Keytruda, Herceptin and PHARMAC
ATTEMPT TO STOP THE SOLD TRIAL
An attempt has recently been made to stop recruitment of New Zealand women with HER2+ breast cancer in to the Synergy or Long Duration (SOLD) clinical trial.
The SOLD trial is a randomised phase 3 study that compares two Herceptin (trastuzumab) regimes for the treatment of women with early HER2+ breast cancer.
Results from large prospective, randomised trials with limited follow-up indicated that giving adjuvant for 12 months reduces the risk of breast cancer recurrence but this was also associated with cardiac problems.
In a smaller Finnish trial (FinHer), women received nine weekly infusions of Herceptin with their chemotherapy. The risk of the cancer returning and the risk of dying were significantly reduced in the all women who were treated with Herceptin.
New Zealand is part of the ongoing quest to determine whether nine weeks of Herceptin is as effective as 12 months. The Auckland School of Medical Sciences’ website states that “the best duration of trastuzumab for early breast cancer is currently uncertain.” The NZ arm of the trial is recruiting women with five centres participating in the study – Auckland, Palmerston North, Wellington, Christchurch and Dunedin.
The debate around whether nine weeks of weekly infusions of Herceptin works as well as 12 months of Herceptin has raged since 2008.
The AWHC previously described the unsatisfactory way the media reported the findings of two studies (the HERA and PHARE trials) which explored different treatment durations of Herceptin. (See article below) What the researchers actually said about the results of their trials were very different to the interpretations trumpeted in media headlines around the world.
Press releases from Roche, the manufacturer of Herceptin, and the Breast Cancer Aotearoa Coalition (BCAC) stated that both cancer trials showed that one year of Herceptin is best, when they did not. For one of the trials the results were inconclusive, for the other the results showed less is just as good as more.
The Breast Cancer Aotearoa Coalition has recently taken the matter further, presenting their interpretation of the results of the PHARE clinical trial at a meeting of the Northern B ethics committee. BCAC claimed that the PHARE trial results are relevant to the SOLD clinical trial and questioned the ethics of continuing to recruit New Zealand women to the SOLD trial. In a letter to the chairperson of the Northern B ethics committee the Breast Cancer Aotearoa Coalition asked the committee to reconsider ethics approval for the SOLD trial. Several members of the BCAC appeared before the ethics committee on 7th May, along with Associate Professor Chris Frampton, a medical biostatistician from the University of Otago. Their areas of concern related to the balance of risks and benefits to patients, and to the issue of free and informed consent.
After they had spoken Professor Vernon Harvey, who was also in attendance, contested their assertions, arguing that the SOLD trial is currently the most important cancer trial in the world because “we don’t know that 12 months of Herceptin is better than nine weeks.”
He acknowledged that all these trials are running behind schedule due to the fact that, unlike the 12 month trials, these trials are independent. Because they are not supported by the pharmaceutical industry, recruitment in the six-month and nine-week trials is much more difficult, he said. Professor Harvey told the ethics committee that the SOLD trial is as relevant now as it was when it was first started.
As the AWHC noted in its previous article on this issue (1), the patent for Herceptin is due to expire in 2014. This means that Roche is not keen to see any research results that undermine their fiercely-held position that 12 months of its over-priced drug is superior to either the six months or nine weeks treatment regime.
After both parties had left, the Northern B ethics committee went in committee to consider their options. It remains to be seen what the ethics committee will do or how the committee will respond to such a challenge, especially considering the strong arguments both sides put forward to support their position.
THE TRUTH ABOUT THE LATEST HERCEPTIN TRIALS
The way the media has reported the latest findings on two studies which explored different treatment durations of Herceptin is a testament to how gullible reporters have become. Admittedly accessing the facts took some time trawling through the press releases from Roche and the Breast Cancer Aotearoa Coalition which were repeated ad nauseam on media websites.
The search for what the researchers actually said about the results of the HERA and PHARE trials finally resulted in finding a very different perspective to that trumpeted in the headlines in the mainstream media.
The data from the two different trials were presented at the European Society of Medical Oncology (ESMO) conference in Vienna on 1 October. The subsequent hype around the reporting of the results had both studies being presented as great news for Roche when they are not. The headlines also trumpeted that both cancer trials showed that one year of Herceptin is best, when they did not. For one of the trials the results were inconclusive, for the other the results showed less is just as good as more.
The HERA trial
The results from the HERA (HERceptin Adjuvant) study revealed that one year of treatment with Herceptin (trastuzumab) is as good as two years of treatment for women with HER2 positive early breast cancer. Roche was of course hoping that the results would show that two years was better than one, and was preparing to file for regulatory approval for two-year use. With the patent for Herceptin due to expire in 2014, the results have put paid to Roche’s ability to squeeze more value out of its over-priced drug. Some reports suggested that the result cost Roche the $1 billion-a-year boost in sales that the drug company was hoping for.
