In the mid-1970s, scientists discovered that certain genes, when mutated, can cause cancer. Based on this observation they theorized that by targeting these oncogenes, or the proteins they code for, they could potentially prevent the spread of cancer.
This basic understanding resulted in the discovery and further identification between 1982 and 1986 of the human epidermal growth factor receptor 2 or HER2-gene (also known as erbB2/neu, ErbB2, or HER2/neu), an EGFR-related tyrosine kinase receptor known to be an oncogene that causes cancer to develop and grow. This basic discovery helped scientists to better understand the functionality of HER2 and implicate it in the pathogenesis of human cancer. This, in turn, unleashed a powerful tool that helped save the lives of many men and women diagnosed with cancer.
The initial development and discovery of HER2, a member of a family of four closely related
receptors (HER1, HER2, HER3, and HER4) that exist in various combinations in a number of different tissues, resulted in what became known as the HER2 oncogene hypothesis, leading to a better understanding of the biology of cancer and, over time, a revolution that still yields results today.
In simple terms, HER2, a transmembrane protein consisting of an extracellular binding domain, a transmembrane fragment, and an intracellular domain with tyrosine kinase activity, instructs cells in the body to form receptors on their surface that send signals telling them to grow and divide. This process is part of the normal mechanism that regulates the growth, division, and repair of healthy cells.
Beyond breast cancer
In about a quarter of cancers, for example in breast cancer, scientists observed higher than normal levels of the HER2 gene. This meant each of these cells didn’t just have the standard 20,000 HER2 receptors but, in contrast, up to 2 million of them, triggering the cancer cells to replicate out of control and the tumors to grow.
Over time, this overexpression of HER2, which occurs in approximately 20–25% of invasive breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment, eventually became known as “HER2-positive” (HER2+) breast cancer.
Mutations and amplification of HER2 and HER2 overexpression represent biologically distinct alterations that can harbor driver oncogenic properties, and, as a result, the discovery of the HER2 gene generated high expectations for the treatment of different cancers carrying HER2 aberrations, including breast cancers but also gastric cancers and non–small-cell lung cancer (NSCLC).
HER2 amplification is recognized as a frequent molecular abnormality and therapeutic target in both breast and gastric cancer, while the development of HER2 inhibition for the treatment of lung cancer was, in turn, inspired by the successful therapeutic history of targeting HER2 amplification in breast cancer.
In the decades since the early discovery of HER2, passionate scientists using basic science, including Alex Ullrich, Ph.D., H. Michael Shepard, Ph.D., Dennis J. Slamon, MD, at that time a practicing oncologist at UCLA’s Jonsson Cancer Center, and many others, have laid the groundwork that, thanks to the discovery of a monoclonal antibody that binds to the extracellular domain of HER2, resulted in trastuzumab (Herceptin®; Genentech).
The hard work of these scientists demonstrated that cancer can be treated by identifying the underlying molecular defects and that it is possible to develop targeted agents to treat patients diagnosed with such cancer.
From 4D5 to Trastuzumab
The murine monoclonal antibody 4D5, which is directed against the extracellular domain of HER2 and from which trastuzumab is derived, is a potent inhibitor of cytostatic growth of human breast cancer cells overexpressing HER2.  However, in early development, scientists found that the clinical use of 4D5 was limited by the genesis of human anti-mouse antibodies.  To counter this problem and to further facilitate clinical research, a 4D5 antibody was humanized by “replacing” the original mouse-derived components, except the antigen-binding region, with complementary human counterparts. The new recombinant humanized anti-HER2 antibody (rhuMAb HER-2), now called trastuzumab, was tested using human tumor xenograft models and demonstrated high affinity to the extracellular domain of HER2, thereby blocking its function in signal transduction.
Then, in early clinical trials, trastuzumab demonstrated no toxicities after weekly administration of the ‘new’ antibody for many months, while in open-label, multicenter clinical phase 2 studies, 10% of patients with metastatic or advanced breast cancer showed an objective partial response.  In further clinical trials, scientists noted that trastuzumab increased the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
In ongoing Phase 2 and later in Pivotal Phase 3 studies with trastuzumab, which started March 1997, scientists demonstrated that trastuzumab in combination with chemotherapy improved survival in patients diagnosed with HER2+ breast cancer.
In one study scientists found that the addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death.
