrary to breast cancer, where HER2 overexpression often occurs concurrently with
HER2 amplification, this co-occurrence has been less consistently observed in lung cancer.
There is no significant correlation between an increase in HER2 gene copy number and
protein overexpression. Mutations in the HER2 gene are also not clearly associated with
increased levels of HER2 amplification. In fact, HER2 amplification is often mutually
exclusive from HER2 mutations, and both have been suggested as distinct entities [1,10].
The lack of correlation between HER2 gene mutations, gene amplification, and protein
overexpression makes it challenging to define HER2 altered lung cancers. The HER2 exon
20 insertion mutation is emerging as a clinically validated predictive biomarker, but the
role of non-exon 20 mutations, amplification, and overexpression are less clear. Currently,
“HER2 positivity” is often used to refer to the presence of a mutation, and more specific
Cancers 2022, 14, 4155 4 of 16

nomenclature and definitions are needed for amplification and overexpression, especially
in clinical trial settings. Likewise, methods to detect “HER2 positivity” in NSCLC should
be standardized and optimized for each type of HER2 alteration.

3. Treatment of HER2-Altered NSCLC

Initial clinical trials of HER2-targeted agents had disappointing results likely due to
lack of patient selection [14,15] and slowed down the progress of clinical development.
However, the development of novel drugs and improved patient selection has yielded an
influx of studies with promising HER2-directed therapies in recent years. Antibody-drug
conjugate (ADC) therapy has shown the most efficacy thus far, and several tyrosine kinase
inhibitors (TKIs) are in development.

3.1. Antibody-Drug Conjugates

3.1.1. Trastuzumab–Deruxtecan (T-DXd)
Fam-trastuzumab–deruxtecan (T-DXd) is emerging as a promising drug in HER2
mutant NSCLC; recently it became the only FDA approved targeted therapy for NSCLC
patients with HER2 mutations. T-DXd is an ADC composed of trastuzumab, a monoclonal
antibody against HER2, linked to a topoisomerase I inhibitor, deruxtecan. A recent study
using lung cancer cell lines and patient-derived xenograft models showed that HER2
mutant NSCLC models showed increased internalization of ADC therapy compared to
wildtype cells, likely explaining the clinical observation of ADC efficacy in this patient
population [16].
A phase I first-in-human clinical study investigated T-DXd for the treatment of patients
with HER2 overexpressing (IHC ≥ 1+) or HER2 mutant advanced non-breast, non-gastric
solid tumors. Anti-tumor efficacy was observed across multiple tumor types, including
HER2 expressing and HER2 mutant NSCLC. Patients with HER2 mutant NSCLC had
increased tumor reduction relative to patients without documented mutations, regardless
of HER2 overexpression status. In the subgroup of patients with NSCLC with HER2
overexpression or a HER2 mutation, the objective response rate (ORR) was 55.6% with a
median progression-free survival (PFS) of 11.3 months [17] (Table 1).
In the DESTINY-Lung01 trial, T-DXd was evaluated in two populations, overexpress-
ing HER2 (IHC 2+ or 3+) and HER2 mutated NSCLC. In an interim analysis of 49 HER2
overexpressing patients, the ORR was 24.5% and median PFS was 5.4 months. All patients
had at least one grade ≥ 1 adverse effect (AE), most commonly nausea and decreased ap-
petite, and grade ≥ 3 AE was reported in 73.5% of patients. One serious AE of interest was
interstitial lung disease (ILD); 16.3% of patients had ILD, with 6% having grade 5 ILD [18].
In a separate study, T-DXd was administered to 91 patients with HER2 mutated NSCLC
that had progressed on standard treatment at the investigator’s discretion. The ORR was
55%, and median PFS was 8.2 months. Efficacy was noted across subgroups, including
patients treated with prior HER2 TKI therapy and in patients with central nervous system
(CNS) metastases. AE included gastrointestinal and hematological events, particularly neu-
tropenia. In this cohort, 26% of patients had ILD of any grade, and 7% had grade 3–5 ILD.
The 2 patients who died of ILD had previously received immunotherapy [19]. Activating
HER2 mutations are thought to enhance receptor internalization and intracellular uptake of
the HER2-ADC complex, which may explain the higher efficacy of T-Dxd in patients with
HER2 mutant NSCLC versus HER2 overexpression [16].

3.1.2. Ado Trastuzumab–Emtansine (T-DM1)

Ado Trastuzumab–emtansine (T-DM1) is an ADC that links trastuzumab with a
cytotoxic microtubule inhibitor, DM-1. T-DM1 was evaluated as part of a phase II basket
trial in 18 HER2 mutant lung cancer patients, 11 with a HER2 exon 20 mutation, and 2 with
a concurrent HER2 amplification. Among these patients, an ORR of 44% and a median
PFS of 5 months were observed. Responses were seen across HER2 mutation subtypes,
including exon 20 insertions as well as transmembrane and extracellular domain point
Cancers 2022, 14, 4155 5 of 16

mutations. There was no association between IHC score and response to T-DM1. Common
adverse effects of T-DM1 included liver transaminitis, thrombocytopenia, and nausea [20].

