Access to New Medicines
As international research continues to unravel the complexity of breast cancer and its many sub-types, a steady stream of exciting new medicines targeting each type comes to market. Some countries adopt and publicly fund these quickly, but New Zealand does not. Government spending on medicines per capita is lower in New Zealand than in most OECD countries and access to new medicines has been low and slow.
Although recent campaigns by BCAC and other New Zealand breast cancer patient groups have resulted in funding for a few new breast cancer medicines, such as Kadcyla, Ibrance and Faslodex, there are still many that are not funded here. Some are available privately if a patient is able to pay for them.
Here we describe some medicines currently funded in Australia, but not in New Zealand. All these drugs offer potential advantages in quality and length of life for New Zealanders with 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.
We also list some new medicines that are showing promise in breast cancer clinical trials. Increasingly, clinical trials are looking at using multiple medicines to treat advanced breast cancer. Sometimes a drug which had a modest effect on its own will be combined with another to see if a significant benefit can be achieved in a greater number of patients.
Breast cancer medicines funded in Australia and not New Zealand (July 2020)
Abraxane® (nab-paclitaxel) is used to treat advanced breast cancer in people who have already received other medicines. It is a taxane that fights cancer by interfering with cell division. Abraxane is a less toxic formulation of the taxane Taxol® (paclitaxel), with the advantage of causing reduced side effects as it is delivered in protein nanoparticles rather than the toxic solvent that Taxol and another taxane Taxotere® (docetaxel) are dissolved in. Abraxane is particularly helpful for patients who have an allergic reaction to Taxol or Taxotere.
Abraxane has been publicly funded in Australia since 2009 and has since become the preferred taxane, with 71% of Australian patients who use a taxane being treated with this drug by September 2011.
Abraxane is available and Medsafe approved, but not publicly funded, in New Zealand. In February 2018 BCAC applied to PHARMAC to have this medicine 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). The potential supplier of nab-paclitaxel has advised BCAC that 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.
Afinitor® (everolimus) 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. Afinitor stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow.
Afinitor 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.
Bondronat® (ibandronate) 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.
Caelyx® (pegylated doxorubicin) 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.
CDK 4/6 inhibitors - Kisqali® (ribociclib), Verzenio® (abemaciclib) – 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 offer very promising new treatments for 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 2020).
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 June 2020, 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.
Halaven® (eribulin) 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. Halaven 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.
Lynparza® (olaparib) is a PARP inhibitor which is approved and funded in New Zealand only for ovarian cancer. In Australia, it is funded for ovarian and germline BCRA-mutated HER2 negative metastatic breast cancer. Extended follow-up of the OlympiAD clinical trial has shown survival benefits for those receiving olaparib instead of standard chemotherapy treatments for this type of breast cancer. The greatest benefit was seen in those given olaparib as their first-line treatment after being diagnosed with metastatic disease.
Tecentriq® (atezolizumab) 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 email@example.com for more information) (June 2020).
Herceptin® (trastuzumab) 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 which 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.
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. Presumably this competitive situation will lead to price reductions. Three trastuzumab biosimilars have been approved by Medsafe NZ – Herzuma® (supplied by Celltrion), Ogivri® (supplied by Mylan and Biocon Biologics), and Trazimera® (supplied by Pfizer). Two others, Kanjinti® (supplied by Amgen) and Ontruzant® (supplied by Merck) have not yet been approved by Medsafe. All five trastuzumab biosimilars are now publicly funded in Australia.
Just how similar biosimilars are in terms of their effects on patients is the subject of some discussion among researchers and clinicians. 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, the biosimilars will not have to go through the extensive clinical trials that the original products did. Probably, 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.
It is very likely that in New Zealand PHARMAC will soon put out a tender for trastuzumab and its biosimilars and award the contract to one product only. Hopefully, by then Australia and other countries will have had some experience in prescribing these and we will benefit from their knowledge of how well these medicines work in ‘real-world’ practice.
Xgeva® or Prolia® (denosumab) 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. It was approved by the United States Food and Drug Administration 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.
Medicines showing promise for the future (July 2020)
For triple negative breast cancer:
Trodelvy® (sacituzumab-govitecan) is an antibody-drug conjugate, which 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.
Keytruda® (pembrolizumab) 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.
Keytruda is funded in New Zealand for treating advanced melanoma. In Australia, it is funded for melanoma, non-small-cell lung cancer and a number of other cancers, but not breast cancer.
Ipatasertib® is an inhibitor of an enzyme called AKT, which (like the enzymes mTOR and PI3K) is part of a signalling pathway that normally controls cell proliferation. In some cancers, AKT is overactive and so inhibiting it should reduce tumour growth. In May 2020, promising final results from the LOTUS trial showed that patients with advanced triple negative breast cancer treated with ipatasertib and paclitaxel had better overall survival than those receiving paclitaxel alone. Further trials are underway: IPATunity130 is a Phase III study also looking at first-line use of ipatasertib and paclitaxel for metastatic triple negative breast cancer, and IPATunity170 will look at ipatasertib plus alpelisib (a PI3K inhibitor) plus paclitaxel for metastatic triple negative breast cancer.
For hormone receptor-positive, HER2-negative, PIK3CA-mutant breast cancer:
PIQRAY® (alpelisib) 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 Food and Drug Administration (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 2020).
For HER2-positive breast cancer:
Nerlynx® (neratinib) 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 Food and Drug Administration approved Nerlynx (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)). In New Zealand, Nerlynx was approved by Medsafe in June 2020. It is not funded by PHARMAC.
Tukysa® (tucatinib) is a selective HER2 tyrosine kinase inhibitor which was approved by the United States Food and Drug Administration 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.