Clinical data from subsequent phase 2 studies showed that many women diagnosed with HER2+ metastatic disease who had relapsed after chemotherapy had a response to trastuzumab  as suggested by the preclinical data. Another study demonstrated that the efficacy of trastuzumab, when given in combination with the chemotherapeutic agent cisplatin, was superior to its effectiveness when used alone. The same study showed in approximately 28% of all patients, trastuzumab, in combination with cisplatin, did not show evidence of tumor progression at one year compared to 14% of the patients treated with chemotherapy alone without increases in overall severe adverse events. 
Trastuzumab entered clinical development in 1991 and was approved in October 1998. This development was, without a doubt, a milestone, one major battle won in what has been dubbed the ‘War on Cancer,’ and others have called the dawn of “personalized medicine.”
However, while trastuzumab demonstrated clear evidence of clinical activity in patients treated with HER2+ metastatic breast cancer, showing a 20% decrease in the risk of death compared with standard chemotherapy, it would take until 2006 that the use of trastuzumab was expanded to include adjuvant treatment of HER2+ breast cancer.
The expansion was based on the results of a joint interim analysis of clinical data from more than 3,500 patients, published in May 2005. The data demonstrated a remarkable 50% reduction of the risk of relapse and a 33% in the risk of death. These results represented another major milestone in breast cancer research. It also gave real hope to women diagnosed with early-stage HER2+ breast cancer.
But what the results also suggested is that trastuzumab in combination with chemotherapy could potentially prevent or
delay early-stage HER2+ breast cancer from developing
into metastatic disease.
Based on this data, the FDA, on November 16, 2006, approved trastuzumab, administered weekly, in combination with chemotherapy for the adjuvant treatment of HER2-overexpressing, node-positive breast cancer.
And while it is true that trastuzumab has been associated with a small risk of cardiotoxicity for women treated with HER2+ breast cancer, which is especially noted among older patients and among patients previously treated with anthracyclines, results from more recent studies demonstrated that trastuzumab does not cause long-term damage to cardiac function, other cardiac symptoms or overall health-related Quality of Life (hrQoL). Fortunately, only a very small number of patients may experience serious cardiac issues.
The risk of cardiotoxicity is an especially important consideration for women who are being treated for metastatic breast cancer. However, in contrast to anthracycline cardiotoxicity, patients who develop cardiotoxicity while receiving trastuzumab generally improved after discontinuation of trastuzumab. And in some cases, reintroducing trastuzumab may be appropriate for patients who previously have experienced trastuzumab-related cardiotoxicity.
Trastuzumab and Gastric cancer
Gastric cancer is difficult to treat and cure and has a poor overall prognosis and a median survival of barely 10 months. Approximate 20% of the cases overexpress HER2, and among them, the combination of trastuzumab plus chemotherapy is considered the recommended first-line treatment, increasing survival versus treatment with chemotherapy alone.
This recommendation is based on data from the multicenter ToGA study (Trastuzumab for Gastric Cancer), an open-label, international, phase 3, randomized controlled trial undertaken in 122 centers in 24 countries, in which overall survival of patients diagnosed with gastric cancer was significantly longer when they were treated with chemotherapy plus trastuzumab than with chemotherapy alone (median, 13.8 months vs. 11.1 months).
In this trial, patients with gastric or gastroesophageal junction cancer were eligible for inclusion if their tumors showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridization. Participating patients were randomly assigned in a 1:1 ratio to receive either a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil (5-FU) plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab.
The results of the study showed the superiority of the combination of trastuzumab with chemotherapy compared with chemotherapy alone in terms of overall survival: 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The results further demonstrated that the benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. based on these results, the trastuzumab plus chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or gastroesophageal junction cancer.
Trastuzumab and Lung Cancer
Globally, lung cancer is the leading cause of cancer-related death, and non–small-cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Ongoing studies have shown that targeted therapies directed toward specific molecular alterations have had tremendous success in improving the prognosis of patients diagnosed with NSCLC. New therapies that target specific oncogenic drivers are routinely recommended for all patients with metastatic or advanced (m)NSCLC that harbor specific genomic alterations, improving outcomes and health-related Quality of Life (hrQoL)
In NSCLC three types of HER2 alterations have been described, including HER2 gene amplification, HER2 overexpression, and HER2 point mutations. The incidence of HER2 protein overexpression in patients with NSCLC is 2.4%-38% and is more frequent in adenocarcinomas with well-differentiated histology. Immunohistochemistry (IHC) is the most common tissue-based assay used to detect and quantify the amount of HER2 protein.