Table 1. Studies of Antibody Drug Conjugates in HER2 altered NSCLC.

Overall
NSCLC Median PFS Median OS
Drug Trial Tumor Types Response Ref
Population (n) (Months) (Months)
Rate
NSCLC, colorectal,
salivary gland,
breast, esophageal, HER2 IHC ≥ 1+ Overall
endometrial, Paget’s or HER2 NSCLC: Overall Overall
disease, biliary tract, mutation 55.6% NSCLC: 11.3 NSCLC: n/r
T-DXd phase I [17]
pancreatic, cervical, (NSCLC n = 18; HER2 HER2 HER2
extraskeletal myxoid exon 20 NSCLC mutant: mutant: 11.3 mutant: 17.3
chondrosarcoma, n = 8) 72.7%
small intestine
adenocarcinoma
phase II
HER2 IHC 2/3+
T-Dxd (DESTINY- NSCLC 24.5% 5.4 n/a [18]
(n = 49)
Lung01)
phase II HER2 mutation
T-DXd (DESTINY- NSCLC (n = 91; 55% 8.2 17.8 [19]
Lung01) exon 20 = 78)
HER2 mutation
T-DM1 phase II NSCLC (n = 18; 44% 5.0 n/a [20]
exon 20 = 11)
HER2 (IHC 3+,
IHC 2+ and FISH
HER2/CEP17 Overall: 6.7%
ratio ≥ 2, or exon IHC/FISH-
T-DM1 phase II NSCLC 20 mutation) positive: 0% 2.0 10.9 [21]
(n = 15, Exon 20:
IHC/FISH+ 14.3%
n = 8, exon 20
n = 7)
HER2 IHC 2/3+ IHC 2+: 0% IHC 2+: 2.6 IHC 2+: 12.2
T-DM1 phase II NSCLC [22]
(n = 49) IHC 3+: 20% IHC 3+: 2.7 IHC 3+: 15.3
HER2 exon
T-DM1 phase II NSCLC 20 mutation 38.1% 2.8 8.1 [23]
(n = 22)
PFS: progression free survival; OS: overall survival; T-DM1: Trastuzumab Emtansine; T-DXd:
Trastuzumab Deruxtecan; IHC: immunohistochemistry; CEP17: chromosome enumeration probe 17;
n/a: not available; n/r: not reached.

In contrast, a phase II trial of T-DM1 monotherapy in relapsed NSCLC with HER2

alterations (IHC 3+, IHC 2+ and FISH HER2/CEP17 ratio ≥ 2, or exon 20 insertion mu-
tation) was terminated early because of limited efficacy. The ORR was 6.7% and median
PFS was 2.0 months [21]. A phase II trial in patients with previously treated advanced
HER2 overexpressing NSCLC also demonstrated limited efficacy of T-DM1. No treatment
responses were observed in the IHC 2+ cohort, although ORR was 20% in the IHC 3+
cohort [22]. A more recent T-DM1 study on only HER2 exon 20 insertion mutated NSCLC
found a numerically higher ORR (38.1%); however, PFS was only 2.8 months [23].

3.1.3. Summary of Evidence regarding HER2 ADC

ADC (Table 1) have shown great clinical benefit in breast and gastric cancers, and there
has been much interest in exploring their benefits in HER2 mutant NSCLC. While results
Cancers 2022, 14, 4155 6 of 16

have been mixed for T-DM1, T-DXd appears promising given the high ORR and durable
responses observed in the DESTINY-Lung01 trial. T-DXd was granted breakthrough
therapy designation by the FDA for HER2 mutant NSCLC; it was recently approved for
advanced and metastatic NSCLC patients with HER2 mutations after first line therapy.
T-DXd will likely be a cornerstone of HER2-directed therapy in this population moving
forward. There are ongoing clinical trials for T-DXd as first line monotherapy and in
combination with immunotherapy and chemotherapy.

