Guiding chemotherapy to a tumour by attaching it to the antibody-based target drug Herceptin (trastuzumab) is effective at treating women with breast cancer who have no other treatment options, a new clinical trial shows.
The two-in-one treatment kept breast cancer at bay in women with a type of the disease called HER2-positive breast cancer who had stopped responding to existing drugs.
As well as being effective in women with high HER2 levels in their tumour, it was also active in a subset of women with lower levels of the HER2 protein who currently have no treatment options.
The new study, led by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, assessed the new treatment in patients for the first time, linking together the chemotherapy agent duocarmazine with trastuzumab – also known as Herceptin – which recognises the HER2 protein.
Women with HER2-positive breast cancer lived for 7.6 months after starting the treatment with no disease progression, whilst those with lower HER2 levels had progression-free survival of 4.9 months, showing that the drug extended life for patients who have run out of other treatment options.
The study was published today (Thursday) in The Lancet Oncology and funded by Synthon Biopharmaceuticals.
25 per cent of all breast cancers have higher than normal levels of HER2, which is a protein that plays a key role in the development of breast cancer.
HER2-positive breast cancers are more aggressive and grow faster than some other subtypes.
HER2-positive breast cancer patients eventually develop resistance to standard therapies, leaving them with a poor prognosis and few further treatment options.
Therefore, scientists began exploring other approaches to deliver anti-cancer drugs to the tumours by linking chemotherapy drugs to an antibody.
The antibody acts as a guide for the attached drug, detecting the HER2 protein on the surface of the cancer cells.
Once these two drugs – attached by a ‘linker’ to form the antibody drug conjugate – are internalised into the cancer cell, the linker is broken by enzymes within the cell to release the cytotoxic drug, resulting in DNA damage to the cancer cell.
This approach allows the drug to be delivered directly to the target cancer cells.
As this method selectively targets the cancer cells, it minimises the damage done to the surrounding healthy cells, reducing toxicity and side effects in the patient.
The well-known breast cancer treatment Kadcyla is an example of this approach.
Kadcyla is made up of the antibody trastuzumab linked to the chemotherapy drug emtansine.
However, HER2-positive cancers that are resistant both to trastuzumab alone and also to the trastuzumab-emtansine conjugate are becoming more common, again leaving these patients without further treatment options.
In this study, scientists linked trastuzumab with another chemotherapy drug, duocarmycin.
When treated with this antibody-drug conjugate, on average breast cancer patients with high levels of HER2 in their tumour survived with no disease progression for more than seven extra months.
This indicates that by linking trastuzumab with a different chemotherapy drug—duocarmycin instead of emtansine—it was possible to overcome previous resistance to treatment.
Also, patients with breast cancer who had low levels of HER2 lived for nearly 5 months longer with no disease progression when treated with trastuzumab duocarmazine than they would have without the treatment.
This is an important finding as there are currently no approved HER2-targeting drugs or antibody-drug conjugate for low-HER2 breast cancer patients.
This high unmet need could be met by the duocarmazine conjugate, potentially giving these patients life-extending options.
The researchers are hopeful that this approach could not only be used to treat breast cancer with high and low HER2 levels, but also to other cancer types with varying HER2 levels such as endometrial, urothelial and oesophageal cancer which have limited treatment options due to drug resistance and poor prognosis—although further studies are required to confirm this.
The late-phase TULIP trial is currently recruiting patients to looking into whether trastuzumab duocarmazine is more effective than the standard chemotherapy for women with HER2-postivie breast cancer.
First author Professor Udai Banerji, Deputy Director of the Drug Development Unit at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, said:
“The approach used in this study of combining the antibody and drug is a highly successful way of targeting tumours.
With the antibody acting as a guide to find and target the cancer, the duocarmazine drug can be released directly to the tumour cells, destroying them whilst minimising the damage to surrounding healthy cells.”
“Trastuzumab duocarmazine has shown promising anti-tumour activity in breast cancer patients with varying levels of the cancer-driving HER2 protein.
As these cancers often develop resistance to the current standard of care, this treatment could be extend the lives of patients who have otherwise run out of options.”
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:
“This trial shows that the innovative approach of linking antibodies to specifically target cancer cells with chemotherapy drugs to kill them is effective in patients who have developed resistance to other treatments.
