Trastuzumab, sold under the brand name Herceptin among others, is a
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
used to treat
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
and
stomach cancer.
It is specifically used for cancer that is
HER2 receptor positive
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
.
[ It may be used by itself or together with other ]chemotherapy medication
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
.[ Trastuzumab is given by slow injection into a vein and injection just under the skin.]
Common side effects include fever, infection, cough, headache, trouble sleeping, and rash.[ Other severe side effects include ]heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, allergic reactions
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
, and lung disease
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
.[ Use during ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
may harm the baby. Trastuzumab works by binding to the HER2 receptor
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
and slowing down cell replication.[
Trastuzumab was approved for medical use in the United States in September 1998, and in the European Union in August 2000.] It is on the World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. A biosimilar
A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved v ...
was approved in the European Union in November 2017, and in the United States in December 2018.
Medical uses
The safety and efficacy of trastuzumab-containing combination therapies (with chemotherapy, hormone blockers, or lapatinib
Lapatinib ( INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...
) for the treatment of metastatic breast cancer. The overall hazard ratios (HR) for overall survival and progression free survival were 0.82 and 0.61, respectively. It was difficult to accurately ascertain the true impact of trastuzumab on survival, as in three of the seven trials, over half of the patients in the control arm were allowed to cross-over and receive trastuzumab after their cancer began to progress. Thus, this analysis likely underestimates the true survival benefit associated with trastuzumab treatment in this population. In these trials, trastuzumab also increased the risk of heart problems, including heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
and left ventricular ejection fraction decline.
In early-stage HER2-positive breast cancer, trastuzumab-containing regimens improved overall survival (Hazard ratio
In survival analysis, the hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions characterised by two distinct levels of a treatment variable of interest. For example, in a clinical study of a drug, the treated populati ...
(HR) = 0.66) and disease-free survival (HR = 0.60). Increased risk of heart failure (RR = 5.11) and decline in left ventricular ejection fraction ( relative risk RR = 1.83) were seen in these trials as well. Two trials involving shorter term treatment with trastuzumab did not differ in efficacy from longer trials, but produced less cardiac toxicity.
The original studies of trastuzumab showed that it improved overall survival in late-stage (metastatic) HER2-positive breast cancer from 20.3 to 25.1 months. In early-stage HER2-positive breast cancer, it reduces the risk of cancer returning after surgery. The absolute reduction in the risk of cancer returning within three years was 9.5%, and the absolute reduction in the risk of death within 3 years was reduced by 3%. However, it increases serious heart problems by an absolute risk of 2.1%, though the problems may resolve if treatment is stopped.
Trastuzumab has had a "major impact in the treatment of HER2-positive metastatic breast cancer." The combination of trastuzumab with chemotherapy has been shown to increase both survival and response rate, in comparison to trastuzumab alone.
It is possible to determine the "erbB2 status" of a tumor, which can be used to predict efficacy of treatment with trastuzumab. If it is determined that a tumor is overexpressing the erbB2 oncogene and the patient has no significant pre-existing heart disease, then a patient is eligible for treatment with trastuzumab. It is surprising that although trastuzumab has great affinity for HER2 and high doses can be administered (because of its low toxicity), 70% of HER2+ patients do not respond to treatment. In fact resistance to the treatment develops rapidly, in virtually all patients. A mechanism of resistance involves failure to downregulate p27 (Kip1) as well as suppressing p27 translocation to the nucleus in breast cancer, enabling cdk2 to induce cell proliferation.
In May 2021, the FDA approved pembrolizumab
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
in combination with trastuzumab, fluoropyrimidine Fluoropyrimidines are a class of anti-cancer drugs, or more specifically antimetabolites, and include:
* Capecitabine
* Carmofur (HCFU)
* Doxifluridine
* Fluorouracil (5-FU)
* Tegafur
Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5- ...
- and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.[ ]
Duration of treatment
The optimal duration of add-on trastuzumab treatment after surgery for early breast cancer is unknown. One year of treatment is generally accepted based on clinical trial evidence that demonstrated the superiority of one-year treatment over none. However, a small Finnish trial also showed similar improvement with nine weeks of treatment over no therapy. Because of the lack of direct head-to-head comparison in clinical trials, it is unknown whether a shorter duration of treatment may be just as effective (with fewer side effects) than the accepted practice of treatment for one year. Debate about treatment duration has become a relevant issue for many public health policy makers because administering trastuzumab for a year is very expensive. Consequently, some countries with a taxpayer-funded public health system, such as New Zealand, chose to fund limited adjuvant therapy. However, subsequently New Zealand has revised its policy and now funds trastuzumab treatment for up to 12 months.