Although there have been conflicting findings regarding the impact of HER2 overexpression on the survival of patients with lung cancer, two meta-analyses analyzed HER2 overexpression in patients with lung cancer. In one analysis of forty studies (6,135 patients) the pooled data showed that HER2 overexpression was a marker of poor prognosis (HR was 1.48 (95% CI: 1.22-1.80). 
Another analysis of data from 2,579 showed that the combined survival differences in patients with NSCLC at 1 year, 3 years, and 5 years, respectively, were 2.7% (95% confidence interval [95% CI], 1.3-6.7%; P = 0.1787), 15.2% (95% CI, 5.8-24.5%; P = 0.0015), and 16.4% (95% CI, 7.9-14.8%; P = 0.0001), suggesting significant poorer survival at 3 years and 5 years among patients with HER2 overexpression. 
Subsequent trials have demonstrated a variety of outcomes, something that may be explained by the distinct responses to trastuzumab in patients with de novo and acquired HER2 amplification. But overall, trastuzumab generally yielded disappointing results in NSCLC with a lack of response consistently been observed in NSCLC regardless of the HER2 status determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH).
Today, the explicit role of HER2 amplification, mutation, and overexpression in lung cancer remains ambiguous, confirming that HER2 alternation in lung cancer is far more complicated than in breast and gastric cancer. This, in turn, may explain why clinical studies targeting HER2-altered NSCLC have, with the exception of HER2 exon 20 mutations (which is emerging as the clearest targetable driver for HER2-directed therapies in lung cancer) yielded relatively disappointing results.
Testing remains critical
A critical element of the success of trastuzumab was the ability to accurately assess and determine the HER2 status of a tumor and identify patients who would truly benefit from HER2-targeted therapies.
And after the approval of trastuzumab determining HER2 status with technologies to assess HER2 status at the protein level (e.g. ELISA), at the RNA level (RT-PCR, microarray), and at the DNA level (fluorescence in situ hybridization, chromogenic in situ hybridization (ISH), silver in situ hybridization or multiplex ligation-dependent probe amplification), became routine. 
Because testing for HER2 gene amplification or HER2 protein overexpression is required for all primary and metastatic breast cancers, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed and published HER2 testing guidelines in 2007 with updates in 2013 and 2018.
The 2018 Focused Update was specially created to address uncommon clinical scenarios designed to improve clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. According to the ASCO/CAP guidelines, HER2 testing can be performed by looking for protein overexpression by immunohistochemistry (IHC) and in case the results are open to more than one interpretation, the test results need to be confirmed by molecular methods such as fluorescence in situ hybridization (FISH) or another in situ hybridization methods to specifically look for HER2 gene amplification. 
However, with ongoing advancements in genomics, computing, and imaging technology there remains an unmet need for further standardization with proper internal and external quality control assessment, better laboratory accreditation, and automation of tissue processing (autostainers) as well as interpretation methods (image analysis), and competency evaluation of already existing methods to ensure accurate, reliable, and clinically meaningful test results to help establish the best predictive strategy for trastuzumab response. Without a doubt, this warrants large clinical trials to help establish the best (and most robust and accurate) diagnostic assays. But until the completion of these crucial studies, the choice of how to establish HER2 status (and level) will probably be based on local preferences which consider both practical and economic issues. 
More HER2-targeting agents
Following the introduction of trastuzumab, other HER2-targeted agents have been developed for the treatment of HER2-overexpressing breast cancer. Among these agents were lapatinib, a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR; ErbB1) that prevent signaling, and HER2 and pertuzumab, a monoclonal antibody that binds subdomain II of the HER2 extracellular domain and prevents HER2 homo- and heterodimerization with other HER-family receptors.
As of April 2015, the FDA has approved five therapies for HER2-positive breast, gastric, and non-small cell lung cancer patients. But the story does not end here. Over time, a number of next generations of trastuzumab, with modifications to the original antibody, have demonstrated improved tumor-killing abilities in patients after treatment with the trastuzumab.
And while trastuzumab alone has had a huge impact on the lives of tens of thousands of patients, it has also laid the basis for new antibody-based targeted drugs, including the engineering of antibody-drug conjugates (ADC), significantly expanding patient benefit.
ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. Among this class of powerful therapeutic agents are 3 next-generation versions of trastuzumab, including [ado-] trastuzumab emtansine (Kadcyla®; Genentech/Roche), [fam-] trastuzumab deruxtecan (Enhertu®; formerly known as DS-8201; Daiichi Sankyo and AstraZeneca), and [vic–] trastuzumab duocarmazine (previously known as SYD985; Byondis).