3.2. Monoclonal Antibodies

3.2.1. Trastuzumab
Trastuzumab is a monoclonal immunoglobulin G1 humanized murine antibody that
binds to the HER2 extracellular domain and inhibits dimerization. In the HOT1303-B
trial, patients with HER2 altered NSCLC (IHC 2/3+ overexpression and/or mutations)
previously treated with at least two lines of therapy received trastuzumab monotherapy.
No patients responded to trastuzumab monotherapy in both overexpressed and mutated
NSCLC [24]. In another similar study, there were no tumor responses to trastuzumab
monotherapy cohort in HER2 expressing NSCLC [25] (Table 2).
Trastuzumab has also been evaluated in combination with chemotherapy in patients
with NSCLC. Older studies of patients with HER2 overexpressing NSCLC treated with
trastuzumab with either docetaxel [25], carboplatin and paclitaxel [26], and cisplatin and
gemcitabine [27] all demonstrated mixed results, with the ORR ranging from 0% with
docetaxel to 36% with cisplatin and gemcitabine. The only randomized trial in this group
compared cisplatin and gemcitabine with or without trastuzumab in untreated HER2
overexpressing (defined as IHC 2+ or 3+) NSCLC patients. Efficacy was similar between
the chemotherapy alone arm (ORR 41%; median PFS 7.0 months) and the combination
chemotherapy and trastuzumab arm (ORR 36%; median PFS 6.1 months). However, the
subset of 6 patients with HER2 IHC 3+ in the trastuzumab arm had a notably higher ORR
of 83% and median PFS of 8.5 months. Both treatment arms had similar proportions of
gastrointestinal and hematologic AE. Rare AE of decreased left ventricular ejection fraction
was noted in the trastuzumab arm [28].

Table 2. Studies of Monoclonal Antibodies in HER2 altered NSCLC.

Median PFS Median OS

Drug Trial NSCLC Population (n) Overall Response Rate Ref
(Months) (Months)
phase II HER2 IHC 2/3+ or
trastuzumab 0% 5.2 n/a [24]
(HOT1303-B) mutation (n = 10)
Trastuzumab: 0%
trastuzumab ± HER2 IHC 2/3+
phase II Trastuzumab + n/a a 5.7 [25]
docetaxel (n = 13)
docetaxel: 0%
HER2 IHC 1+ or HER2
trastuzumab +
shed antigen level >15
cisplatin/ phase II 38% 36 weeks n/a [27]
ng/mL by ELISA
gemcitabine
(n = 21)
trastuzumab +
phase II HER2 IHC ≥ 1+
paclitaxel/ 24.5% 3.3 10.1 [26]
(ECOG 2598) (n = 56)
carboplatin
HER2 IHC 2/3+, Control arm: 41% (50%
HER2/CEP17 ratio ≥ 2, in HER2 Control arm: 7.0 Control arm: n/r
gemcitabine/cisplatin
phase II Serum HER2 ECD >15 IHC 3+) Trastuzumab Trastuzumab Trastuzumab [28]
± trastuzumab
ng/mL by ELISA arm: 36% (83% in HER2 arm: 6.1 arm: 12.2
(n = 101) IHC 3+)
pertuzumab +
phase II HER2 exon 20 mutation
trastuzumab + 29% 6.8 n/a [29]
(IFCT-1703 R2D2) (n = 45)
docetaxel
PFS: progression free survival; OS: overall survival; IHC: immunohistochemistry; CEP17: chromosome enu-
meration probe 17; ECD: extracellular domain; n/a: not available; n/r: not reached. a Event free survival was
4.3 months.
Cancers 2022, 14, 4155 7 of 16

3.2.2. Pertuzumab
Pertuzumab is a humanized monoclonal anti-HER2 antibody that binds HER20 s dimer-
ization domain and inhibits HER2 signaling. Pertuzumab monotherapy was evaluated
in 43 patients with previously treated, unselected NSCLC, and no responses were seen.
However, this poor response may be related to a lack of selection for HER2 status [14].
The IFCT-1703 R2D2 trial evaluated the combination of pertuzumab, trastuzumab, and
docetaxel in patients with HER2 mutated NSCLC after progression through platinum-based
chemotherapy. The ORR was 29% and the median PFS was 6.8 months. The most frequent
grade 3 AE were neutropenia, diarrhea, and anemia [29].

3.2.3. Summary of Evidence regarding HER2 Monoclonal Antibodies

While HER2 monoclonal antibodies (Table 2) have benefited patients with advanced
HER2 breast and gastric cancers, results in NSCLC have been more limited. In contrast
to ADCs, monoclonal antibody monotherapy has not demonstrated objective tumor re-
sponses. Monoclonal antibody and chemotherapy combination regimens have resulted in
numerically higher ORR. However, further data comparing combination therapy versus
chemotherapy alone are needed to define whether there is a role for monoclonal antibody-
based regimens in select patients with HER2 altered NSCLC.