Adverse effects
Some of the common side effects of trastuzumab are flu-like symptoms (such as fever, chills and mild pain), nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
.
Cardiac toxicity
One of the more serious complications of trastuzumab is its effect on the heart, although this is rare. In 2-7% of cases, trastuzumab is associated with cardiac dysfunction, which includes congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
. As a result, regular cardiac screening with either a MUGA scan
Radionuclide angiography is an area of nuclear medicine which specialises in imaging to show the Functional imaging, functionality of the right and left Ventricle (heart), ventricles of the heart, thus allowing informed diagnostic intervention i ...
or echocardiography
An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart.
It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound.
Echocardiography has become routinely used in t ...
is commonly undertaken during the trastuzumab treatment period. The decline in ejection fraction appears to be reversible.
Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. NRG-1 activates the MAPK pathway and the PI3K/AKT pathway as well as focal adhesion kinases (FAK). These are all significant for the function and structure of cardiomyocytes. Trastuzumab can therefore lead to cardiac dysfunction.
Approximately 10% of people are unable to tolerate the drug because of pre-existing heart problems; physicians are balancing the risk of recurrent cancer against the higher risk of death due to cardiac disease in this population. The risk of cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
is increased when trastuzumab is combined with anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...
chemotherapy (which itself is associated with cardiac toxicity).
Birth control
Women having periods (or whose periods stopped due to chemotherapy) may need to use barrier contraception (such as condom
A condom is a sheath-shaped barrier device used during sexual intercourse to reduce the probability of pregnancy or a sexually transmitted infection (STI). There are both male and female condoms. With proper use—and use at every act of in ...
s) while taking trastuzumab, and for at least six months afterwards. This is because of the possibility of harming a developing fetus.
Mechanism of action
The ''HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
'' gene (also known as ''HER2/neu'' and ''ErbB2'' gene) is amplified in 20–30% of early-stage breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
s. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and recycling of HER2. It may also upregulate cell cycle inhibitors such as p21Waf1 and p27Kip1.
The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation. The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of ligands (e.g. EGF etc.) to HER receptors is required to activate the pathway. The pathway initiates the MAP kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...
pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway. In cancer cells the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). This overexpression leads to strong and constant proliferative signaling and hence tumor formation. Overexpression of HER2 also causes deactivation of checkpoints, allowing for even greater increases in proliferation.
The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called EGFs) to inside the cell, and turn genes on and off. The HER
Her is the objective and possessive form of the English-language feminine pronoun She (pronoun), she.
Her, HER or H.E.R. may also refer to:
Arts, entertainment and media Music
* H.E.R. (born 1997), American singer
**H.E.R. (album), ''H.E.R.'' ...
(human epidermal growth factor receptor) protein, binds to human epidermal growth factor, and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably.
HER2 is localized at the cell surface, and carries signals from outside the cell to the inside. Signaling compounds called mitogens
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
(specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize
A dimer () ('' di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular. Dimers also have significant implications in polymer chemistry, inorganic ch ...
), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
pathway and the MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
). ERBB2 is the preferred dimerization partner for the other family members and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. It has been reported that Trastuzumab induces the formation of complementarity-determining regions (CDRs) leading to surface redistribution of ERBB2 and EGFR in CDRs and that the ERBB2-dependent MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
phosphorylation and EGFR/ERBB1 expression are both required for CDR formation. CDR formation requires activation of both the protein regulator of actin polymerization N-WASP
Neural Wiskott-Aldrich syndrome protein is a protein that in humans is encoded by the ''WASL'' gene.
The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors ...
, mediated by ERK1/2, and of the actin-depolymerizing protein cofilin
ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contractio ...
, mediated by EGFR/ERBB1. Furthermore, this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation.
Normal cell division—mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
—has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2
Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
(CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. This is caused by phosphorylation by Akt.
Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Monoclonal antibodies that bind to this region have been shown to reverse the phenotype of HER2/neu expressing tumor cells. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT. In addition, trastuzumab suppresses angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as CDKN1B
Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the ''Cip/Kip'' family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded pro ...
. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.
Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...
is another important mechanism of action.
Predicting response
Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are conducted out on clinical specimens to obtain information about the health of a patient to aid in diagnosis, treatment, and prevention of disease. Clinical Medical labor ...
, the most commonly employed methods for this are immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
(IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature. It is also possible to estimate ''HER2'' copy number from microarray data.