“Drug resistance is a major challenge we face in getting cancer treatments to work. By adapting the technique of antibody-drug conjugates to overcome resistance to current treatments, the lives of patients can be extended to give them valuable time with friends and family.
“This research is part of the ICR’s ambitious strategy to understand cancer’s complexity and evolution – and to overcome evolution and drug resistance through the world’s first ‘Darwinian’ drug programme.”
Herceptin (chemical name: trastuzumab) can be used to treat HER2-positive breast cancer that is either early-stage or advanced-stage/metastatic.
Herceptin is currently approved by the U.S. Food and Drug Administration:
- to treat metastatic HER2-positive breast cancer to stop the cancer from growing
- to treat earlier stages of HER2-positive breast cancer, either as part of a regimen with chemotherapy or alone after a chemotherapy regimen that includes an anthracycline, to reduce the risk of the breast cancer coming back (recurrence)
- in combination with Perjeta (chemical name: pertuzumab) and Taxotere (chemical name: docetaxel) before surgery to treat HER2-positive, early-stage (the cancer must be larger than 2 cm or cancer must be in the lymph nodes), inflammatory, or locally advanced-stage breast cancer with a high risk of metastasizing or becoming fatal
- in combination with Perjeta and chemotherapy after surgery to treat HER2-positive, early-stage breast cancer with a high risk of recurrence
How Herceptin works
Cancer cells grow in an uncontrolled fashion. Herceptin works on the surface of the cancer cell by blocking the chemical signals that can stimulate this uncontrolled growth.
Genes are like instruction manuals that tell each cell of your body how to grow, what kind of cell to become, and how to behave. Genes do this by ordering the cell to make special proteins that cause a certain activity — such as cell growth, rest, or repair.
Some cancer cells have abnormalities in genes that tell the cell how much and how fast to grow. Sometimes the cancer cells have too many copies of these genes with abnormalities.
When there are too many copies of these genes, doctors refer to it as “overexpression.”
With some forms of gene overexpression, cancer cells will make too many of the proteins that control cell growth and division, causing the cancer to grow and spread.
Some breast cancer cells make too many copies of (overexpress) a particular gene known as HER2. The HER2 gene makes a protein known as a HER2 receptor. HER2 receptors are like ears, or antennae, on the surface of all cells.
These HER2 receptors receive signals that stimulate the cell to grow and multiply. But breast cancer cells with too many HER2 receptors can pick up too many growth signals. This causes them to start growing and multiplying too much and too fast.
Breast cancer cells that overexpress the HER2 gene are said to be HER2-positive.
Herceptin works by attaching itself to the HER2 receptors on the surface of breast cancer cells and blocking them from receiving growth signals.
By blocking the signals, Herceptin can slow or stop the growth of the breast cancer. Herceptin is an example of an immune targeted therapy.
In addition to blocking HER2 receptors, Herceptin can also help fight breast cancer by alerting the immune system to destroy cancer cells onto which it is attached.
This video animation illustrates how Herceptin attaches itself to the HER2 receptors on the surface of breast cancer cells and blocks them from receiving growth signals.
Is Herceptin right for you?
Herceptin is used to treat breast cancers that are HER2-positive.
Four different tests can be used to figure out if the cancer is HER2-positive and if it will likely respond to Herceptin:
IHC (ImmunoHistoChemistry)
IHC is the most commonly used test to see if a tumor has too much of the HER2 receptor protein on the surface of the cancer cells.
The IHC test gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample. If the score is 0 to 1+, it’s called “HER2 negative.” If the score is 2+, it’s called “borderline.” A score of 3+ is called “HER2 positive.”
If the IHC test results are borderline, it’s likely that a FISH test will be done on a sample of the cancer tissue to determine if the cancer is HER2-positive.
FISH (Fluorescence In Situ Hybridization)
The FISH test also looks to see if the cancer is HER2-positive. This test is the most accurate, but it is more expensive and takes longer to return results. This is why an IHC test is usually the first test done to see if a cancer is HER2-positive. The FISH test shows how many copies of the HER2 gene are in tumor cells. The more copies of the gene, the more HER2 receptors the cells have.
With the FISH test, you get a score of either “positive” or “negative” (some hospitals call a negative test “zero”). If the cancer is FISH positive, it will probably respond well to Herceptin.
