After 20 years of the cancer drug Herceptin is less more?

  • 15 to 20% of breast cancer patients suffer a type of the disease that could benefit from the drug Herceptin
  • Herceptin is very effective and normally administered for 12-months but it is expensive and can cause heart damage
  • New research has found that the treatment period for Herceptin could be reduced from 12-months to 6 without compromising outcomes
  • A 6-month course would reduce the cost of the drug, increase access and potentially reduce the number of patients suffering debilitating side effects
  • The research findings reignited broader concerns about the sustainability of cancer care and the competing interests of patients, producers and providers
  • Herceptin’s patents are expiring and biosimilars are entering the market which is expected to lower costs and increase access
 
After 20 years of the cancer drug Herceptin is less more?

Findings of a phase III clinical study funded by UK government grants and presented at the June 2018 meeting of the American Society of Clinical Oncology (ASCO) suggest that the time a patient needs to spend on Herceptin, (chemical name trastuzumab), a drug widely used to treat an aggressive form of breast cancer, could be halved from 12 to 6 months. This would save insurers, governments, healthcare providers and patients significant sums of money and possibly reduce the incidence of side effects, which can include heart problems.
 
In this Commentary
 
This Commentary: (i) summarizes the findings of the clinical study and some expert reactions to it and (ii) describes the different subtypes of breast cancer and the drug trastuzumab.  The Commentary also broaches a broader concern about the escalating costs of life-saving or life-extending cancer therapies, which show no sign of either slowing or reversing. According to ASCO, in the US, newly approved cancer drugs cost on average US$10,000 per month, with some costing as much as US$30,000 per month. This causes financial hardship for many American patients and their families. In the UK, which has a large devolved public healthcare system, cancer therapies are a postcode lottery because medicines that patients receive depend on whether their local healthcare provider can afford them. In emerging economies, where the prevalence of breast cancer is rising, only a privileged few breast cancer patients have access to trastuzumab. Notwithstanding, patients should gain some comfort from Herceptin’s patents expiring and biosimilar versions of trastuzumab entering the market, which is expected to make the drug cheaper and more accessible.  
 
Breast cancer and HER2

Breast cancer is a heterogenic disease and biomolecular changes in breast cancer involve the expression of genes. The disease is classified according to the 4 subtypes of genes expressed: (i) luminal A, which accounts for 51 to 61% of all breast cancer patients, (ii) luminal B, which accounts for 14 to 16%, (iii) basal-like, which accounts for 11-20% and (iv) the HER2 subtype, which accounts for 15 to 20% of all breast cancer patients and is the focus of this Commentary. Each subtype has different clinical features, different prognoses and different responses to therapies. HER2 protein overexpression is the result of amplification of the HER2 gene and is associated with aggressive tumour growth and consequent high rates of recurrence and mortality in patients. HER2-positive breast cancer is not inherited but is a somatic genetic mutation, which occurs after conception and therefore the new DNA does not enter the eggs or sperm.
 
Trastuzumab the first gene targeted drug
 
Trastuzumab was first approved by the US Food and Drug Administration (FDA) in 1998 and became the first FDA-approved therapeutic antibody targeted to a specific cancer-related molecular marker. The FDA recommended that the drug should be administered for 12 months. Robert Leonard, formerly Professor of Cancer Studies at Imperial College London, UK, and a consultant medical oncologist specialising in breast cancer at the BUPA Cromwell Hospital, the London Clinic and the London Oncology Clinic describes HER2 positive breast cancer and trastuzumab: see video below.  “We like to talk about targeted therapies since we’ve learnt more about the basic biology of cancer, which uses subtle techniques of investigation including biological and immunological profiling of cancers. We now have the ability for new molecules to target specific abnormalities in cancer cells and these can be effective in sublimating standard breast cancer treatments. A good example are Herceptin and Lapatinib, both of which target the HER2 pathway, which is a very important pathway in breast cancer,” says Leonard.
 
Trastuzumab and advanced breast cancer
Trastuzumab’s approval followed 4 randomized clinical studies involving more than 8,000 patients with stages II or III HER2-positive breast cancers. These showed that when trastuzumab was administered for a period of 12 months in combination with or after chemotherapy agents, it potentiated the efficacy of chemo- and immunotherapy; reduced the risk of breast cancer recurrence by approximately 50% and significantly improved survival. In 2000, trastuzumab's use for advanced breast cancer was approved in Europe and has since been approved in a number of countries outside Europe. In 2002 the UK government’s watchdog, the National Institute for Health and Clinical Excellence (NICE), endorsed the use of trastuzumab for advanced HER2 breast cancer.