There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest and Ventana Pathway. These are highly standardised, semi-quantitative assays which stratify expression levels into; 0 (<20,000 receptors per cell, no visible expression), 1+ (~100,000 receptors per cell, partial membrane staining, < 10% of cells overexpressing HER-2), 2+ (~500,000 receptors per cell, light to moderate complete membrane staining, > 10% of cells overexpressing HER-2), and 3+ (~2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER-2). The presence of cytoplasmic expression is disregarded. Treatment with trastuzumab is indicated in cases where HER2 expression has a score of 3+. However, IHC has been shown to have numerous limitations, both technical and interpretative, which have been found to impact on the reproducibility and accuracy of results, especially when compared with ISH methodologies. It is also true, however, that some reports have stated that IHC provides excellent correlation between gene copy number and protein expression.
Fluorescent in situ hybridization (FISH) is viewed as being the "gold standard" technique in identifying patients who would benefit from trastuzumab, but it is expensive and requires fluorescence microscopy and an image capture system. The main expense involved with CISH is in the purchase of FDA-approved kits, and as it is not a fluorescent technique it does not require specialist microscopy and slides may be kept permanently. Comparative studies of CISH and FISH have shown that these two techniques show excellent correlation. The lack of a separate chromosome 17 probe on the same section is an issue with regards to acceptance of CISH. As of June 2011 Roche has obtained FDA approval for the INFORM HER2 Dual ISH DNA Probe cocktail developed by Ventana Medical Systems
Ventana Medical Systems, Inc. was a medical device company that develops, manufactures, and markets instrument reagent systems that automate tissue and slide staining in anatomic pathology laboratories. These products assist in the diagnosis and t ...
. The DDISH (Dual-chromagen/Dual-hapten In-situ hybridization) cocktail uses both HER2 and Chromosome 17 hybridization probes for chromagenic visualization on the same tissue section. The detection can be achieved by using a combination of ultraView SISH(silver in-situ hybridization) and ultraView Red ISH for deposition of distinct chromgenic precipitates at the site of DNP or DIG labeled probes.
The recommended assays are a combination of IHC and FISH, whereby IHC scores of 0 and 1+ are negative (no trastuzumab treatment), scores of 3+ are positive (trastuzumab treatment), and score of 2+ (equivocal case) is referred to FISH for a definitive treatment decision. Industry best practices indicate the use of FDA-cleared Automated Tissue Image Systems by laboratories for automated processing of specimens, thereby reducing process variability, avoiding equivocal cases, and ensuring maximum efficacy of trastuzumab therapy.
Resistance
One of the challenges in the treatment of breast cancer patients by herceptin is our understanding towards herceptin resistance. In the last decade, several assays have been performed to understand the mechanism of Herceptin resistance with/without supplementary drugs. Recently, all this information has been collected and compiled in form of a database HerceptinR. This databas
HerceptinR
is a collection of assays performed to test sensitivity or resistance of Herceptin Antibodies towards breast cancer cell lines. This database provides comprehensive information about experimental data perform to understanding factors behind herceptin resistance as well as assays performed for improving Herceptin sensitivity with the help of supplementary drugs. This is the first database developed to understand herceptin resistance that can be used for designing herceptin sensitive biomarkers.
History
The drug was first discovered by scientists including Dr. Axel Ullrich
Axel Ullrich (born 19 October 1943) is a German cancer researcher and has been the director of the molecular biology department at the Max Planck Institute of Biochemistry in Martinsried, Germany since 1988. This department's research has primar ...
and Dr. H. Michael Shepard at Genentech, Inc. in South San Francisco, CA. Earlier discovery about the ''neu'' oncogene by Robert Weinberg's lab and the monoclonal antibody recognizing the oncogenic receptor by Mark Greene's lab also contributed to the establishment of HER2 targeted therapies. Dr. Dennis Slamon
Dennis Joseph Slamon (born August 6, 1948), is an American oncologist and chief of the division of Hematology-Oncology at UCLA. He is best known for his work identifying the HER2/neu oncogene that is amplified in 25-33% of breast cancer patient ...
subsequently worked on trastuzumab's development. A book about Dr. Slamon's work was made into a television film called '' Living Proof'', that premiered in 2008. Genentech developed trastuzumab jointly with UCLA
The University of California, Los Angeles (UCLA) is a public land-grant research university in Los Angeles, California. UCLA's academic roots were established in 1881 as a teachers college then known as the southern branch of the California St ...
, beginning the first clinical trial with 15 women in 1992. By 1996, clinical trials had expanded to over 900 women, but due to pressure from advocates based on early success, Genentech worked with the FDA to begin a lottery system allowing 100 women each quarter access to the medication outside the trials. Herceptin was Fast-tracked by the FDA and gained approval in September 1998.
Biocon Ltd and its partner Mylan obtained regulatory approval to sell a biosimilar in 2014, but Roche contested the legality of the approval; that litigation ended in 2016, and Biocon and Mylan each introduced their own branded biosimilars.