SPoT-Light HER2 CISH (Subtraction Probe Technology Chromogenic In Situ Hybridization)
The SpoT-Light HER2 CISH test looks for how many copies of the HER2 gene are in the tumor cells of a breast cancer tissue sample. The SPoT-Light test is less complicated than the FISH or IHC tests.
With the SPoT-Light test, you get a score of either “positive” or “negative.” If the cancer is SPoT-Light HER2-positive, it will probably respond well to Herceptin.
Inform HER2 Dual ISH (In Situ Hybridization)
The Inform HER2 Dual ISH test uses a special stain that makes HER2 proteins change color. The test can be used on tissue samples that have been stored in wax or other chemicals. The Inform HER2 Dual ISH test offers more precise results than the IHC HER2 test. It is also less expensive and doesn’t need the special microscope of the FISH HER2 test.
With the Inform HER2 Dual ISH test, you get a score of either “HER2 positive” or “HER2 negative.”
What to expect when taking Herceptin
Herceptin can only be given by intravenous (IV) infusion, which means it is delivered directly into your bloodstream through an IV or a port. The first dose of Herceptin takes about 90 minutes. After that, it only takes about 30 minutes to get other doses of Herceptin. Your Herceptin treatment schedule will depend on whether you are receiving it with other medicines. You can talk to your doctor about your treatment schedule options.
If you’ve been diagnosed with early-stage HER2-positive breast cancer, you’ll likely receive Herceptin together with a chemotherapy regimen. You will receive it for a specific amount of time.
If you’ve been diagnosed with metastatic HER2-positive breast cancer, you will keep being treated with Herceptin as long as you are getting benefits from the medicine and aren’t having troubling side effects.
It’s important to know that women who are pregnant or planning to get pregnant should not take Herceptin. Herceptin can harm the developing fetus. If there is any chance you can become pregnant, you must use effective birth control while you’re taking Herceptin and for at least 7 months after your last dose.
Also, women who are breastfeeding or plan to breastfeed shouldn’t take Herceptin. Together, you and your doctor will decide if you should take Herceptin or breastfeed.
Paying for Herceptin
If your doctor prescribes Herceptin and you face any difficulties getting it covered by insurance, or you don’t have insurance, you can get in touch with Access Solutions, sponsored by Genentech (the maker of Herceptin).
Access Solutions can help investigate your insurance coverage benefits, appeal denied claims, and provide other assistance. You can also reach Access Solutions at 1-866-422-2377.
Herceptin side effects
Like almost all medicines, Herceptin can cause side effects, some of them severe. The most common side effects of Herceptin are:
- headache
- diarrhea
- nausea
- chills
- fever
- heart problems
- infection
- insomnia
- cough
- rash
If you are receiving Herceptin with chemotherapy, you may also experience chemotherapy side effects.
Herceptin also may cause serious side effects, including:
Heart problems
Herceptin may cause serious heart problems, including some that don’t have symptoms, such as reduced heart function, and some that do have symptoms, such as congestive heart failure. Symptoms to watch for include swelling of the ankles or legs, shortness of breath, cough, or weight gain of more than 5 pounds in less than 24 hours. Contact your doctor immediately if you have any of these symptoms.
Your risk of heart problems is higher if you are receiving Herceptin in combination with anthracycline chemotherapy.
Before starting Herceptin therapy, you should have an echocardiogram or a MUGA (multigated blood-pool imaging) scan to check how well your heart is functioning.
An echocardiogram uses sound waves to take detailed pictures of the heart as it pumps blood. For this quick test, you lie still for a few minutes while a device that gives off sound waves is briefly placed on your ribs, over your heart. There is no radiation exposure with this test.
A MUGA scan takes about an hour. In this test, a tiny amount of radioactive material is injected into a vein in your arm. This material temporarily hooks onto your red blood cells. You lie still while a special camera that can detect the radioactive material takes pictures of the blood flow through your heart as it beats.
Your doctor will continue to monitor your heart function while you are receiving Herceptin, as well as after you complete treatment.
Lung problems
Herceptin may cause inflammation of the lungs, which can be life-threatening. Symptoms include trouble breathing, cough, tiredness, and fluid in the lungs.
