The History of HER2 Inhibitors: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Yinan Zhang.

HER2 is highly expressed in a variety of malignant tumors and affects the prognosis of patients, making it a highly sensitive target for cancer therapy. Since the approval of the first HER2 inhibitor, trastuzumab, in 1998, HER2-targeted drugs have rapidly evolved. Currently, targeting HER2 drugs mainly include monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). 

  • HER2 inhibitors
  • cancer
  • antibodies
  • tyrosine kinase inhibitors
  • antibody-drug conjugates

1. Introduction

Cancer stands as a pressing global public health concern today. With the rapid advances in biotechnology, targeted therapy has surfaced as a promising treatment approach for cancer [1]. HER2, also known as ERBB2 and HER-2/neu, is a 185 kDa transmembrane protein encoded by the HER2 gene, which is situated on chromosome 17q21 [2]. HER2 belongs to the EGFR family of receptor tyrosine kinases and comprises three parts: extracellular domain (ECD), transmembrane domain (TMD), and intracellular domain (ICD) [3]. The extracellular domain can further be subdivided into four distinct subdomains (I–IV). The EGFR family includes HER 1, 2, 3, and 4. Unlike other members, HER2 lacks endogenous ligands and must form dimers with other members of the family to initiate downstream signaling pathways, such as the PI3K/Akt/mTOR and RAS-RAF-MEK-ERK pathway for cell growth and proliferation [4,5][4][5].

2. Antibodies

2.1. Trastuzumab (Herceptin)

Trastuzumab reduces tumor growth and survival by binding to the ECD subdomain IV of HER2, blocking downstream signaling pathways, and inducing antibody-dependent cellular cytotoxicity (ADCC) [21][6]. The original phase II trial demonstrated the safety and efficacy of trastuzumab in patients with HER2-positive MBC previously receiving extensive therapy [22][7]. In a phase III trial containing 469 patients with MBC and overexpression of HER2, patients received chemotherapy alone or in combination with trastuzumab [23][8]. Trastuzumab plus chemotherapy improved the median progression-free survival (PFS) by 2.8 months, median survival by 4.8 months, and objective response rate (ORR) by 18%. Cardiac dysfunction was the most significant adverse event (AE). Subsequently, NCT00004067 and NCT00005970 evaluated trastuzumab in patients with early-stage HER2-positive breast cancer. A total of 4046 patients with operable breast cancer who tested positive for the HER2 gene were enrolled in both studies and received doxorubicin plus cyclophosphamide, followed by paclitaxel with or without trastuzumab. Trastuzumab plus chemotherapy led to increased 10-year overall survival (OS) (84% vs. 75.2%) and 10-year PFS (73.7% vs. 62.2%) [24,25][9][10]. This great success has prompted trials of trastuzumab in other malignancies. In the landmark ToGA trial, trastuzumab combined with conventional chemotherapy improved OS by 2.7 months in HER2-positive advanced patients with gastric or gastro-oesophageal junction (G/GEJ) cancer compared with chemotherapy alone [26][11].

2.2. Pertuzumab (Perjeta)

Pertuzumab, an IgG1 mAb targeting the ECD subdomain II of HER2, prevents HER2 from forming dimers [27][12]. In a phase III, randomized, multicenter, international clinical trial (NCT00567190), researchers assessed the effectiveness and safety of trastuzumab, combined with pertuzumab and chemotherapy, as the first-line treatment in 808 participants who were diagnosed with HER2-positive MBC. Patients in the pertuzumab group exhibited a notably extended median PFS (18.5 vs. 12.4 months), as well as improved 8-year OS rates (37% vs. 23%) and median OS (57.1 vs. 40.8 months) compared with patients receiving trastuzumab plus chemotherapy [28,29][13][14]. These findings provided a basis for the approval of pertuzumab. Then, in December 2017, the combination of pertuzumab, trastuzumab, and chemotherapy gained approval for post-operative treatment of HER2-positive early breast cancer (EBC) [30,31,32][15][16][17]. Trastuzumab plus pertuzumab is also being studied in tumors beyond breast cancer [33,34,35,36,37,38,39,40,41][18][19][20][21][22][23][24][25][26].

