Striving for Better Care

More treatment options are needed to extend and improve the lives of New Zealanders with advanced breast cancer. 

Different medicines are needed for the different sub-types of breast cancer (hormone receptor positive/negative, HER2 positive/negative, triple negative, etc.), and different patients with the same sub-type may respond differently to a single medicine. On top of this, as breast cancer progresses, different medicines are needed to suppress tumour growth and spread.

This is why advanced breast cancer patients have a variety of treatment pathways, involving different sequences and combinations of drugs. Not everyone receives each drug, and as soon as the cancer progresses, you will be moved on to a new drug or combination of drugs (a new ‘treatment line’).

When treating advanced breast cancer, oncologists aim to maximise the quality and length of life for each patient by individually tailoring their treatments, so that the most effective treatment line can be used when it is needed. It is by no means a one-size-fits-all situation, and to get the best outcomes, both patients and oncologists need access to a range of drugs.

Overseas and New Zealand research shows that the more lines of treatment given, the longer patients with advanced cancer live, with a better quality of life.  In New Zealand, few patients receive more than 2 or 3 lines of treatment and between 10 and 30% receive no systemic drug treatment after diagnosis at all (“I’m Still Here” Breast Cancer Foundation NZ, Sept 2018). The Breast Cancer Foundation NZ is currently working on an updated version of this report.

In 2019 three more medicines for treating advanced breast cancer (Ibrance®, Kadcyla®, Faslodex®) were approved in New Zealand, after extensive petitioning by Metavivors NZ, BCAC and others. Since then, many new medicines for advanced breast cancer have been shown to be effective, but none has been approved for funding by PHARMAC.

Here we describe some medicines currently funded in Australia, but not in New Zealand. We also list breast cancer medicines that are recommended in European guidelines, but not funded in Australia or New Zealand. All these drugs offer potential advantages in quality and length of life for New Zealanders with advanced breast cancer and would give oncologists additional options for optimising treatment of the different sub-types of breast cancer. Additionally, individual patients can vary widely in their responses to a medicine and their responses may also change over time. This is why it is vitally important for doctors to have a range of medicines in their toolkits, particularly for treating advanced breast cancer.

Breast cancer medicines funded in Australia and not New Zealand (July 2022)

CDK 4/6 inhibitors - ribociclib (brand name Kisqali®), abemaciclib (brand name Verzenio®) – CDK 4/6 inhibitors are a group of medicines that prevent over-proliferation of cancer cells by inhibiting enzymes that the cells need in order to divide. These drugs improve survival of those with advanced oestrogen receptor positive breast cancer. There are several on the market now, and each offers slightly different benefits.

After a petition to Parliament led by BCAC Committee Member Terre Nicholson and submissions to the Health Select Committee by Terre and other Metavivors during 2018/19, PHARMAC finally called for tenders to supply one of the CDK 4/6 inhibitors to the New Zealand public health system. Ibrance® (palbociclib), supplied by Pfizer, won the tender and is the only CDK 4/6 inhibitor that is funded in New Zealand at present.  

The other contender was Kisqali® (ribociclib), supplied by Novartis. It has been approved by Medsafe and is available in New Zealand but not publicly funded. The application to PHARMAC for Kisqali funding is still ‘live’ but there is no indication of when or if it might be funded (July 2022).

A third CDK 4/6 inhibitor, Verzenio® (abemaciclib, supplied by Lilley), has been classified by Medsafe but has not yet been approved for use in New Zealand. There is no current application with PHARMAC to seek public funding for this medicine.

As of July 2022, Australia has approved funding for all three CDK 4/6 inhibitors – Ibrance, Kisqali and Verzenio - for first- and second-line use with either an aromatase inhibitor or fulvestrant in patients with metastatic hormone receptor positive, HER2-negative breast cancer. All three are also available via the National Health Service throughout the United Kingdom, but with some restrictions depending on which country the patient lives in.

In New Zealand PHARMAC funds Ibrance with an endocrine partner (fulvestrant or an aromatase inhibitor) for advanced breast cancer, either first-line (as the first endocrine treatment for advanced breast cancer) or second-line (after the advanced breast cancer has relapsed or progressed on prior endocrine therapy).