Herceptin Hylecta (injectable Herceptin)
Herceptin Hylecta (chemical name: trastuzumab and hyaluronidase-oysk) is an injectable form of Herceptin. It is a combination of Herceptin and hyaluronidase, an enzyme that helps your body use the Herceptin.
Traditional Herceptin is given by intravenous (IV) infusion, which means the medicine is delivered directly into your bloodsteam through an IV or port. The first dose of Herceptin takes about 90 minutes. After that, it only takes about 30 minutes to get other doses of Herceptin.
Herceptin Hylecta is given subcutaneously, which means it is injected under your skin using a hypodermic needle, much like a vaccine. The injection takes about 2 to 5 minutes and is given in your thigh, alternating between left and right for each dose.
It’s important to know that Herceptin Hylecta is given in different doses than IV Herceptin. Herceptin Hylecta is given at a fixed dose of 600 milligrams, while the dose of IV Herceptin is based on your weight.
You can receive a Herceptin Hylecta injection at an infusion center along with a chemotherapy regimen. If you are being treated with only Herceptin Hylecta, you may be able to receive the injection at your doctor’s office.
Herceptin Hylecta is approved to treat HER2-positive breast cancer that has spread to the lymph nodes (node-positive), or is not in the lymph nodes but is considered to be at high risk of recurrence:
- after surgery as part of a treatment regimen that includes Adriamycin (chemical name: doxorubicin), Cytoxan (chemical name: cyclophosphamide), and either Taxol (chemical name: paclitaxel) or Taxotere (chemical name: docetaxel)
- after surgery as part of a treatment regimen with Taxotere and carboplatin
- after surgery as a single treatment for people who have been treated with a chemotherapy regimen that includes an anthracycline
Herceptin Hylecta also is approved to treat metastatic HER2-positive breast cancer:
- in combination with Taxol as the first treatment for metastatic disease
- as a single treatment for people who have been treated with one or more chemotherapy regimens for metastatic disease
Side effects
Like Herceptin, Herceptin Hylecta can cause side effects, some of them severe. Common Herceptin Hylecta side effects include:
- fatigue
- joint pain
- diarrhea
- injection site reaction
- upper respiratory tract infection
- rash
- muscle pain
- nausea
- headache
- swelling
- flushing
- fever
- cough
- pain in extremities
- chills
- infection
- insomnia
Like Herceptin, less common but more severe side effects of Herceptin Hylecta include weakening of the heart muscle and other heart problems, as well as serious lung problems.
Also like Herceptin, women who are pregnant or planning to get pregnant should not be treated with Herceptin Hylecta. Herceptin Hylecta can harm the developing fetus. If there is any chance you can become pregnant, you must use effective birth control while you’re being treated with Herceptin Hylecta and for at least 7 months after your last dose. Visit Treatment for Breast Cancer During Pregnancy for more information.
Herceptin biosimilars
Herceptin is a monoclonal antibody, “biologic” drug. This means that it is made from living organisms, in this case a protein from a mouse cell. A monoclonal antibody is a type of protein made in the lab that can bind to substances in the body, including cancer cells. Each monoclonal antibody is made so that it binds only to one substance. Herceptin binds to the HER2 receptor proteins in cancer cells.
Because they are made from living organisms, biologic drugs are much more complex to make than conventional drugs that are made from a mixture of chemicals. The chemical structure of conventional drugs can be easily identified and duplicated, which is why there are so many generic drugs on the market.
A biosimilar is a new type of biologic drug. A biosimilar is almost identical to a biologic drug that is already approved by the FDA (or similar organizations in other countries). It can help to think of a biosimilar as a generic version of a biologic drug, though that comparison isn’t completely accurate.
The makers of biosimilars don’t have access to the original cell lines used to make the biologic drug. They also don’t have access to the exact purification process or other manufacturing steps used by the makers of the biologic drug.
Biologic drugs can be very sensitive to changes in the manufacturing process. If one small step is done differently, the biosimilar may have very different effects than the original biologic drug.
So, the U.S. Food and Drug Administration (FDA) requires that any biosimilar drug go through the same rigorous clinical trials that original biologic drugs do before the agency will approve the biosimilar.