[Ado-] trastuzumab emtansine links, via a stable thioether linker, the anti-HER2 antibody trastuzumab to the potent antimitotic agent, microtubule-inhibitory agent emtansine (also known as DM1, a derivative of maytansine), thereby primarily targeting delivering chemotherapy to cells overexpressing the HER2 receptor. After cleavage of the linker, the cytotoxic payload is released intracellularly and provides a large therapeutic index with limited systemic toxicity.
The efficacy of trastuzumab emtansine as an adjuvant, neoadjuvant, first-line, and second-line metastatic therapy for HER2+ breast cancer has been evaluated and confirmed in various randomized trials. And while there are various effective therapies for the initial management of HER2+ metastatic breast cancer exist, many patients will, over time, experience disease progression. Most second-line therapies are associated with either significant toxicities or limited improvements in overall survival (OS). However, in phase 3 clinical trials comparing the efficacy and safety of trastuzumab emtansine with lapatinib–capecitabine or physician’s choice, ado-trastuzumab emtansine had a better tolerability profile and improved progression-free survival compared with lapatinib-capecitabine or physician’s choice and increased overall survival compared with lapatinib-capecitabine.
In February 2013 the US Food and Drug Administration (FDA) approved ado-trastuzumab emtansine for the treatment of HER2+ primary or metastatic breast cancer that has progressed on trastuzumab.
Trastuzumab emtansine in lung cancer
A number of clinical trials have confirmed that trastuzumab emtansine demonstrated a true therapeutic benefit for patients diagnosed with non-small cell lung cancer (NSCLC) with HER2 mutations. Based on these results the National Comprehensive Cancer Network (NCCN) Guideline recommends trastuzumab emtansine as a targeted agent for the treatment of HER2-mutant NSCLC. .
In one phase 2 study, conducted between February 2019 and July 2020, with A775_G776insYVMA the most frequent HER2 exon-20 insertion mutation (accounting for 86.4%) being confirmed by next-generation sequencing or multiplex polymerase chain reaction (PCR) platforms and a history of one or two lines of chemotherapy, participating patients received trastuzumab emtansine (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study, objective response rate or ORR, was 38.1% (90% CI, 23.0–55.9%), with a disease control rate of 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low.
The results of this study not only demonstrate the potential benefit of trastuzumab emtansine as a treatment option for patients diagnosed with NSCLC with HER2 exon-20 insertion mutations but confirm that further investigation of biomarkers for trastuzumab emtansine is warranted to improve its efficacy for NSCLC with such mutations. 
But despite the activity of trastuzumab emtansine in the treatment of HER2+ primary or metastatic breast cancer, intrinsic and acquired resistance to the drug remains a major challenge for clinicians.
Trastuzumab emtansine mediates its activity in a variety of ways, including HER2 signaling blockade, Fc-mediated immune response, and payload-mediated microtubule poisoning. Although resistance mechanisms to each of these features have been demonstrated, scientists concluded that resistance mechanisms were most strongly supported by the experimental data related to dysfunctional intracellular metabolism of the construct and subversion of emtansine (DM1-) mediated cell killing.
Overall, as a result of resistance, the activity of trastuzumab emtansine decreased in tumors with heterogenous, reduced, or loss of HER2 expression.
Trastuzumab deruxtecan is made up of a humanized anti-HER2 monoclonal antibody produced using an identical amino acid sequence to trastuzumab and covalently linked by via a tetrapeptide-based self-immolative maleimide linker to the membrane-permeable topoisomerase I inhibitor deruxtecan (DXd), a derivative of exatecan.
One of the key differences between trastuzumab emtansine and trastuzumab deruxtecan is that the latter has a much higher drug-to-antibody ratio (DAR) than trastuzumab emtansine (8 versus 3.5). The higher DAR seen in trastuzumab deruxtecan allows for a greater payload delivery per antibody engagement, while, at the same time, avoiding rapid in vivo clearance, which can occur with high DAR and result in off-target toxicities through increased exposure to the payload in plasma.
As a result of this higher DAR and unlike trastuzumab emtansine, trastuzumab deruxtecan is effective against cancers with a low-HER2 expression that is less sensitive to trastuzumab emtansine.
Trastuzumab deruxtecan was approved for the treatment of adult patients with unresectable or metastatic HER2+ breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. In addition to HER2+ breast cancer, the drug is being developed for the treatment of other HER2-expressing solid tumors, including gastric cancer, colorectal cancer, and non-small cell lung cancer (NSCLC).