Bevacizumab (brand name Avastin®) inhibits the growth of blood vessels around tumours. It is used in the treatment of advanced triple negative breast cancer. It has Medsafe approval in New Zealand but is not funded by PHARMAC.

Denosumab (brand names Xgeva® or Prolia®) is a monoclonal antibody that reduces tumour formation and growth in people whose cancer has spread to the bones. Recent Australian research has shown this drug also has the potential to prevent breast cancer in people with a BRCA gene mutation who are at high risk of getting breast cancer.

This medicine is Medsafe approved but not funded in New Zealand for treatment of bone metastases. An application to PHARMAC for its use in this way was lodged in 2018, but has been given a low priority by its clinical advisory team. It was approved by the United States Food and Drug Administration (FDA) in 2010 for prevention of skeletal events (fractures) in patients with bone metastases from solid tumours. It is funded in Australia for elderly patients with low bone density and people with osteoporosis who have had a fracture after minimal trauma.

Eribulin (brand name Halaven®) is used to treat late-stage metastatic breast cancer that is hormone receptor-positive and HER2-negative that has previously been treated with anthracycline and taxane chemotherapies. It is a “non-taxane microtubule inhibitor” that kills cancer cells by inhibiting cell division. Eribulin has been registered and publicly funded in Australia since 2013 and was recommended for inclusion on the New Zealand Pharmaceutical Schedule in 2012 but is not funded in New Zealand. Pharmaceutical company Eisai has recently applied for Medsafe registration, which would allow some reimbursement for patients with health insurance, but doesn’t plan to seek PHARMAC funding because of perceived low likelihood of success. BCAC has asked the company to directly import this product and to establish a cost-share programme for NZ patients.

Everolimus (brand name Afinitor®) is used in the treatment of hormone receptor-positive, HER2-negative advanced breast cancer in post-menopausal women, in conjunction with the aromatase inhibitor exemestane after failure of letrozole or anastrozole. It is only used in patients whose tumour has tested negative for HER2. Everolimus stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow.

Everolimus is Medsafe approved but not publicly funded for breast cancer in New Zealand. It has been funded in Australia since 2014. In July 2018 BCAC applied to PHARMAC to have this medicine publicly funded. In July 2019, BCAC was informed that this application had been declined by PHARMAC.

Ibandronate (brand name Bondronat®) is a bisphosphonate used to reduce bone loss in those whose metastatic cancer has moved to their bones. It is funded specifically for breast cancer in Australia but not in New Zealand. Its approval by Medsafe NZ has lapsed.

Nab-paclitaxel (brand name Abraxane®) is used to treat advanced breast cancer in people who have already received other medicines. It can also be used in those with early breast cancer. It is a taxane that fights cancer by interfering with cell division. Abraxane is a less toxic formulation of the taxane, paclitaxel (brand name Taxol®), with the advantage of causing reduced side effects as it is delivered in protein nanoparticles rather than the toxic solvent that paclitaxel and another taxane docetaxel (brand name Taxotere®) are dissolved in. Abraxane is particularly helpful for patients who have an allergic reaction to paclitaxel or docetaxel. 

Abraxane has been publicly funded in Australia since 2009. This medicine is available and Medsafe approved in New Zealand, but not publicly funded. In February 2018 BCAC applied to PHARMAC to have Abraxane funded. In May 2019 PHARMAC's Pharmacology and Therapeutics Advisory Committee (PTAC) recommended it be funded only if "cost-neutral" to weekly paclitaxel (the currently funded option). Meeting this price requirement would be extremely difficult because of the higher cost of creating a humanised nanoparticle albumin bound (nab) paclitaxel compared with the other taxanes which are simply dissolved in solvent. In July 2021 PHARMAC’s Cancer Treatments Advisory Committee (CTAC) re-examined the evidence for Abraxane and recommended it with high priority for those allergic to other taxanes and with medium priority for others with advanced breast cancer. The committee noted its faster infusion time reducing the burden on clinical resources, the clinical benefits, reduced toxicity and greater suitability of Abraxane over other taxanes. Despite these recommendations PTAC retained its “only if cost neutral” decision for this medicine.