There are three Herceptin biosimilars that have been approved by the FDA:
- Herzuma (chemical name: trastuzumab-pkrb)
- Ogivri (chemical name: trastuzumab-dkst)
- Ontruzant (chemical name: trastuzumab-dttb)
Herzuma, Ogivri, and Ontruzant have been approved as biosimilars, not as products that are interchangeable with Herceptin. This means that if you start treatment with Herceptin, you can’t switch to one of the biosimilars in the middle of treatment. Similarly, if you start treatment with a biosimilar, you can’t switch to Herceptin in the middle of treatment.
Right now, it’s not clear when Herzuma, Ogivri, and Ontruzant will be available in the United States or how much the drugs will cost.
Herzuma
Herzuma is approved to treat non-metastatic HER2-positive breast cancer that has spread to the lymph nodes (node-positive) or is not in the lymph nodes but is considered to be at high risk of recurrence:
- after surgery as part of a treatment regimen that includes Adriamycin (chemical name: doxorubicin), Cytoxan (chemical name: cyclophosphamide), and either Taxol (chemical name: paclitaxel) or Taxotere (chemical name: docetaxel)
- after surgery as part of a treatment regimen with Taxotere and carboplatin
Herzuma is also approved to treat metastatic HER2-positive breast cancer:
- in combination with Taxol as the first treatment for metastatic disease
- as a single treatment for people who have been treated with one or more chemotherapy regimens for metastatic disease
Common Herzuma side effects include:
- headache
- diarrhea
- nausea
- chills
- fever
- infection
- heart problems
- insomnia
- cough
- rash
Serious side effects include worsening of neutropenia (low white blood cell count) caused by chemotherapy.
Like Herceptin, less common but more severe side effects of Herzuma include weakening of the heart muscle and other heart problems.
Ogivri
Ogivri is approved to treat non-metastatic HER2-positive breast cancer that has spread to the lymph nodes (node-positive) or is not in the lymph nodes but is considered to be at high risk of recurrence:
- after surgery as part of a treatment regimen that includes Adriamycin (chemical name: doxorubicin), Cytoxan (chemical name: cyclophosphamide), and either Taxol (chemical name: paclitaxel) or Taxotere (chemical name: docetaxel)
- after surgery as part of a treatment regimen with Taxotere and carboplatin
- as a single treatment after people have been treated with anthracycline-based chemotherapy
Ogivri also is approved to treat metastatic HER2-positive breast cancer:
- in combination with Taxol as the first treatment for metastatic disease
- as a single treatment for people who have been treated with one or more chemotherapy regimens for metastatic disease
Ogivri can also be used to treat metastatic, HER2-positive stomach cancer.
Common side effects of Ogivri include:
- low white blood cell counts
- peripheral neuropathy
- diarrhea
Less common but more severe side effects of Ogivri include heart damage and lung damage.
Ontruzant
Ontruzant is approved to treat non-metastatic HER2-positive breast cancer that has spread to the lymph nodes (node-positive) or is not in the lymph nodes but is considered to be at high risk of recurrence:
- after surgery as part of a treatment regiment that includes Adriamycin (chemical name: doxorubicin), Cytoxan (chemical name: cyclophosphamide), and either Taxol (chemical name: paclitaxel) or Taxotere (chemical name: docetaxel)
- after surgery as part of a treatment regimen with Taxotere and carboplatin
- as a single treatment after people have been treated with anthracycline-based chemotherapy
Ontruzant also is approved to treat metastatic HER2-positive breast cancer:
- in combination with Taxol as the first treatment for metastatic disease
- as a single treatment for people who have been treated with one or more chemotherapy regimens for metastatic disease
Ontruzant also can be used to treat metastatic, HER2-positive stomach cancer.
Ontruzant can only be given by intravenous (IV) infusion, which means it is delivered directly into your bloodstream through an IV or a port.
Common side effects of Ontruzant include:
- headache
- diarrhea
- nausea
- chills
- fever
- infection
- heart problems
- insomnia
- cough
- rash
Like Herceptin, less common but more severe side effects include heart damage and lung damage.
It’s important to know that women who are pregnant or planning to get pregnant should not take Ontruzant. Ontruzant can harm the developing fetus. If there is any chance you can become pregnant, you must use effective birth control while you’re taking Ontruzant and for at least 7 months after your last dose.
Journal information: Lancet Oncology
Provided by Institute of Cancer Research
