Targeted therapy  |  Avastin  |  Erbitux  |  Stivarga  |  Vectibix  |  Zaltrap  |  Immunotherapy  |  Keytruda  Opdivo  |  Biosimilars
 
| Targeted therapy
 
The development of targeted therapy, or precision medicine, is an exciting step in the treatment of metastatic bowel cancer as it may make it possible to identify and destroy specific cancer cells without harming or damaging other normal healthy cells.
 
Targeted therapy is usually given in combination with other standard chemotherapy treatment and makes it possible for your oncologist to tailor your treatment program to:
  • reduce side effects
  • extend survival, and
  • limit toxicity exposure

These treatments may:

  • stop cancer cells from dividing and growing
  • seek out cancer cells and kill them
  • encourage the immune system to attack cancer cells
  • alter the growth of blood vessels into the tumour

Types of targeted therapies used in the treatment of bowel cancer including the following:

  • Monoclonal antibodies: monoclonal antibodies are made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attached to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

    There are different types of monoclonal antibody therapy:
    • Vascular endothelial growth factor (VEGF) inhibitor therapy: cancer cells makes a substance called VEGF, which causes new blood vessels to form (angiogenesis) and helps the cancer grow. VEGF inhibitors block VEGF and stop new blood vessels from forming. This may kill cancer cells because they need blood vessels to grow. Bevacizumab is a VEGF and angiogenesis inhibitor.
  •  
    • Epidermal growth factor receptor (EGFR) inhibitor therapy: EGFRs are proteins found on the surface of certain cells, including cancer cells. Epidermal growth factor attaches to the EGFR on the surface of the cell and causes the cells to grow and divide. EGFR inhibitors block the receptor and stop the epidermal growth factor from attaching to the cancer cell. This stops the cancer cell from growing and dividing. Cetuximab and panitumumab are EGFR inhibitors. 
  • Angiogenesis inhibitors: angiogenesis inhibitors stop the growth of new blood vessels that tumours need to grow.
    • Aflibercept is a vascular endothelial growth factor trap that blocks an enzyme needed for the growth of new blood vessels in tumours.

    • Regorafenib is used to treat bowel cancer that has spread to other parts of the body and has not gotten better with other treatment. It blocks the action of certain proteins, including vascular endothelial growth factor. This may help keep cancer cells from growing and may kill them. It may also prevent the growth of new blood vessels that tumours need to grow.


Targeted Therapies




| Avastin (Bevacizumab)

At what stage is this treatment used?
 
Bevacizumab (Avastin) is an antibody drug that binds to and neutralizes a protein called VEGF-A.
 
It is effective as first-line treatment for metastatic bowel cancer and is used in combination with chemotherapy.
 
The drug is also approved as part of second line treatment in combination with chemotherapy.
 
Patients receive bevacizumab as an intravenous infusion every two weeks and can be scheduled on the same day that chemotherapy is given.
 
Patients may continue bevacizumab even after stopping chemotherapy, as long as the disease is controlled and side effects are manageable.
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Bevacizumab is PBS-subsidised as a treatment option in combination with first-line chemotherapy (i.e. first-line treatment option), of a patient with previously untreated metastatic bowel cancer with a WHO performance status of 0 or 1.

  • Bevacizumab is PBS-subsidised as a treatment option in combination with second-line chemotherapy, of a patient with RAS wild-type metastatic bowel cancer with a WHO performance of 0 or 1, who have been previously treated with PBS-subsidised first-line anti-EGFR antibodies.
Download the Consumer Medicine Information (CMI) for Bevacizumab.

| Erbitux (Cetuximab)
 
At what stage is this treatment used?
 
Cetuximab is used as a first or second-line treatment option for patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic bowel cancer in combination with chemotherapy.
 
Cetuximab can also be given as a single agent in patients who have failed or are intolerant to oxaliplatin-based therapy and irinotecan-based therapy.
 
Before you are prescribed cetuximab, your specialist will test your cancer cells to see if they contain either the normal (wild-type) or mutant forms of genes called RAS.
 
Cetuximab is used to treat patients who express normal (wild-type) RAS genes.
 
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Cetuximab is PBS-subsidised as a treatment in combination with first-line chemotherapy, of a patient with a WHO performance status of 0 or 1 and previously untreated RAS wild-type metastatic bowel cancer, who does not have progressive disease.