Pegylated doxorubicin (brand name Caelyx®) is a cytotoxic chemotherapy agent that has been formulated in liposomes so that it is less likely to cause side effects. In New Zealand, doxorubicin is funded but this pegylated version is not. Although applications to PHARMAC for funding this medicine were made in 2006 and 2011, there has been no approval. BCAC understands that the sponsor of this product has given up on getting this treatment funded in New Zealand. It has been funded in Australia since 2003.

Sacituzumab govitecan (brand name Trodelvy®) is an antibody-drug conjugate, that blocks cancer cell proliferation by interfering with DNA repair. The antibody sacituzumab targets the drug to a DNA-enzyme (topoisomerase 1) complex in the cell and the govitecan molecule binds to the DNA and causes it to break, thus halting cell replication. In April 2020, a Phase III trial called ASCENT was stopped early because sacituzumab-govitecan worked so well in patients with metastatic triple negative breast cancer, it was not necessary to continue the trial. On this evidence, sacituzumab govitecan was given accelerated approval by the FDA in the United States in April 2020. It is publicly funded in Australia (March 2022) and England (July 2022), but is not approved by Medsafe or funded by PHARMAC in New Zealand. BCAC has contacted the pharmaceutical company Gilead Sciences to encourage them to apply for Medsafe registration and PHARMAC funding for Trodelvy and to establish a cost-share programme for NZ patients until funding is secured.

Trastuzumab biosimilars (various brand names). Trastuzumab (brand name Herceptin®) was developed in the United States in the 1990s by pharmaceutical research and development company Genentech and was first approved for use as a targeted therapy for HER2-positive breast cancer in the USA in 1998. Genentech was bought by pharmaceutical company Roche in 2006.

Trastuzumab is a ‘biologic’ medicine – it is a monoclonal antibody that has to be grown in a living cell culture system, rather than a drug that can be produced by a purely chemical reaction. The patents on Herceptin expired in Europe in 2014 and in the United States in 2019. This has allowed other companies to develop biosimilar versions of trastuzumab. A biosimilar is basically a copy of a drug that has been made in a slightly different biological system from the original.

Regulators have developed evaluation processes aimed at ensuring that biosimilars are highly similar to the original product, in terms of their efficacy and safety, including clinical trials in some cases. However, biosimilars will not have to go through the extensive clinical trials that the original products did. It is likely that any subtle differences will become evident only as clinicians gain experience in prescribing these medicines and their patients report their experiences with them. This has been the case for generic medicines, which are complete copies of chemical (not biologic) drugs. These should be identical molecules to the original, but sometimes they can produce different effects in some patients.

Currently, Herceptin (supplied by Roche) is the only version of trastuzumab that is publicly funded by PHARMAC in New Zealand, but there are several biosimilars now on the global market. This competitive situation has led to price reductions. Four trastuzumab biosimilars have been approved by Medsafe NZ – Herzuma® (supplied by Celltrion), Ogivri® (supplied by Mylan and Biocon Biologics), Trazimera® (supplied by Pfizer), and Kanjinti® (supplied by Amgen). A fifth, Ontruzant® (supplied by Merck) has not yet been approved by Medsafe. All five trastuzumab biosimilars are now publicly funded in Australia.

PHARMAC’s website shows an application for funding Herzuma was lodged by Celltrion in May 2019 and in October 2019 the Cancer Treatments Subcommittee noted the potential for cost savings with this product. BCAC is mystified as to why PHARMAC has not moved quickly to tender for a trastuzumab biosimilar given the substantial cost savings likely. As of July 2022, more than three years after the original application, this has not been initiated.

Trastuzumab as a re-treatment (various brand names) for advanced HER2-positive breast cancer.  Trastuzumab (original brand name Herceptin®) has been funded for use in the treatment of early HER2-positive breast cancer in New Zealand since 2008. It can also be used to treat advanced breast cancer, but PHARMAC has limited this to a single use. Once a patient’s cancer progresses on this medicine, it cannot be used again in New Zealand. However, European guidelines state that it should be available for this purpose and Australia and many other countries do fund re-treatment with trastuzumab under these circumstances. The HER2CLIMB clinical trial has shown that people with advanced HER2-positive breast cancer who had been previously treated with trastuzumab (Herceptin), pertuzumab (Perjeta) and trastuzumab emtansine (Kadcyla) and were then re-treated with trastuzumab along with tucatinib (Tukysa, see below) and capecitabine chemotherapy had longer before their cancer advanced and lived longer.