3.3. Tyrosine Kinase Inhibitors

A number of TKIs have been developed to target distinct ERBB family members. Dual
EGFR/HER2 TKIs (lapatinib) and pan-HER inhibitors (afatinib, neratinib, dacomitinib, py-
rotinib, poziotinib, tarloxotinib, and mobocertinib) which irreversibly bind to EGFR/HER1,
HER2, and HER4 tyrosine kinases have been under active investigation (Figure 1). We have
highlighted TKIs that specifically included patients with HER2 exon 20 mutant NSCLC
(Table 3).

Table 3. Studies of Tyrosine Kinase Inhibitors in HER2 exon 20 mutation NSCLC.

Overall Median PFS Median OS

Drug Trial NSCLC population (n) Ref
Response Rate (Months) (Months)

HER2 exon 20 mutation

pyrotinib phase II 53.3% 6.4 n/a [30]
(n = 15)

HER2 mutation
pyrotinib phase II (n = 60; HER2 exon 20 30% 6.9 14.4 [31]
mutation n = 56)

HER2 mutation
pyrotinib phase II (n = 78, HER2 exon 20 19.2% 5.6 10.5 [32]
mutation = 62)

HER2 amplification
pyrotinib phase II 22.2% 6.3 12.5 [33]
(n = 27)

HER2 exon 20 mutation

poziotinib phase II 27% 5.5 15 [34]
(n = 30)

phase II HER2 exon 20 mutation

poziotinib 27.8% 5.5 n/a [35]
(ZENITH20) (n = 90)

EGFR Exon 20 insertion,

HER2 activating mutation,
phase II or any solid tumors with HER2 cohort:
tarloxotinib n/a n/a [36]
(RAIN-701) NRG1, EGFR, HER2 or 22%
HER4 fusion
(n = 23; HER2 n = 11)
Cancers 2022, 14, 4155 8 of 16

Table 3. Cont.

Overall Median PFS Median OS

Drug Trial NSCLC population (n) Ref
Response Rate (Months) (Months)

phase II HER2 exon 20 mutation

afatinib 8% 15.9 weeks 56.0 weeks [37]
(NICHE) (n = 13)

afatinib HER2:
afatinib HER2:
EGFR and HER2 17 weeks
afatinib ± 0% afatinib +
phase II (n = 41; HER2 exon 20 afatinib + paclitaxel n /a [38]
paclitaxel paclitaxel
mutation n = 7) (EGFR and HER2):
HER2: 33.3%
6.7 weeks

phase II neratinib: 0% neratinib: 3.0 neratinib: 10.0

neratinib ± HER2 exon 20 mutation
(PUMA-NER- neratinib + neratinib + TEM: neratinib + TEM: [39]
TEM (n = 60)
4201) TEM: 19% 4.1 15.8

HER2 exon 20 HER2 exon 20

HER2 exon 20
HER2 exon 20 mutation mutation: 12% mutation: 9.0
mutation: 3.0
dacomitinib phase II (n = 26) or amplification HER2 HER2 [40]
HER2 amplification:
(n = 4) amplification: amplification:
n/a a
0% n/a a
PFS: progression free survival; OS: overall survival; IHC: immunohistochemistry; n/a: not available;
TEM: temsirolimus. a Range for PFS was 1–5 months, and range for OS was 5–22 months.

3.3.1. Pyrotinib
Preclinical and phase I clinical data from breast cancer indicate that pyrotinib can
irreversibly inhibit multiple HER receptors (EGFR/HER1, HER2, and HER4) and HER2
overexpressing cells in vitro and in vivo. Studies have shown a 19–53% ORR and a median
PFS of 5–6 months in pretreated HER2 mutant NSCLC, even in patients that received prior
HER2 directed therapy [30–32]. HER2 mutant patients with non-exon 20 mutations had an
ORR comparable to exon 20 mutations [32]. Pyrotinib has also been studied in in HER2
amplified NSCLC, demonstrating an ORR of 22.2%, and PFS of 6.3 months. The presence of
other mutations (HER2, EGFR, or TP53) was not associated with ORR, PFS, or OS in HER2
amplified NSCLC [33]. AEs from pyrotinib included diarrhea, elevated blood creatinine,
vomiting, and anemia [31,32]. Pyrotinib is a promising agent for HER2 mutant NSCLC and
further investigation is in progress in clinical trials.