  • Cetuximab is PBS-subsidised as monotherapy or in combination with first-line chemotherapy, of a patient with a WHO performance status of 2 or less and with RAS wild type metastatic bowel cancer after failure to respond to first-line chemotherapy. The treatment must be the sole PBS-subsidised anti-EGFR antibody therapy for this condition.

  • Patients who have progressive disease on panitumumab are not eligible to receive PBS-subsidised cetuximab. Patients who have developed intolerance to panitumumab of a severity necessitating permanent treatment withdrawal are eligible to receive PBS-subsidised cetuximab.
Download the Consumer Medicine Information (CMI) for Cetuximab.

| Stivarga (Regorafenib)
 
At what stage is this treatment used?
 
Regorafenib (Stivarga), a targeted therapy that comes in pill form, is a tyrosine kinase inhibitor (TKI).
 
This kind of treatment is designed to target cancer cells and the blood vessels feeding them by interfering with chemical signals or pathways inside abnormal cells.
 
Regorafenib targets the signaling of multiple growth factors involved in tumor angiogenesis, including VEGF receptors, Fibroblast Growth Factor (FGF) receptors, Platelet-Derived Growth Factor (PDGF) receptors, and the angiopoietin receptor TIE-2. Additional targets of regorafenib include RAF, BRAF, RET and KIT.
 
Regorafenib is approved for treating patients with metastatic) bowel cancer in the third-line setting, after the cancer has progressed or has recurred after multiple treatments.
 
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Regorafenib has been approved by the Therapeutic Goods Administration (TGA) for use in Australia, however, it is not currently listed on the PBS as a subsidised treatment.

Download the Consumer Medicine Information (CMI) for Stivarga.


| Vectibix (Panitumumab)
 
At what stage is this treatment used?
 
Panitumumab is used as a first or second-line treatment option for patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic bowel cancer in combination with chemotherapy.
 
Panitumumab can also be given as a single agent in patients who have failed or are intolerant to oxaliplatin-based therapy and irinotecan-based therapy.
 
Before you are prescribed panitumumab, your specialist will test your cancer cells to see if they contain either the normal (wild-type) or mutant forms of genes called RAS.
 
Panitumumab is used to treat patients who express normal (wild-type) RAS genes.
 
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Panitumumab is PBS-subsidised as a treatment in combination with first-line chemotherapy of a patient with a WHO performance status of 0 or 1 and previously untreated RAS wild-type metastatic bowel cancer, who does not have progressive disease.

  • Panitumumab is PBS-subsidised as monotherapy or in combination with chemotherapy, of a patient with a WHO performance status of 2 or less and with RAS wild type metastatic bowel cancer after failure to respond to first-line chemotherapy.

  • The treatment must be the sole PBS-subsidised anti-EGFR antibody therapy for this condition. Patients who have progressive disease on cetuximab are not eligible to receive PBS-subsidised panitumumab. Patients who have developed intolerance to cetuximab of a severity necessitating permanent treatment withdrawal are eligible to receive PBS-subsidised panitumumab.
Download the Consumer Medicine Information (CMI) for Vectibix.

| Zaltrap (Aflibercept rch)

At what stage is this treatment used?

Aflibercept (Zaltrap) is a type of targeted drug known as a fusion protein. This drug is designed to target multiple growth factors involved in cancer and angiogenesis, specifically proteins called VEGF-A, VEGF-B and a related protein called placental growth factor (PlGF).

Aflibercept is approved for use as treatment in second-line therapy in combination with chemotherapy (FOLFIRI) for metastatic bowel cancer.

Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Aflibercept had previously been approved by the Therapeutic Goods Administration (TGA) for use in Australia, however, as of January 2020 Zaltrap is no longer listed on the Australian Register of Therapeutic Goods (ARTG). The ARTG is the register for all therapeutic goods that can be lawfully supplied in Australia. Sometimes a special provision is made to make available some medicines that are not listed in response to the needs of patients. To find out more visit the access to therapeutic goods on the ARTG website.
Download the Consumer Medicine Information (CMI) for Zaltrap.
 

| Immunotherapy

What is cancer immunotherapy?

Immunotherapy is treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defences against cancer. This type of cancer treatment is also called biotherapy or biologic therapy.


What the immune system does?
 