Trastuzumab deruxtecan in gastric cancer
Today, trastuzumab in combination with chemotherapy is considered a standard frontline treatment for patients with HER2-overexpressing metastatic gastric cancer. However, this treatment option offers only a modest survival advantage compared with chemotherapy alone. One of the observed benefits of trastuzumab deruxtecan is that it can kill cancer cells by the bystander effect of its payload.
And while trastuzumab has been the only agent that really worked in gastric cancer, results from a new study confirmed that trastuzumab deruxtecan may provide clinical benefit in patients who have had prior treatment with trastuzumab or trastuzumab emtansine in gastric cancer.
In one study scientists evaluated the bystander killing effect of trastuzumab deruxtecan and compared this with that of trastuzumab emtansine. They confirmed that in contrast to trastuzumab emtansine, which had a low level of permeability, the payload of trastuzumab deruxtecan was highly membrane-permeable. They also confirmed that following the internalization and release of the payload of the trastuzumab deruxtecan drug complex, the bystander killing effect of the drug was limited to cells neighboring HER2+ cells that do not express HER2, suggesting low concern in terms of systemic toxicity. Based on these observations, the scientists concluded that trastuzumab deruxtecan has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to trastuzumab emtansine. 
In a phase 1 trial, the agent demonstrated a confirmed objective response rate (ORR) of 43.2% in patients with heavily pretreated HER2+ metastatic gastric cancer who received a dose of 5.4 mg/kg or 6.4 mg/kg. 
Based on the demonstrated results from the phase 2 DESTINY-Gastric01 trial (NCT03329690) the FDA, on January 15, 2021, approved trastuzumab deruxtecan for the treatment of patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. 
The trial data showed that treatment with trastuzumab deruxtecan resulted in an improvement in overall survival (OS) compared with irinotecan or paclitaxel, at 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7), respectively, in patients with advanced, HER2+ gastric or GEJ adenocarcinoma who had progressed following a trastuzumab-based regimen (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). 
Trastuzumab deruxtecan and lung cancer
HER2 targeting has, without a doubt, transformed the treatment of patients with breast and gastric cancers. Research has shown that compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the clearest targetable driver for HER2-directed therapies in lung cancer. However, these therapies have not yet been approved for the treatment of patients with NSCLC.  One of the reasons is that the efficacy and safety of trastuzumab deruxtecan in patients with HER2-mutant NSCLC have not been investigated extensively enough. But trials are ongoing and the results of a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment, showed durable anticancer activity 
In the trial (DESTINY-Lung01) a total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). The objective response was seen in 55% of the patients (95% confidence interval [CI], 44 to 65). In addition, the median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1).
The investigators observed that the safety profile was generally consistent with those reported in previous studies. Grade 3 or higher drug-related adverse events occurred in 46% of patients, with the most common event being neutropenia, which occurred in 19% of patients. Furthermore, adjudicated drug-related interstitial lung disease was seen in 26% of patients and was fatal in 2 patients.
In the study, results were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.
Trastuzumab deruxtecan has truly generated excitement in breast and gastric cancers and as confirmed in the DESTINY-Lung01, has demonstrated early signs of promise in the treatment of patients with NSCLC with HER2 mutations or HER2 overexpression. Additional studies are needed to further explore treatment options.
Trastuzumab duocarmazine (previously known as SYD985), is a HER2-targeting antibody-drug conjugate comprised of the anti-HER2 monoclonal antibody trastuzumab, covalently bound via a cleavable linker, to the duocarmycin prodrug seco-duocarmycin-hydroxybenzamide-azaindole, also known as seco-DUBA. The prodrug is a member of a class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of DNA-alkylating and DNA-binding moieties and that bind into the minor groove of DNA.
Duocarmycins are derived from Streptomyces species and similar to calicheamicin, the members of this family of naturally occurring antitumor antibiotics are potent cytotoxic agents that cannot be used clinically on their own because of delayed toxicity, including hepatotoxicity. Like pyrrolobenzodiazepines (PBDs) duocarmycins are DNA minor groove–binding agents, forming sequence-selective covalent linkages to the N3-position of specific adenine bases.
Trastuzumab duocarmazine targets a broad range of HER2-expressing tumors such as breast cancer, endometrial (uterine) cancer, and urothelial (bladder) cancer. In preclinical trials, trastuzumab duocarmazine has demonstrated notable clinical activity in heavily pretreated patients with HER2+ metastatic cancer, including HER2+ trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile.