3.3.2. Poziotinib
Poziotinib is an irreversible EGFR/HER1, HER2, and HER4 receptor inhibitor. Its
smaller size and more flexible structure help circumvent steric hindrance in the drug-
binding pocket from HER2 exon 20 insertions. In preclinical studies using in vitro and
patient-derived xenograft models of EGFR/HER2 exon 20 mutant NSCLC, poziotinib
demonstrated the most potent activity against HER2 exon 20 mutations compared to
other TKIs (erlotinib, afatinib, dacomitinib, neratinib, osimertinib, AZ5104, pyrotinib, lapa-
tinib, and irbinitinib) [41,42]. A phase II trial evaluated poziotinib in metastatic NSCLC
with HER2 exon 20 insertion mutations, and the ORR was 27% with a median PFS of
5.5 months [34]. The ZENITH20 trial was designed to evaluate poziotinib in a large,
prospective multi-cohort study (n = 603), which included a subgroup of 90 pretreated
patients with HER2 exon 20 mutations. An ORR of 28% was observed, with a median PFS
of 5.5 months. The most common AE reported were rash, diarrhea, and stomatitis, and,
notably, toxicity was not increased in patients receiving sequential immune checkpoint
inhibitors (ICI) and poziotinib [35]. Poziotinib is under active investigation for the HER2
exon 20 population in clinical trials (Table 4).
Cancers 2022, 14, 4155 9 of 16

Table 4. Select Ongoing Clinical Trials in HER2 exon 20 mutation NSCLC patients.VI. Conclusion.

Drug Mechanism of Action Development Phase Sponsor NCT Number

Trastuzumab phase III
ADC AstraZeneca NCT05048797
Deruxtecan (DESTINY-Lung04)
Pertuzumab +
Intergroupe Francophone de
Trastuzumab + Monoclonal antibody phase II NCT03845270
Cancerologie Thoracique
Docetaxel
Pyrotinib TKI phase III (PYRAMID-1) Jiangsu HengRui Medicine Co NCT04447118
Pyrotinib +
TKI phase II Shanghai Chest Hospital NCT04382300
Thalidomide
Tianjin Medical University
Pyrotinib TKI phase II NCT04063462
Cancer Institute and Hospital
Poziotinib TKI phase III (PINNACLE) Spectrum Pharmaceuticals NCT05378763
Poziotinib TKI phase II MD Anderson Cancer Center NCT03066206
Poziotinib TKI phase II Spectrum Pharmaceuticals NCT03318939
Mobocertinib TKI phase I/II Takeda NCT02716116
BDTX-189 phase
TKI Black Diamond Therapeutics NCT04209465
(tuxobertinib) I/II(MasterKey-01)
DZD9008 phase I/II
TKI Dizal Pharmaceuticals NCT03974022
(sunvozertinib) (WU-KONG1)
AST2818
TKI phase I ArriVent BioPharma NCT05364073
(furmonertinib)
BAY2927088 TKI phase I Bayer NCT05099172

3.3.3. Mobocertinib
Mobocertinib is irreversible EGFR/HER1, HER2, and HER4 receptor inhibitor with a
higher affinity for EGFR exon 20 insertions due to a covalent bond with cysteine 797 in EGFR.
It is FDA approved in NSCLC patients with EGFR exon 20 insertions, and has demonstrated
anti-tumor activity in HER2 exon 20 insertion mutants in pre-clinical models [43]. It was
particularly effective in HER2 exon 20 G776 > VC tumors, and synergistic with T–DM1 on
HER2 exon 20 YVMA tumors for both first–line and second–line settings after acquired
resistance [44]. This agent is being actively investigated in HER2 exon 20 mutated NSCLC,
and clinical efficacy data has not yet been reported [45].

3.3.4. Tarloxotinib
Tarloxotinib is designed as a prodrug that releases the activated pan-HER inhibitor,
tarloxotinib-effector, under hypoxic conditions in tumors [46]. The RAIN-701 trial evaluated
tarloxotinib in NSCLC patients with an EGFR exon 20 insertions or HER2 activating
mutations after platinum-based chemotherapy, and in any solid tumors with an NRG1,
EGFR, HER2 or HER4 fusion. Among the 9 evaluated patients with HER2 mutation, an
ORR of 22% was observed. This agent is no longer being developed as monotherapy [36].

3.3.5. Afatinib
Afatinib is an irreversible EGFR/HER1, HER2, and HER4 receptor inhibitor. While
afatinib is approved in metastatic NSCLC with activating EGFR mutations, it has shown
disappointing efficacy in HER2 mutated NSCLC. [47] While afatinib showed promise in
preclinical studies [47], afatinib monotherapy in 13 patients with HER2 exon 20 mutated
NSCLC after platinum-based chemotherapy had only an 8% ORR and a median PFS of
15.9 weeks in the NICHE trial [37]. Similarly, an ORR of 0% and a median PFS of
17 weeks were observed in 7 patients with HER2 exon 20 mutated NSCLC receiving
afatinib monotherapy. There was one response out of three HER2 exon 20 mutant NSCLC
Cancers 2022, 14, 4155 10 of 16

patients receiving combination afatinib and paclitaxel [38], with AE including diarrhea,
vomiting, abdominal pain. There are no strong data supporting afatinib monotherapy
for the treatment of HER2 exon 20 mutant NSCLC, and the data on afatinib combination
therapy is limited.