Researchers involved in Breast Cancer Trials (Australia and NZ) (BCT) are initiating a new clinical trial, TUGETHER, that will test a combination of Tukysa, pembrolizumab (Keytruda) and trastuzumab re-treatment in advanced HER2-positive breast cancer. BCT wants to involve NZ patients in this trial and this would provide an exciting opportunity for some NZ women to gain early access to a very promising combination of treatments. Sadly, because PHARMAC does not fund the basic backbone of this trial, trastuzumab re-treatment, NZ patients are ineligible for the trial.

Sub-cutaneous trastuzumab is an alternative formulation of trastuzumab that can be given by injection rather than by intravenous infusion. This has huge benefits in terms of convenience and efficiency as it can be administered without a lengthy visit to an infusion centre at a hospital. Australia funds this version of this medicine but New Zealand does not. The supplier applied to PHARMAC for funding in 2013, but was told in 2015 that it would only be considered if the product could be made “cost-neutral”, i.e. the same as the intravenous formulation. There has been no further progress with this.

Vinorelbine oral capsules are an alternative formulation of a cytotoxic chemotherapy drug usually given intravenously for advanced breast cancer. Both forms of vinorelbine are funded in Australia. In New Zealand, intravenous vinorelbine is funded but the capsules are not, even though their use would save time and effort not only for patients, but also for hospital infusion centre staff.

Breast cancer medicines recommended in European guidelines but not funded in Australia or New Zealand (July 2022)

Alpelisib (brand name PIQRAY®) is an inhibitor of an enzyme called PI3K which is part of a biochemical pathway that normally controls cell proliferation in our bodies. In some cancers, the gene encoding PI3K is mutated (called a PIK3CA mutation) and PI3K is over-expressed, contributing to tumour growth. Alpelisib can inhibit PI3K and help to reduce the growth of cancer cells. Novartis, the manufacturer of alpelisib, supplies it along with a test for the PIK3CA mutation, as a product called PIQRAY.

In May 2019 the USA FDA approved PIQRAY for use with fulvestrant to treat those whose advanced hormone receptor-positive, HER2-negative, PIK3CA-mutant breast cancer had progressed on endocrine therapy. In the SOLAR-1 phase III clinical trial, those receiving this combination had had median progression-free survival of 11.0 months, compared to only 5.7 months for those receiving fulvestrant alone. There is a similar Australian-based clinical trial with alpelisib (called CAPTURE) under way at present (July 2022). PIQRAY was funded in England in July 2022.

Atezolizumab (brand name Tecentriq®) is an immunotherapy treatment for metastatic triple negative breast cancer (TNBC). Tecentriq has been shown (in the Impassion130 clinical trial) to improve survival in patients with metastatic triple negative breast cancer whose tumours have high PD-L1 expression. In March 2020, Tecentriq was provisionally funded in Australia for use with nab-paclitaxel to treat metastatic triple negative breast cancer patients with high levels of PD-L1; final approval will depend on further evidence of benefit. NICE (medicines assessor) in the United Kingdom recommended Tecentriq for a similar use in May 2020. Tecentriq is Medsafe-approved in New Zealand, but not PHARMAC-funded. However, Tecentriq supplier Roche has applied to PHARMAC for it to be funded and at present offers a Cost Share Programme (contact nz.costshare@roche.com for more information).

Margetuximab (brand name Margenza®) is an immunotherapy treatment for those who have advanced HER2-positive breast cancer and have already received two or more other medicines that target HER2. Margetuximab is not Medsafe-registered or funded in New Zealand.