Trastuzumab duocarmazine beyond breast cancer
Trastuzumab duocarmazine has been investigated in a number of cancers. In one cancer, Uterine serous carcinoma (USC), an aggressive form of endometrial cancer. In one study, using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, scientists were able to confirm that trastuzumab duocarmazine demonstrated activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. They noted that the investigational drug is 10- to 70-fold more potent than trastuzumab emtansine in comparative experiments and that, unlike trastuzumab emtansine, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression.
In another study, trastuzumab duocarmazine demonstrated clinical activity against carcinosarcomas (CS), highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression.
In this study, the data confirmed that trastuzumab duocarmazine and trastuzumab emtansine induced similar levels of antibody-dependent cellular cytotoxicity (ADCC) against CS cell lines with low and high HER2/neu expression when challenged in the presence of effector cells. But in contrast, trastuzumab duocarmazine was 7- to 54-fold more potent than trastuzumab emtansine in the absence of effector cells. SYD985, unlike trastuzumab emtansine, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC50 values were 0.060 μg/mL and 3.221 μg/mL (P < 0.0001) against HER2/neu 0/1+ cell lines and 0.013 μg/mL and 0.096 μg/mL (P < 0.0001) against HER2/neu 3+ cell lines for trastuzumab duocarmazine versus trastuzumab emtansine, respectively. Importantly, unlike trastuzumab emtansine, trastuzumab duocarmazine induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells.
Additional In vivo studies confirmed that trastuzumab duocarmazine is more active than trastuzumab emtansine in CS and is highly effective against HER2/neu expressing xenografts and PDX. 
On December 23, 1971, National Cancer Act was signed into law. Last year we celebrated the 50th anniversary of this unique event which kicked off what some have dubbed the national “War on Cancer.” With enormous amounts of public funding available for cancer research, the National Cancer Act encouraged passionate and creative scientists which, in time, led to the discovery of HER2. This discovery resulted in the development of a radical, new breast cancer treatment that, and, without a doubt, sparked the precision medicine revolution and thereby changed ‘Strategies in the ‘War on Cancer.’
And while we recognize the many scientists who have paid a role in this groundbreaking research, HER2 and trastuzumab would not have been possible without the many heroic women with advanced breast cancer who volunteered to participate in clinical trials.
But the story of HER2, trastuzumab and trastuzumab-based antibody-drug conjugates is not the end, it is just the beginning. The key lesson learned is that discovery can only succeed with sustained investments in basic (molecular) research, which in time will, without a doubt not only result in a better understanding of the biology of cancer, but also to continued discoveries and developments… and powerful new drugs.
Today, the continued hard work and dogged determination of scientists and researchers trying to understand the fundamental biology by which cancer grows, in the hopes of finding new ways in treating the disease and the courage of patients and support from patient advocates have, today, been translated into more than 17 million cancer survivors in the United States in 2021.
The story of the discovery of HER2 and the development of trastuzumab and other targeted agents clearly demonstrates what is possible with a better understanding of the biology of a disease, a target to treat, well-tolerated antibodies to precisely and effectively hit the specific target and to help patients.
Over the next five decades, and with the proper investments in the infrastructure designed to increase multidisciplinary, collaborative (early) cancer research, treatment, and prevention we can continue to contribute to the reduction in cancer mortality and increase the health-related Quality of Life (hrQoL) and survival of many cancer patients.
ToGA Study – A Study of Herceptin (Trastuzumab) in Combination With Chemotherapy Compared With Chemotherapy Alone in Patients With HER2-Positive Advanced Gastric Cancer – NCT01041404
T-DM1 and Osimertinib Combination Treatment to Target HER2 Bypass Track Resistance in EGFR Mutation Positive NSCLC (TRAEMOS) – NCT03784599
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01] – NCT03329690
DS-8201a in HER2-positive Gastric Cancer That Cannot Be Surgically Removed or Has Spread (DESTINY-Gastric02) – NCT04014075
Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2+ Gastric Cancer (DESTINY-Gastric03) (DG-03) – NCT04379596
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer (DESTINY-Lung01) – NCT03505710
Highlights of prescription information
Trastuzumab (Herceptin®; Genentech) (Prescribing Information)
Trastuzumab emtansine (Kadcyla®; Genentech/Roche)(Prescription information)
Trastuzumab deruxtecan (Enhertu®; formerly known as DS-8201; Daiichi Sankyo and AstraZeneca)(Prescribing Information)
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