3.3.6. Neratinib
Neratinib is an irreversible EGFR/HER1, HER2, and HER4 receptor inhibitor. Ner-
atinib showed good antitumor activity against multiple HER2 mutations in preclinical
studies; the addition of an mTOR inhibitor to a HER2 inhibitor resulted in synergistic tumor
growth inhibition in breast and lung cancer cell line and mouse models [48,49]. However,
this was not replicated in human studies, and neratinib monotherapy led to no objective
responses in HER2 mutant NSCLC patients [39,50]. A modest response was observed with
the combination of neratinib and temsirolimus, with an ORR of 19% seen in the PUMA-
NER-4201 trial selected for HER2 exon 20 mutations [39]. The primary AE of neratinib in
combination with temsirolimus were diarrhea, nausea, and increased stomatitis.

3.3.7. Dacomitinib
Dacomitinib is an oral TKI that irreversibly inhibits the EGFR/HER1, HER2, and
HER4, and has been shown to have promising efficacy in EGFR lung cancer studies [51].
Twenty-six NSCLC patients with HER2 exon 20 mutations and 4 patients with HER2
amplifications were treated with dacomitinib in a multicenter phase II trial. The ORR was
12% and 0% in HER2 exon 20 mutant and HER2 amplified patients, respectively, [40].

3.3.8. Summary of Evidence regarding HER2 TKIs

Overall, while there has been progress on TKIs for HER2 altered NSCLC, patient
numbers are low and clinical efficacy appears modest relative to TKIs targeting other
NSCLC oncogenes (ie EGFR, ALK, ROS1). Less selective HER2 TKIs, including afatinib,
neratinib, and dacomitinib, have had disappointing results with low or no objective tumor
response. More selective HER2 TKIs, such as poziotinib, mobocertinib and pyrotinib, have
demonstrated a better affinity for EGFR and HER2 exon 20 variants. Accordingly, these
agents have shown ORR in the 22–28% range and are being actively studied. Further work
is needed to improve upon the clinical efficacy and toxicity management for HER2 TKIs.
Similar to ADCs, the more selective HER2 TKIs show promise in becoming a cornerstone
of HER2-directed therapy in the coming years.

3.4. Immunotherapy
While immune checkpoint inhibitors (ICI) are a key part of NSCLC management,
retrospective data have shown limited benefit of ICI in NSCLC patients with actionable
oncogenic alterations. Hypotheses for poor response to ICIs in lung cancers with driver mu-
tations such as EGFR are a lower tumor mutation burden and a “cold”, immunosuppressive
tumor microenvironment [52].
One retrospective study evaluating ICI in 551 patients with NSCLC with various
oncogenic alterations included 29 patients had HER2 exon 20 activating mutations. The
ORR was 19% for all patients with oncogenic drivers, and it was 7% for patients with HER2
mutated NSCLC. Among the patients with HER2 mutated NSCLC, the median PFS was
2.1 months [53].
A similar retrospective study of 122 patients with HER2 mutated NSCLC included
26 patients that were treated with ICI. PD-L1 expression was <1% in 67 patients (77%),
1–49% in 9 patients (10%), and ≥50% in 11 patients (13%). Relative to a cohort of NSCLC
patients that were not biomarker-selected, PD-L1 expression was lower among patients
with HER2 mutations. The ORR to ICI was 12%, and these responses were observed in
patients with HER2 non-exon 20 (non-HER2 YVMA) mutations. In these three patients, the
median PFS was 1.9 months and the median OS was 10.4 months [54].
Cancers 2022, 14, 4155 11 of 16

Another retrospective multicenter study analyzed clinical characteristics and outcomes

among patients with BRAF-, HER2-, MET-, or RET-mutated NSCLC treated with ICI.
Twenty-three out of 107 patients had HER2 exon 20 mutations. Median PFS and OS were
4.7 months and 16.2 months, respectively, for the entire cohort. Among patients with HER2
mutated disease, the ORR was 27% (6 PR), median PFS was 2.2 months, and median OS
was 20.4 months [55].
These studies indicate that patients with HER2 mutated NSCLC have limited ben-
efit from ICI monotherapy, possibly due to similar underlying biology as other tumors
with driver oncogene. Patients with HER2 mutated NSCLC are more likely to be never
smokers [3], thus may have a “cold” tumor immune microenvironment. An analysis of
TCGA (The Cancer Genome Atlas) evaluated associations between HER2 mutated solid
tumors and immune features. This study showed that HER2 mutation was associated
with microsatellite instability, tumor mutation burden, and improved response to immune
checkpoint inhibitor therapy [56]. In contrast, in a recent study in EGFR and HER2 exon
20 insertion mutated patient NSCLC tumors, the average tumor mutational burden was
3.3 mutations/Mb and response to anti-PD1 blockade therapy was low [57]. This suggests
that the immune biology of HER2 mutated tumors are likely heterogeneous across different
tumor types and HER2 mutated NSCLC may have a similar biology as that observed for
EGFR mutated NSCLC, although this needs to be elucidated further.
Given the limited clinical benefit of ICI in HER2 mutated NSCLC, targeted therapies
and chemotherapy should be considered for patients before considering immunotherapy
as a single agent. The additive benefit of ICI in combination with chemotherapy in HER2
mutated NSCLC is likely low although this has not been established in clinical trials.
Preclinical data in mouse models suggest that combination therapy with T-DXd and anti-
PD1 antibody may be more effective than either monotherapy [58]. Since drugs such as
T-DXd might increase T-cell activity and upregulate PD-L1 expression, ICI in combination
with HER2 therapy remains a future area of investigation.