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Trastuzumab and early stage breast cancer
Shortly afterwards, trastuzumab expanded its use to early stage HER2 breast cancer. Findings of 2 papers in the October 2005 edition of the New England Journal of Medicine (NEJM), suggested that following initial interventions, a 12-month course of trastuzumab in combination with other agents, could also be a lifesaver for those still in the early stages of breast cancer because it reduced the risk of recurrence and death of patients by 46% compared with chemotherapy alone. In this respect trastuzumab has been viewed as a possible “cure” for early stage breast cancer. Based on these findings, trastuzumab’s approval was extended for the treatment of early stage HER2 cancers. Commenting on the 2 studies in the same edition of the NEJM Gabriel Hortoboagyi, a breast cancer specialist from MD Anderson Cancer Center in Huston, USA, said, “the results reported in this issue of the Journal are not evolutionary but revolutionary. . . . . . trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” In September 2013, a time-saving subcutaneous formulation of trastuzumab was approved in Europe, which can be administered in just 2 to 5 minutes, rather than the standard 30 to 90 minutes intravenously.
 
Was the 12 months treatment time a “guess”?
After regulatory approval in 1998 and following some subsequent clinical studies, a 12-month regimen for trastuzumab became the standard of care. Notwithstanding, some oncologists view the 12-month treatment period as a “guess”, and some smaller trials have questioned the duration of treatment.
 
Clinical study and the 2018 ASCO Meeting
 
The study presented at the 2018 ASCO meeting is the largest and most significant study to-date, which suggests that the treatment time for trastuzumab could be halved. The randomized clinical study followed 4,088 women with early-stage breast cancer across 152 sites in the UK for a median of more than 5 years: 2043 received trastuzumab for 6 months and 2045 received the drug for 12 months. The disease-free survival rate at 4 years was 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. In addition, 4% of patients on the shorter treatment dropped out due to cardiac toxicity versus 8% of those treated for a year. Across both groups, cardiac function recovered within a few months following treatment with trastuzumab but patients in the 6-month group recovered more rapidly.

Helena Earl, Professor of Clinical Cancer Medicine at the University of Cambridge, UK and the study’s lead investigator is confident that the study will, “mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer." According to Richard Schilsky, ASCO’s Chief Medical Officer, “There’s no reason to not immediately change practice. The findings are persuasive”.
 
Expert reaction to the study

Although oncologists view the study’s findings as “persuasive”, changing the length of treatment time for trastuzumab might not occur quickly. Generally, clinicians appear hesitant to immediately support a shorter duration of trastuzumab as a new standard of care. Some believe that since so few women have died or relapsed after being treated with trastuzumab, longer follow-up may be required to make sure the findings hold up before guidelines are changed. 

“My guess is that people will continue to aim for a year of treatment' because of lingering concerns that longer use is better, as a smaller previous study suggested,” says Harold Burstein, a breast cancer expert at the Dana-Farber Cancer Institute in Boston, USA. However, Burstein is mindful that a shorter treatment regimen might increase access to trastuzumab for patients in emerging economies where the prevalence of breast cancer is increasing but where many women cannot afford a 12-month treatment course of the drug.  Other experts suggest that the study’s findings are significant for women who suffer the toxic effects of trastuzumab.

Jennifer Litton, a breast cancer specialist at MD Anderson Cancer Center points to another issue the ASCO study raises. She suggests the study’s findings show just how important it can be to study drugs that are already on the market. “It's really important that we continue to have public funding for clinical trials, so we can continue to ask all of these questions for our patients. Scaling back treatment whenever possible is important to patients,” says Litton.

Industry response
A spokesperson for Roche Genentech, Herceptin's developers, suggested that the ASCO study should be viewed along with several smaller studies, which conclude that the optimum duration for trastuzumab is 12 months. The goal of the treatment, “is to provide people with the best chance for a cure.” Courtney Aberbach, a spokesperson for Genentech, which was acquired by Roche, in March 2009 for US$$46.8bn, suggested that previous studies had not found that a shorter duration worked as well as the longer one. She said the 12-month course was still the only regimen approved for early-stage disease by the FDA and recommended by several international organizations that issue treatment guidelines.

The HERA Trial
Industry views are influenced by a clinical study sponsored by Roche in the expectation that the 12-month trastuzumab treatment period could be doubled. Referred to as the HERA trial, the study was conducted by France's Institut National du Cancer and reported at the 2012 meeting of the European Society for Medical Oncology (ESMO). HERA was an international multi-centre, phase III randomized study involving 5,102 women with early HER2-positive breast cancer. After finishing primary therapy with surgery, chemotherapy and radiotherapy, they were randomly assigned to trastuzumab therapy every 3 weeks for 1 year, 2 years or observation.
 
In April 2012, when the study’s findings were presented at the ESMO meeting, the overall survival rate of the 24-month treatment cohort versus the 12-month cohort was comparable. The principal conclusion of the study was that 12-month treatment remains the standard of care for HER2 positive early breast cancer patients. Results also suggested that shortening treatment of trastuzumab to 6 months may offer a worse result than a 12-month course of treatment. While the study’s findings meant that Roche missed an opportunity to expand sales of trastuzumab on the back of a longer recommended treatment period, they were also a relief to the company, which had faced the risk of losing significant sales revenues from trastuzumab had a shorter treatment period turned out to be as effective as the current standard of 12-months.
 