Neratinib (brand name Nerlynx®) is a tyrosine kinase inhibitor. Tyrosine kinases are enzymes that play important roles in normal cell growth and metabolism. In some cancers, tyrosine kinases are abnormally activated and so inhibiting them could be effective in controlling the cancer. In February 2020, the United States FDA approved neratinib in combination with the chemotherapy drug capecitabine for those whose advanced HER2-positive breast cancer had progressed on two previous lines of anti-HER2 therapy (such as Herceptin (trastuzumab), Perjeta (pertuzumab) or Kadcyla (trastuzumab emtansine)). Recent research results have shown that it is also effective in treating early breast cancer that is both HER2-positive and hormone receptor-positive. In New Zealand, Nerlynx was approved by Medsafe in June 2020. It is not funded by PHARMAC.

Olaparib (brand name Lynparza®) is a PARP inhibitor which is approved and funded in New Zealand and Australia only for ovarian cancer in those carrying a BRCA gene mutation. Extended follow-up of the OlympiAD clinical trial has shown survival benefits for those receiving olaparib instead of standard chemotherapy treatments for germline BCRA-mutated HER2-negative metastatic breast cancer. The greatest benefit was seen in those given olaparib as their first-line treatment after being diagnosed with metastatic disease.

Pembrolizumab (brand name Keytruda®) is an antibody used in cancer immunotherapy. It is one of a number of new medicines called checkpoint inhibitors that support the body’s immune system to recognise and destroy cancer cells. Some types of cancers have a protein on the cell surface that masks the cancer from the body’s immune system. Keytruda and other similar new drugs are designed to lock onto and deactivate this protein, exposing the cancer cells to the body’s immune system, allowing the body’s T-cells to destroy the cancer. Breast cancer clinical trials currently under way with Keytruda (KEYNOTE trials) and other similar drugs are producing very promising results, particularly in triple negative breast cancer that test positive for the tumour masking protein, PD-L1.

The FDA has approved Keytruda for use in both early and advanced triple negative breast cancer. In New Zealand, in August 2022 Medsafe approved Keytruda in combination with chemotherapy for patients with high-risk early-stage triple negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant therapy (before surgery) and continued after surgery on its own. Medsafe also approved Keytruda in combination with chemotherapy in advanced TNBC where tumours express PD-L1 (CPS ≥10) as determined in a validated test. Keytruda is funded in New Zealand for treating advanced melanoma, and recently funding was also approved for lung cancer. In Australia, it is funded for melanoma, non-small-cell lung cancer and a number of other cancers, but not yet breast cancer.  

Pertuzumab for neoadjuvant treatment (brand name Perjeta®) is another immunotherapy drug that targets the HER2 receptors on breast cancer cells. It is funded as a treatment for advanced HER2-positive breast cancer, but it is also effective when used as a pre-surgery (neo-adjuvant) treatment in patients with early HER2-positive breast cancer and at high risk of recurrence.

Talazoparib (brand name Talzenna®) is another PARP inhibitor which can be used to treat advanced triple negative breast cancer.

Trastuzumab deruxtecan (brand name Enhertu®) is an antibody-drug conjugate composed of trastuzumab, which targets the drug to HER2 receptors on breast cancer cells, and deruxtecan, a cytotoxin which then kills those cells. Clinical trials called DESTINY- Breast03 and DESTINY- Breast04 have recently shown that this medicine improves survival in two groups of patients with advanced breast cancer – those whose HER2-positive cancer has returned after first line treatment with trastuzumab and taxanes, and also those with ‘HER2-low’ advanced cancer. HER2-low is a new category – up until now these cancers have been lumped together in the HER2-negative category. Read more about Enhertu here.

Tucatinib (brand name Tukysa®) is a selective HER2 tyrosine kinase inhibitor which was approved by the United States FDA in May 2020 for treatment of advanced HER2-positive breast cancer. Results of the HER2CLIMB clinical trial presented in May 2020 showed that tucatinib combined with capecitabine demonstrated survival benefits in patients who had already progressed after several lines of treatment for their advanced HER2-positive breast cancer. Encouragingly, these benefits were also seen among patients who had brain metastases. Often cancer medicines do not work well for these tumours as there is a ‘blood-brain barrier’ which normally functions to protect the brain, but has the unfortunate side-effect of preventing many medicines from getting into this tissue.

8 July 2022