3.5. Cytotoxic Chemotherapy

Data on the use of cytotoxic chemotherapy, specifically in HER2-altered NSCLC are
limited. Wang et al. found that HER2 mutated NSCLC has inferior outcomes with first
line pemetrexed based chemotherapy relative to NSCLC with other oncogenic driver muta-
tions, with reduced PFS compared with ALK/ROS1-rearranged patients (5.1 months vs.
9.2 months, p = 0.004). Furthermore, there was a trend toward reduced PFS with exon
20 A775_G776insYVMA mutation compared to other HER2 variants (4.2 vs. 7.2 months,
p = 0.085) [59]. In a retrospective study, Cappuzzo et al. tested tumor samples from
184 NSCLC patients for HER2 gene copy number (28.8% HER2 by FISH) and found that
HER2 gene copy number was not associated with response to first line chemotherapy.
However, this analysis was based on post hoc testing of tumor samples, and this study
pre-dated the incorporation of pemetrexed-based chemotherapy regimens into the treat-
ment of non-squamous NSCLC [60]. The Cancer and Leukemia Group B evaluated if
expression of HER2 was predictive of response to chemotherapy or survival in unresectable
NSCLC patients in a retrospective study; HER2 overexpression did not predict response
to chemotherapy or survival [61]. Finally, a study evaluated the treatment outcomes of
44 patients with HER2 mutated NSCLC and observed that first line pemetrexed based
chemotherapy led to numerically longer progression-free survival (5.9 vs. 4.6 months, not
statistically significant) compared to HER2-TKI therapy, although overall survival was
numerically longer in patients who received HER2 directed therapy as first line (10.8 vs.
9.8 months, not statistically significant) [62].
Overall, these data suggest that HER2 exon 20 mutated NSCLC may be less responsive
to chemotherapy relative to NSCLC with other driver mutations, however, whether a HER2
directed therapy will be superior to chemotherapy remains unanswered and will need to
be investigated in future studies.
Cancers 2022, 14, 4155 12 of 16

4. Practical Treatment Considerations

As more data on different HER2 alterations emerge, the term “HER2-positive” is no
longer sufficient. To clarify which patients respond to therapy, patients in HER2 targeted
therapy studies should be defined by the specific HER2 alteration [10]. In particular, the
HER2 exon 20 insertion mutant population represents a significant unmet clinical need
in NSCLC. A consensus for HER2 alteration testing in NSCLC by experts from academic
centers in the United States, China, Japan, and South Korea was recently published as an
effort to improve standardization [63].
Upfront HER2 mutation testing, preferentially sequencing for exon 20 mutations,
has been suggested as part of a larger routine testing panel using NGS. Since diagnostics
and treatment in HER2 amplification and overexpression is limited, routine testing in all
NSCLC is not recommended. However, HER2 amplification testing can be considered to
guide treatment, such as in cases of acquired resistance to EGFR TKI therapy [63]. The
practical challenges of obtaining sufficient tissue from patients can limit the ability to test
for the growing list of actionable genomic alterations, including the heterogeneity of HER2
alterations. Liquid biopsies can be a useful alternative when tissue is insufficient. A wide
variety of HER2 mutations, including exon 20 insertions, have been successfully detected
in ctDNA from a large series of >8000 NSCLC liquid biopsy cases [64].
The influx of investigational HER2-directed agents has been particularly robust in
the last decade, yet, currently, there is only one FDA-approved HER2-targeted therapy
for NSCLC. Platinum-based chemotherapy remains the preferred first line of therapy at
this time. T-Dxd was just recently approved for patients with advanced and metastatic
HER2 mutant NSCLC who have received prior systemic therapy. Patients should consider
enrolling in HER2 targeted therapy clinical trials during any line of treatment when pos-
sible. In the future, as more ADCs and TKIs are approved by regulatory bodies, optimal
sequencing of these agents will depend on more mature efficacy data from clinical trials
and toxicity profiles. Where immunotherapy should be sequenced in treatment remains
unclear, and likely will depend on the timing of HER2-directed therapies. Furthermore, the
safety of HER2 ADCs and TKIs after immunotherapy is unknown at this time. Therefore,
the use of immunotherapy likely will need to be reserved for later lines of therapy.
An important challenge in the administration of HER2 agents is the potentially sig-
nificant cutaneous and GI toxicities from EGFR inhibition in HER2-targeted therapies.
For example, poziotinib was associated with high proportions of grade ≥ 3 rash (48.9%)
and diarrhea (25.6%). All 25 patients who achieved PR on the trial required a dose inter-
ruption and 22 required a dose reduction [35]. Pyrotinib was also associated with any
grade diarrhea and anemia in 85.9% and 35.9% of patients [33]. In patients with EGFR
exon 20 mutated NSCLC receiving mobocertinib, 83% had diarrhea of any grade, and 21%
of all patients had grade ≥ 3 diarrhea [45]. For T-DXd, ILD has been reported as a rare but
serious AE, particularly in patients who received immunotherapy prior [19]. This indicates
the importance of proactive side effect management during HER2 targeted therapy.