Unsustainable of cancer care

Cancer treatment has always been expensive, but the costs of newer molecular targeted therapies, such as trastuzumab, have escalated, which significantly reduces access for a lot of breast cancer patients to efficacious drugs. According to a 2015 study by the US National Bureau of Economic Research, each year between 1995 and 2013 the prices of cancer drugs increased 10%. This finding led some health professionals to suggest that cancer therapies are becoming “unsustainable”. In England, NICE has come under intense criticism from patient groups for rejecting numerous cancer drugs for use on the NHS because they were not judged to be cost effective. The UK’s Cancer Drugs Fund, which was set up in 2011 to plug gaps in NHS funding for cancer drugs, overspent its allocated budget by 35% between 2013 and 2015. The debate of the rising cost of cancer therapies is exacerbated by the revenues generated by cancer drugs for big pharmaceutical companies. For example, in 2017 Roche-Genentech recorded annual sales of US$6.8bn for Herceptin alone, which some analysts suggested was driven partly by the duration of the treatment and partly by strong sales growth of the drug in Brazil and China.

When vast revenues from the sale of drugs are mentioned there is negative reaction directed at giant pharmaceutical companies. In their defence drug producers stress the vast costs of developing new drugs and the tenure of patents, which limit the time drug companies have to recoup R&D costs before copycats are introduced into the market. According to the most recent report from the Tufts Center for the Study of Drug Development, and published in the May 2016 edition of the Journal of Health Economics; the cost of developing a medicine from invention to pharmacy shelves is estimated to be some US$2.7bn. Patents protect drugs for 20 years after the initial invention. This exclusivity is designed to promote a balance between new drug innovation and greater public access to drugs, which result from copycat versions.  Notwithstanding, big pharmaceutical companies stress that it can take 8 to 12 years after invention to accumulate enough data to get a drug past the FDA.
 
Biosimilars

For 20 years now Roche-Genentech has benefited from its 90% market share of the HER2-positive global breast cancer market. Notwithstanding, the main EU patent for Herceptin expired in 2014 and is due to expire in the US in 2019. Already, the market has experienced the entry of biosimilar versions of trastuzumab, which are expected to be cheaper and therefore extend patient access to the drug. Biosimilars are not to be confused with generic drugs. Regulators require biosimilars to be “highly similar” to the “reference product” but not exact copies of the biologic medicine. Biologic medicines are comprised of large complex molecules, which may be composed of living material. Here we provide some examples of the biosimilar versions of trastuzumab, which are coming onto the market.
 
Trastuzumab biosimilars
 
In December 2017, a biosimilar version of trastuzumab was approved by the FDA and is marketed in the US as Ogivri. Approval of Ogivri was based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data, which demonstrated that Ogivri is biosimilar to trastuzumab. In 2018, Merck Sharp and Dohme (MSD) launched Ontruzan, in the UK, which is Europe’s first biosimilar to Herceptin. Clinical studies have shown Ontruzan to be similar to trastuzumab in terms of its structure, biological activity and efficacy, safety and immunogenicity profile. Studies also showed that in early breast cancer, breast pathologic complete response rates were 51.7% with Ontruzant and 42% with Herceptin, while overall response rates were 96.3% and 91.2% respectively. Mylan and Biocon have launched a biosimilar version of trastuzumab called Canmab in India, and Celltrion, has launched Herzuma, another biosimilar version of trastuzumab in South Korea. According to Mark Verrill, head of the Department of Medical Oncology at the Newcastle upon Tyne Hospitals NHS Foundation Trust, UK, “The launch of biosimilar trastuzumab provides a high-quality treatment alternative for patients, while offering significant potential savings for health providers and patients.”
 
Takeaways
 
The clinical study presented at the June 2018 meeting of ASCO suggested that the treatment time for trastuzumab could be reduced from 12 months to 6 without compromising outcomes. This would significantly reduce the cost of trastuzumab and thereby make the drug available to more breast cancer patients. Although the study’s findings are “persuasive” there is a reticence among clinicians to reduce the treatment time of trastuzumab. The ASCO study throws light on the challenges to reconcile the competing interests of patients, healthcare providers and drug companies. While pharmaceutical companies spend billions on R&D they are challenged to reconcile the demands of shareholders and society. Public funds for medical research, while important, are limited especially at a time of relatively slow economic growth and fiscal constraint. Given that there does not appear to be any credible suggestion to curtail the vast and escalating cost of cancer care more generally, the current situation, which incentivises giant pharmaceutical companies to invest in R&D with 20-year patents, appears to be a formula that will prevail for some time to come, and patients will have to wait significant lengths of time before they get access to biosimilars.  

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