Society and culture
Economics
Trastuzumab costs about for a full course of treatment, Trastuzumab brought in $327 million in revenue for Genentech in the fourth quarter of 2007.
Australia has negotiated a lower price of A$50,000 per course of treatment.
Since October 2006, trastuzumab has been made available for Australian women and men with early-stage breast cancer via the Pharmaceutical Benefits Scheme
The Pharmaceutical Benefits Scheme (PBS) is a program of the Australian Government that subsidises prescription medication for Australian citizens and permanent residents, as well as international visitors covered by a reciprocal health care ag ...
. This is estimated to cost the country over A$470 million for 4–5 years supply of the drug.
Roche has agreed with Emcure in India to make an affordable version of this cancer drug available to the Indian market.
Roche has changed the brand name of the drug and has re-introduced an affordable version of the same in the Indian market. The new drug named Herclon would cost approximately RS75,000 INR (1,200) in the Indian market.
On September 16, 2014, Genentech notified hospitals in the United States that, as of October, trastuzumab could only be purchased through their selected specialty drugs
Specialty drugs or specialty pharmaceuticals are a recent designation of pharmaceuticals that are classified as high-cost, high complexity and/or high touch. Specialty drugs are often biologics—"drugs derived from living cells" that are injectab ...
distributors not through the usual general line wholesalers. By being forced to purchase through specialty pharmacies, hospitals lost rebates from the big wholesalers and the ability to negotiate cost-minus discounts with their wholesalers.
Biosimilars
By 2014, around 20 companies, particularly from emerging market
An emerging market (or an emerging country or an emerging economy) is a market that has some characteristics of a developed market, but does not fully meet its standards. This includes markets that may become developed markets in the future or were ...
s, were developing biosimilar
A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved v ...
versions of trastuzumab
after Roche/Genentech's patents expired in 2014 in Europe, and in 2019 in the United States. In 2013, Roche/Genentech relinquished its patent right for the drug in India because of the difficult IP environment there.
In January 2015, BIOCAD announced the first trastuzumab biosimilar approved by the Ministry of Health of the Russian Federation
The Ministry of Health of the Russian Federation (russian: Министерство здравоохранения Российской Федерации, in short russian: Минздрав России, translit=Minzdrav Rossii) is a ministry of ...
. Iran also approved its own version of the monoclonal antibody in January 2016, as AryoTrust, and announced its readiness to export the drug to other countries in the Middle-East and Central Asia when trade sanctions
Economic sanctions are commercial and financial penalties applied by one or more countries against a targeted self-governing state, group, or individual. Economic sanctions are not necessarily imposed because of economic circumstances—they ma ...
were lifted.
In 2016, the investigational biosimilar MYL-1401O has shown comparable efficacy and safety to the Herceptin branded trastuzumab.
Trastuzumab-dkst (Ogivri, Mylan GmbH) was approved in the United States in December 2017, to "treat patients with breast cancer or gastric or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER-2 gene." Ogivri was approved for medical use in the European Union in December 2018.
In November 2017, the European Commission approved Ontruzant, a biosimilar-trastuzumab from Samsung Bioepis Co., Ltd, for the treatment of early breast cancer, metastatic breast cancer and metastatic gastric cancer. Ontruzant is the first trastuzumab biosimilar to receive regulatory approval in Europe.
Herzuma was approved for medical use in the European Union in February 2018. Herzuma, a trastuzumab biosimilar, was approved in the United States in December 2018.[ ] The approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic, clinical immunogenicity, and other clinical data demonstrating that Herzuma is biosimilar to US Herceptin. Herzuma has been approved as a biosimilar, not as an interchangeable product.
Kanjinti was approved for medical use in the European Union in May 2018.
Trazimera was approved for medical use in the European Union in July 2018.
Ogivri was approved for medical use in Canada in May 2019.
Trazimera was approved for medical use in Canada in August 2019.
Herzuma was approved for medical use in Canada in September 2019.
Kanjinti was approved for medical use in Canada in February 2020.
Zercepac was approved for medical use in the European Union in July 2020.
Trastucip and Tuzucip were approved for medical use in Australia in July 2022.
Related conjugates
Apart from the biosimilars noted above, trastuzumab is also a component of some antibody-drug conjugate
Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...
s, such as trastuzumab emtansine
Trastuzumab emtansine, sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. Trastuzumab alone stops growth of can ...
. Another ADC, trastuzumab deruxtecan
Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan (a derivative of ...
was approved for use in the United States in December 2019.
References
Further reading
* Bazell, Robert. ''Her-2: the making of Herceptin, a revolutionary treatment for breast cancer''. Random House, 1998. 214 pages.
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External links
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