5. Future Directions
Initial outcomes of HER2-directed therapies have been disappointing, likely due to
lack of appropriate patient selection in clinical trials, lack of target selectivity in case of TKI
therapies such as afatinib and lack of mechanistic understanding for antibody-based thera-
pies in HER2 altered NSCLC. However, significant strides have been made in the past few
years with the recognition of the HER2 exon 20 insertion mutation as an oncogenic driver
mutation and improved patient selection for this biomarker in clinical trials. Promising
therapies have now emerged, notably the newly FDA approved trastuzumab deruxtecan,
as well as poziotinib and pyrotinib. Future and ongoing studies aim to obtain mature
efficacy and toxicity data of these agents and to clarify their role in the overall treatment
journey of a patient. For example, DESTINY-Lung04 (NCT05048797) is a phase 3 study
that compares trastuzumab deruxtecan to platinum-based chemotherapy in the first line
setting. The primary endpoint is PFS, and the results of this study will provide data on the
Cancers 2022, 14, 4155 13 of 16

key question of optimal first line therapy in this patient population. Similarly, PINNACLE
(NCT05378763) is a phase 3 study that compares poziotinib to docetaxel in patients who
have had prior systemic therapy, with PFS as the primary endpoint. This study will address
the role of poziotinib after initial treatment with platinum-based chemotherapy.
Additionally, several clinical trials are actively investigating novel TKIs such as
BDTX-189, DZD9008, AST2818 and BAY2927088 (Table 4). This next generation of TKIs
are designed to inhibit ErbB mutations while sparing ErbB wildtype, with the goal of
optimizing anti-tumor efficacy without excessive toxicities [65,66].
Many opportunities remain in the field of HER2 altered NSCLC. Therapeutic investiga-
tion into HER2 over-expressed and amplified NSCLC is in its early stage and there is a need
for a more in-depth investigation into their oncogenic biology, as well as better defining
biomarkers to allow further investigation in clinical trials. The role of immunotherapy in
HER2 altered NSCLC remains unclear and while there is unlikely to be a clinical trial of
immunotherapy specifically in this patient population, a better understanding of the tumor
immune microenvironment in HER2 altered NSCLC could allow for more rational use of
these agents in this patient population.
HER2 alterations are now recognized as important oncogenic alterations in NSCLC.
While HER2 amplification and overexpression are less defined in NSCLC, the HER2 exon
20 mutation is now a well clinically validated biomarker. Novel TKIs and ADC-based
therapies offer higher response rates and improved survival in HER2 altered NSCLC; these
therapeutic breakthroughs and increasing understanding of HER2 pathways bring hope
for this challenging disease.

Author Contributions: Conceptualization, C.S.B.; Data curation, N.F.U.; Writing—original draft

preparation, NFU; Writing—reviewing and editing, N.F.U., C.M.M. and C.S.B. All authors have read
and agreed to the published version of the manuscript.
Funding: C.M.M. received research funding from Merck & Co.; C.S.B. received consulting fees from
AstraZeneca, Blueprint Medicines, Daiichi, Takeda, TurningPoint Therapeutics, Guardant Health,
Pfizer, Jansen, Regeneron and Silverback Therapeutics. She also received research funding (funding
to institution) from Spectrum, Turning Point Therapeutics, Daiichi Sankyo, AbbVie, AstraZeneca,
Lilly, Loxo, Jansen, Rain Therapeutics, Pfizer, Blueprint Medicines.
Conflicts of Interest: N.F.U. has no conflicts of interest.

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