2.3. Margetuximab (Margenza, MGAH22)

Margetuximab is an anti-HER2 chimeric IgG1 mAb derived from the precursor to trastuzumab that also targets the subdomain IV of HER2. Its Fc domain was engineered to boost binding to CD16A while decreasing binding to CD32B in order to further enhance the antitumor activity on the basis of trastuzumab [42][27]. In 2020, based on the findings of SOPHIA (NCT02492711), margetuximab was approved for chemotherapy combination treatment in patients with HER2-positive MBC who had previously undergone anti-HER2 regimens [43,44][28][29]. In this randomized phase III trial, researchers found that margetuximab plus chemotherapy exhibited better PFS over trastuzumab plus chemotherapy (median, 5.8 vs. 4.9 months) [45][30]. Margetuximab is also being studied for HER2-positive gastro-oesophageal adenocarcinoma. For instance, 95 participants were enrolled and treated with margetuximab plus pembrolizumab in a phase I/II single-group trial (NCT02689284). Among the response-evaluable population, the ORR, disease control rate (DCR), median PFS, and OS were 18.48%, 53%, 2.73 months, and 12.48 months, respectively [47][31]. 

2.4. Inetetamab (Cipterbin)

Inetetamab, a novel mAb binding to the HER2 receptor ECD subdomain IV, is currently only available in China and has been approved in combination with vinorelbine for HER2-positive breast cancer patients who have undergone chemotherapy by China National Medical Products Administration (NMPA) in July 2020. Like margetuximab, the Fc domain of inetetamab was engineered to produce a stronger ADCC effect. Patients receiving inetetamab and vinorelbine had longer PFS (39.1 vs. 14.0 weeks), higher ORR (46.7% vs. 18.45%), and DCR (79.72% vs. 45.63%) than patients receiving vinorelbine alone in a phase III trial [48][32].

2.5. Zanidatamab (ZW25)

Bispecific antibodies (bsAbs) feature two different binding domains that allow them to attach to two antigenic epitopes simultaneously [49][33]. With the unique concept and incomparable advantages of mAbs, bsAbs are considered to be the next generation antibody. In the last decade, nine bsAbs have gotten FDA approval, seven of which are indicated for tumors. ZW25 is an IgG1 bispecific, biparatopic antibody binding to the ECD II and ECD IV domain of HER2 and has greater antitumor activity than trastuzumab plus pertuzumab preclinically through multiple antitumor mechanisms such as sufficient saturation binding to tumor cells [50][34]. In a phase I trial [51][35], ZW25 was well tolerated, with no dose-limiting toxicities. Diarrhea was the most common AE, and no treatment-related serious AEs or deaths occurred. Overall, among 83 evaluable HER2-expressing patients, 37 patients had an OR (ORR 31%; 95% CI 27.0–49.0), including 8 patients with biliary tract cancer (38%), 10 patients with colorectal cancer (38%), and 13 patients with other cancer types (36%).

2.6. Others

1E11, a HER2-targeted mAb binding to ECD subdomain IV, inhibited tumor growth when combined with trastuzumab in the preclinical model of gastric cancer [53][36]. KN026, a new bsAb based on trastuzumab and pertuzumab, exhibited comparable efficacy as the two drugs in patients with HER2-positive MBC [54][37]. Furthermore, KN026 demonstrated favorable safety and antitumor activity for patients with advanced G/GEJ cancer having high-level HER2 expression [55][38]. There are presently a dozen clinical trials of KN026 registered at ClinicalTrials.gov, primarily involving breast cancer and G/GEJ cancer. MBS301, another bsAb that has been glycoengineered from trastuzumab and patuzumab, is currently being studied in HER2-positive recurrent or metastatic tumors (NCT03842085) [56][39].

3. Tyrosine Kinase Inhibitors

3.1. Lapatinib (Tykerb)

Lapatinib is the first TKI targeting HER2 to be approved that reversibly competes with adenosine triphosphate for its binding site on the tyrosine kinase domain and inhibits downstream pathways and tumor cell proliferation [15][40]. Combination therapy (lapatinib plus capecitabine) was well tolerated and reduced disease progression events (49 vs. 72) and extended PFS (8.4 vs. 4.4 months) in a large phase III trial for HER2-positive patients with locally advanced or metastatic breast cancer, which established its initial approval in 2007 [57,58][41][42].