Your immune system is a collection of organs, special cells, and substances that help protect you from infections and some other diseases. Immune cells and the substances they make travel through your body to protect it from germs that cause infections. They also help protect you from cancer in some ways.
 
The immune system keeps track of all of the substances normally found in the body. Any new substance that the immune system doesn’t recognise raises an alarm, causing the immune system to attack it. For example, germs contain substances such as certain proteins that are not normally found in the human body. The immune system sees these as 'foreign' and attacks them. The immune response can destroy anything containing the foreign substance, such as germs or cancer cells.
 
The immune system has a tougher time targeting cancer cells, though. This is because cancer starts when cells become altered and start to grow out of control. The immune system doesn’t always recognise cancer cells as foreign.
 
Clearly there are limits on the immune system’s ability to fight cancer on its own, because many people with healthy immune systems still develop cancer. Sometimes the immune system doesn’t see the cancer cells as foreign because the cells aren’t different enough from normal cells. Sometimes the immune system recognises the cancer cells, but the response might not be strong enough to destroy the cancer. Cancer cells themselves can also give off substances that keep the immune system in check.
 
To overcome this, researchers have found ways to help the immune system recognise cancer cells and strengthen its response so that it will destroy them.

Types of cancer immunotherapy
 
The main types of immunotherapy now being used to treat cancer include:
  • Monoclonal antibodies: These are man-made versions of immune system proteins. Antibodies can be very useful in treating cancer because they can be designed to attack a very specific part of a cancer cell.

  • Immune checkpoint inhibitors: These drugs basically take the ‘brakes’ off the immune system, which helps it recognise and attack cancer cells.

  • Cancer vaccines: Vaccines are substances put into the body to start an immune response against certain diseases. We usually think of them as being given to healthy people to help prevent infections. But some vaccines can help prevent or treat cancer.

  • Other, non-specific immunotherapies: These treatments boost the immune system in a general way, but this can still help the immune system attack cancer cells.
Immunotherapy drugs are now used to treat many different types of cancer.

| Immunotherapy for bowel cancer
 
An important part of the immune system is its ability to keep itself from attacking the body's normal cells. To do this, it uses 'checkpoint' proteins on immune cells, which act like switches that need to be turned on (or off) to start an immune response.
 
Cancer cells sometimes use these checkpoints to keep the immune system from attacking them. But drugs that target these checkpoints hold a lot of promise as cancer treatments.
 
Pembrolizumab (Keytruda) and Nivolumab (Opdivo) are drugs that target PD-1 (programmed cell death protein 1). PD-1 is a protein found on the surface of immune system cells called T cells. It normally helps keep these cells from attacking 'good' cells in the body.
 
When PD-1 attaches to another protein called PDL-1 on a cancer cell, it stops the T cell from killing the cancer cell. PD-1 inhibitors attach to PDL-1 and allow the T cells to kill cancer cells.
 
Pembrolizumab and nivolumab block the cancer cells' ability to attach to PD-1, so, the immune system can then 'see' the cells as 'bad'. This boosts the immune response against the cancer cells and can shrink some tumors or slow their growth.
 
These drugs can be used for people whose bowel cancer cells have tested positive for specific gene changes, such as a high level of microsatellite instability (MSI-H), or changes in one of the mismatch repair (MMR) genes.
 
The drugs are used for people whose cancer is still growing after treatment with chemotherapy. They might also be used to treat people whose cancer can't be removed with surgery, has come back (recurred) after treatment, or has spread to other parts of the body (metastasised).
 
Pembrolizumab (Keytruda) is given as an intravenous (IV) infusion. Treatment takes about 30 minutes and is given every three weeks.
 
Nivolumab (Opdivo) is given as an (IV infusion) that takes one hour. It's given every two weeks.
Immunotherapy

| Keytruda (Pembrolizumab)
 
At what stage is this treatment used?
 
The US Food and Drug Administration (FDA) granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker) in May 2017.
 
This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.
 
Keytruda is indicated for the treatment of patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
 
This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with bowel cancer that has progressed following treatment with certain chemotherapy drugs.
 
MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell.
 
Tumors with these biomarkers are most commonly found in bowel, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places.
 
Approximately five percent of patients with metastatic bowel cancer have MSI-H or dMMR tumors.
 
Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells.
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • In 2019, Keytruda received provisional-approval from the Therapeutic Goods Administration (TGA) for use in Australia as a treatment option for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) bowel cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Continued approval will depend on verification and description of clinical benefit in the confirmatory trials.
  • Keytruda is not currently listed on the PBS as a subsidised treatment.

Download the Consumer Medicine Information (CMI) for Keytruda.


| Opdivo (Nivolumab)
 
At what stage is this treatment used?
 
In July 2017, the US Food and Drug Administration (FDA) granted accelerated approval to nivolumab (Opdivo) for the treatment of patients twelve years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic bowel cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
 
The approval was based on data from Study CA209142, a multicenter, open-label, single arm study conducted in 53 patients with locally determined dMMR or MSI-H metastatic bowel cancer who had disease progression during, after, or were intolerant to prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
 
This was a subset of the 74 patients who received at least one prior regimen for treatment of metastatic disease containing a fluoropyrimidine with oxaliplatin or irinotecan for treatment of metastatic disease. All patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression.
 
Is this drug available via the Pharmaceutical Benefits Scheme (PBS) as a subsidised treatment?
  • Opdivo has not been approved by the Therapeutic Goods Administration (TGA) for use in Australia as a treatment option for bowel cancer, and is not currently listed on the PBS as a subsidised treatment. Sometimes a special provision is made to make available some medicines that are not listed in response to the needs of patients. To find out more visit the access to therapeutic goods on the ARTG website.

Biosimilars

Biosimilars

A medicine made from living organisms, such as protein, bacteria or yeast, is known as a biological medicine.

Since the 1980s, hundreds of biological medicines have been approved for the treatment of diseases such as cancers, diabetes, heart attacks, rheumatoid arthritis, Crohn's disease and many more.
 
Around 300 new biological medicines are currently under development for the treatment of cancer and related conditions.
 
A biosimilar medicine is a very similar version of an already-approved biological medicine, in terms of its characteristics, quality, safety and efficacy.
 
A biosimilar medicine is not considered a generic medicine, as it is virtually impossible to make an exact copy of a living organism.  However, much like generics, biosimilar medicines are also based on original medicines that have reached the end of their patents.
 
Biosimilar medicines are developed to increase treatment options, and can usually be produced at a lower cost than the original biological medicine.

How biological and biosimilar medicines work

Unlike traditional chemical medicines which are made by combining chemical ingredients, biological and biosimilar medicines are made from living organisms.

Biological medicines usually have more complex and larger structures than their traditional counterparts.  For example, Aspirin, a chemical medicine, contains 21 atoms, while a biological medicine may contain more than 20,000 atoms.  
Biosimilars

As a result, biological medicines are more sensitive and are more likely to cause an immune reaction in the body than chemical medicines.
 
Once administered, a biological medicine can mimic the natural protein in a patient, thereby helping to reduce symptoms and slow the progression of a disease. Biological medicines, such as vaccines, can also prevent disease.
 
Biological, and biosimilar, medicines are often administered by injection or infusion, whereas chemical medicines are usually taken as a tablet or capsule. Many traditional medicines can be self-administered, but biological medicines are often administered in hospital as an injection or with the assistance of medical staff.

Why aren't biosimilar medicines considered the same as generic medicines?
 
Once a product patent expires, manufacturers are legally allowed to develop a generic version of a chemical product, or a biosimilar version of a biological product.
 
While it's relatively easy to manufacture an exact generic copy of a simple chemical structure, it's almost impossible to make an exact copy of a living organism.
 
Therefore, if someone is talking about a generic medicine, they are referring to the exact copy of a traditional chemical medicine that is no longer under patent.
 
A biosimilar, on the other hand, refers to a highly similar but not identical version of a biological medicine.

Why can't different manufacturers make an exact copy of a biological medicine?

There are three main reasons why it is virtually impossible for different manufacturers to replicate a biological medicine:
  • As living organisms, there will always be some differences between medicines even if this does not affect how the medicine works
  • The structures are large and complex, making it difficult to create an exact copy
  • The final medicine is highly dependent on the manufacturing process, and once the original patent for a medicine expires each manufacturer has to make their own decisions around the cell lines, conditions to grow the cells, stabilising compounds to use, as well as how the medicine is packaged and stored.