3.2. Neratinib (Nerlynx, HKI-272)

Neratinib is an irreversible, pan-HER TKI that inhibits the proliferation of tumor cells by reducing EGFR and HER2 autophosphorylation and inhibiting the downstream pathways including MAPK and AKT [59][43]. The ExteNET (NCT00878709) enrolled 2840 participants with HER2-positive EBC who had already undergone the standard duration of trastuzumab treatment. In this trial, neratinib as an extended adjuvant therapy reduced the invasive disease-free survival (iDFS) events, but meaningful improvement in OS was not observed [60,61][44][45]. TBCRC 022 showed good effects of combining neratinib with capecitabine for the treatment of HER2-positive breast cancer and central nervous system (CNS) metastases [62,63][46][47]. Cristina Saura et al. found that the combination treatment extended PFS and reduced the interventions for CNS disease compared to lapatinib plus capecitabine [64][48].

3.3. Tucatinib

Tucatinib is a highly selective TKI targeting HER2 without significantly affecting EGFR [66][49]. Tucatinib has demonstrated therapeutic activity both as a single agent and in combination with chemotherapy or other HER2 inhibitors. In the HER2CLIMB trial, the use of tucatinib in combination with trastuzumab and capecitabine improved OS (21.6 vs. 12.5 months) in patients with HER2-positive MBC over those in the placebo-combination group with acceptable toxicity and also improved CNS-PFS (9.9 vs. 4.2 months) among the patients with brain metastases [67,68,69,70][50][51][52][53]. Based on these findings, tucatinib got the FDA approval in 2020 for the treatment of HER2-positive MBC, including brain metastatic. Furthermore, in the MOUNTAINEER trial, tucatinib was given with trastuzumab for patients with refractory HER2-positive metastatic colorectal cancer (mCRC). The trial reported an impressive ORR of 38% and demonstrated favorable safety profiles, which subsequently led to the FDA’s accelerated approval of tucatinib in January 2023 for this specific patient population [71,72][54][55].

3.4. Pyrotinib

Pyrotinib is an oral irreversible dual ErbB TKI developed by Jiangsu Hengrui Medicine and is applied and explored only in China at present. In August 2018, pyrotinib plus capecitabine was used for HER2-positive advanced or metastatic breast cancer [73][56]. Pyrotinib plus capecitabine showed activity and safety, with significant improvement in ORR and PFS when compared to the use of lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer [74,75,76][57][58][59].

3.5. Poziotinib (HM781-36B)

Poziotinib is an irreversible pan-HER inhibitor that can bind in multiple sites of the HER family and inhibits downstream pathways [80][60]. Preclinical studies demonstrated its antitumor potency in HER2-amplified or HER2-mutant cancer models [81,82,83][61][62][63]. Poziotinib exhibited clinical benefit in HER2 exon 20-mutated NSCLC with an ORR of up to 39% with a manageable toxicity profile [84,85,86][64][65][66]. The main AEs reported were diarrhea and stomatitis. The NOV120101-203 trial showed the meaningful activity of poziotinib in patients with HER2-positive MBC, with a PFS of 4.04 months [87][67].

3.6. Others

Epertinib (S-222611) is a reversible and selective TKI of EGFR and HER2 that exhibited great antineoplastic activity over lapatinib in the preclinical study and is well tolerated in patients with solid tumors [89,90][68][69]. In a phase Ib trial, epertinib exhibited an ORR of 16% in HER2-positive breast cancer and 8.3% in upper gastrointestinal cancer [91][70]. Epertinib combined with trastuzumab also showed good effective antitumor activity in HER2-positive MBC patients who had previously undergone treatment [92][71]. DZD1516 is a highly selective HER2-target drug that possesses the ability to penetrate the blood–brain barrier. It is presently being evaluated in a phase I study (NCT04509596). JBJ-08-178-01 is synthesized to treat HER2-mutant tumors and has represented great growth inhibition in HER2 exon 20-mutated NSCLC models [93][72].

4. Antibody–Drug Conjugates

4.1. Trastuzumab Emtansine (T-DM1, Kadcyla)

ADCs are currently the fastest growing and promising class of antitumor drug that consist of three key elements: antibodies that target specific antigens, cytotoxic drug payloads, and linkers that can or cannot be cut [94][73]. Therefore, ADCs combine antibody cancer specificity with chemotherapeutic cytotoxicity and reduce toxic side effects on normal cells. A hundred years ago, it was proposed that there was a “magic bullet” drug that could specifically eliminate tumor cells through toxins and targeting agents. This idea became a reality eighty years later, with the first successful ADC. As of August 2023, there are two ADCs targeting HER2 approved by the FDA, one approved by the NPMA, one under review, and many more in clinical development. On 22 February 2013, T-DM1 developed by Genentech and ImmunoGen got the FDA approval for the indication of second-line monotherapy in patients with HER2-positive MBC with prior trastuzumab and taxane treatment, either individually or together [95][74]. Mertansine (DM1), a tubulin disruptor that inhibits mitosis and induces apoptosis, is linked to trastuzumab via an irreducible thioether linker. Every T-DM1 contains a trastuzumab molecule and an average of 3.6 DM1 molecules [96][75]. T-DM1 outperformed non-conjugated trastuzumab in preclinical models of HER2-positive breast, lung, and gastric cancer [96,97,98][75][76][77]. The first-in-human study of T-DM1 in HER2 breast cancer patients revealed a favorable tolerability profile and strong antineoplastic activity [99][78]. The landmark EMILIA trial enrolled 991 HER2-positive MBC participants who had previously been treated (NCT00829166). Patients randomly received T-DM1 or capecitabine and lapatinib.

4.2. Trastuzumab Deruxtecan (T-DXd, DS-8201, Enhertu)

T-DXd consists of three components: trastuzumab, a topoisomerase I inhibitor deruxtecan (DXd) that induces irreversible DNA damage and prevents DNA replication, and a novel cleavable linker with superior stability [110][79]. The molecular ratio of DXd to antibody is 7–8. T-DXd is the second approved ADC targeting HER2 after T-DM1 and has stronger effects and therapeutic potential due to its excellent structure. In December 2019, given the DESTINY-Breast01 (NCT03248492), the FDA gave fast track approval for T-DXd indicated for unresectable or metastatic HER2-positive breast cancer treated with HER2-targeted agents [111][80]. In the DESTINY-Breast03 trial (NCT03529110) comparing the effectiveness and safety of T-DXd and T-DM1 in HER2-positive patients with MBC, T-DXd exhibited substantially higher median PFS and OS than T-DM1, which reaffirmed T-DXd for second-line treatment [112][81]. Since T-DXd was first approved, numerous clinical studies have been conducted to explore the ADC in breast cancer with low HER2 expression and other tumors. In January 2021, the approval of T-DXd was granted for patients with locally advanced or metastatic HER2-positive gastric cancer who previously received a trastuzumab-based therapy as a result of the DESTINY-Gastric01 trial (NCT03329690) [19][82].

4.3. Disitamab Vedotin (RC48, Aidixi)

RC48 is composed of a new HER2-targeted mAb hertuzumab, an antimitotic agent monomethyl auristatin E (MMAE), and a cleavable stable linker, exhibiting antitumor effects by inhibiting HER2 phosphorylation, inducing cell cycle arrest and apoptosis [113,114][83][84]. Preclinical studies and a phase I trial yielded good results in HER2-positive solid tumors [114,115][84][85]. RC48 was approved in June 2021 by NMPA for the treatment of patients with HER2-overexpressing locally advanced or metastatic G/GEJ cancer who have had more than one type of systemic chemotherapy regimens.

4.4. Trastuzumab Duocarmazine (SYD985)

SYD985 consists of trastuzumab linked to a DNA alkylating agent (seco-DUBA) based on duocarmycins via a cleavable peptide linker [118][86]. SYD985 showed good antitumor activity in HER2-expressing breast, ovarian, and uterine cancer in vitro and in vivo [119,120,121,122][87][88][89][90]. The first-in-human trial (NCT02277717) found that SYD985 was well tolerated in refractory cancer patients with various HER2 statuses. The most common treatment-related severe AEs are infusion-related reactions and dyspnea. A promising efficacy was observed in patients with HER2-positive breast cancer (ORR 43%) and HER2-low breast cancer (ORR 28%) [123][91]. These study findings led to SYD985 receiving fast-track designation from the FDA.

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