What are the differences between substitution, interchangeability and switching?
  • Substitution - if two or more medicines are considered substitutable, the pharmacist may dispense either of these medicines from the script, provided the prescriber (i.e. GP or specialist)  has not indicated ‘brand substitution not permitted’, and they have permission from the patient. This applies most often to generic medicines and biological medicines with a biosimilar that has been recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) as substitutable. Substitutable medicines are marked in the Schedule of Pharmaceutical Benefits with an ‘a’ (a-flagged). It is important that the prescriber of the biologic is notified of the switch. This allows for appropriate monitoring of a patient's response to treatment , as well as tracking of adverse events.
  • Interchangeability - if two or more medicines are considered interchangeable, the prescriber (i.e. GP or specialist) may choose to prescribe either of the medicines for a patient to treat the same condition; however, the pharmacist must dispense as prescribed. This generally occurs between two different medicines, rather than brands or biosimilars of the same medicine. 

    In 2017, the US Food and Drug Administration (FDA) issued draft guidance detailing the agency's expectations for demonstrating biosimilar interchangeability. To be approved as interchangeable, it must demonstrate that it 'can be expected to produce the same clinical result as the reference product in any given patient' when substituted, and 'the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.'  
  • Switching between medicine brands could occur in either case. One would be at the direction of the prescriber (prescribing an interchangeable medicine), the other would occur at the pharmacy level (brand substitution).

What are the biosimilar uptake drivers?

As part of the 2017 Budget process the Government reached agreement with Medicines Australia, the Generic and Biosimilar Medicines Association and the Pharmacy Guild of Australia to implement biosimilar uptake drivers. Two specific biosimilar uptake drivers are being implemented:

  • encouraging prescribing of a biosimilar brand rather than the reference biological brand for treatment naïve patients. 

    For the purpose of this uptake driver a patient is ‘treatment naïve’ if they have not previously taken the biological medicine intended to be prescribed. That is, they have not taken either the reference or biosimilar brand of the particular biological medicine.

    Continued use of a biosimilar brand after it is first taken by a patient is a matter for the patient in consultation with their prescriber and pharmacist.

    A patient is not treatment naïve if they took any brand of the particular biological medicine in the past, even if that treatment occurred some time ago.

  • providing for a simpler and faster approval process for prescribing biosimilar brands (e.g. streamlined authority) while maintaining an existing higher level authority requirement for the reference biological brand (e.g. written authority).

    There are three broad types of authority requirement for prescribing PBS medicines:

    Written authority – the prescriber is required to obtain from the Department of Human Services an authority approval in writing for prescribing the medicine. 

    Immediate authority – the prescriber can get the authority to prescribe either online or by phone (which can occur during a consultation).


    Streamlined authority – if the prescriber is satisfied that the specific eligibility criteria and rules for prescribing on the PBS are met, they mark a ‘streamlined authority code’ on the prescription. A ‘streamlined authority’ provides the simplest and fastest method for demonstrating authority to prescribe the medicine. 

In the public hospital setting, brand decisions are made by clinician-led committees on behalf of doctors and patients.


Will the use of biosimilar medicines be forced?

In Australia, there is no current mandated requirement for GPs, pharmacists or patients to use biosimilar medicines.

By way of contrast, the Government of Alberta (Canada) has announced that it will begin forcibly switching 26,000 patients from their physician-chosen biologic medicines to government-chosen biosimilars beginning 1 July 2020. According to the Alliance for Safe Biologic Medicines (ASBM), only half of Albertan patients- those on public pharmacare plans- will be subject to the forced-switching policy. Patients on private health plans, including Ministry of Health officials, will not be forced to switch. Children and pregnant women are also exempted.

On 27 May 2019 the Government of British Columbia (BC, Canada) announced 20,700 patients would be forcibly switched from their existing medicines to the government’s choice of preferred biosimilar products and cease the reimbursement of their current biologic medicine. The policy disregards important scientific considerations for patients on biologic medicines and most alarmingly, eliminates patient choice, according to the Alliance for Safe Biologic Medicines (ASBM).


Biosimilar medicines and bowel cancer

There is a growing number of biosimilar medicines available in Australia, and some of these are relevant to cancer patients receiving chemotherapy (see Table 1).
 
For example, the active substance known as epoetin lambda is used to treat anaemia in patients receiving chemotherapy for certain types of cancer.  The active substance known as filgrastim is used to help the body make new white blood cells following treatment with some types of chemotherapy. 
 

Biosimilar medicines and bowel cancer

 

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