The PHARE trial
In presenting the results of the PHARE (Protocol of Herceptin Adjuvant with Reduced Exposure) study Professor Xavier Pivot said the results were “inconclusive,” but showed a “trend in favour of 12 months treatment” rather than six months. He said his team was carrying out deeper analysis of the data and would present more results in December. “The results probably won’t give a black and white answer and the researchers will probably need to look at subsets of patients to see who benefits from six months of treatment and who should get a full year,” he added.
As Roche faced a loss of up to $1.5 billion in revenue from Herceptin should the six months treatment regime be shown to be just as effective as 12 months, the drug company was quick to issue a press statement saying that the PHARE trial confirmed the one year’s trial was the best length of treatment. They went further in claiming that women who got six months of Herceptin were 28% more likely to die or have their breast cancer recur than those who got 12 months of Herceptin.
Not so, said the professor
Professor Xavier Pivot, an oncologist at the University of Franche-Comte who led the PHARE study, responded immediately with a statement saying that the Roche statement wasn’t accurate. While the PHARE trial showed a trend toward a year being better than six months, the data wasn’t statistically significant. So while investigators couldn’t say that six months are just as good as a year, they also couldn’t say that a year is better.
Data still developing
Professor Richard Gelber, the senior biostatistician on Roche’s own trial, agreed that the French study was inconclusive. PHARE hasn’t been going long enough for the data to be mature, he said. As the data is still developing, he advised doctors to wait at least a year before telling the public six months’ treatment is inferior. This is of course not the message that Roche wanted told.
Billions of dollars are at stake as doctors and health systems around the world attempt to come to grips with the data presented in Vienna. If researchers can show that six months of treatment are just as good or better than a year, public and private health systems as well as women with HER2 positive breast cancer stand to gain. For example, in countries that cannot afford the cost of 12 months of Herceptin, governments would be able to offer women six months of Herceptin.
It is very disturbing to see how the results of these two trials have been presented in the media. The AWHC is also aware that Roche was quick to contact any reporter who didn’t spin the story the way they want it spun.
The Cost of Herceptin
The following article about Health Minister Tony Ryall's refusal to release the cost to the government - and of course the New Zealand taxpayer - of the 52-week course of Herceptin appeared in the Otago Daily Times on 9 November 2009:
WOMEN CHOOSING NINE WEEKS OF HERCEPTIN
Contrary to expectations, it was reported at a District Health Board meeting that many women in the Auckland region with early HER2 positive breast cancer are choosing to have nine weeks of therapy with the anti-cancer drug Herceptin rather than the 52-week treatment regime promoted by Roche, the pharmaceutical company that manufactures the drug.
Despite Pharmac’s recommendations to the contrary, the current government agreed to provide public funding for the 52 weeks of Herceptin as an election bribe in the lead up to last year’s general election. Minister of Health Tony Ryall said that the exorbitant cost of the drug would be funded from the extra $180 million the government planned to spend on pharmaceuticals over the next three years.
At a meeting of the Auckland District Health Board's Hospital Advisory Committee on 2 September 2009, it was reported that the uptake of the 52-week course of Herceptin was considerably less than expected. It seems that many of the women with HER2 positive breast cancer are doing their own research on the efficacy of the nine-week course and the health risks associated with the use of this very toxic drug, and following discussions with their specialist they arrive with their decision made. Aware of the increased risk of heart damage and the necessity of having the five to eight echocardiograms instead of the two to check heart function that are required for the 52-week course, they are choosing the nine-week course of Herceptin.
Tony Ryall’s press release
If Health Minister Tony Ryall’s recent press release is anything to go by, it appears that Auckland women are not the only ones who have chosen to go with the nine-week course. On 23 October 2009 his office issued a press release – presumably in response to the earlier comment in the Dominion Post editorial that referred to “his daft decision to fund Herceptin” – with the numbers of women who have received the 52-week course. The press release stated “the Minister says 174 women with breast cancer were on a twelve months Herceptin course as at the end of August 2009.”
Given that in New Zealand 2,300 women are diagnosed with breast cancer each year and approximately 25% of them will have HER2 positive breast cancer, that figure is surprisingly low.
Research trials continue
There are a number of international trials underway on Herceptin that aim to test whether a shorter course will produce the same results as the 52-week course.
In the UK a trial comparing six months with 12 months of Herceptin for early breast cancer is underway. Known as the Persephone trial, the study has two aims – to find out if six months works as well as 12 months, and to see if having treatment for a shorter time can help lower the risk of damage to the heart. Recruitment started in October 2007 and will continue until October 2012.
An international trial, the Synergism or Long Duration (SOLD) trial comparing the nine-week course of Herceptin with 12 months is also underway. Led by the Finnish Breast Cancer Group and Heikki Joensuu from Finland whose earlier FinHer study provided the first evidence that nine weeks works just as well as 52 weeks, the SOLD trial includes New Zealand women who have chosen to enter it.
Dr Susan Love
The world-renowned breast cancer specialist and researcher, Dr Susan Love predicted that subsequent trials would confirm the efficacy of shorter courses of Herceptin when she spoke at the conference for Breast Cancer Survivors held in Rotorua in 2007. “If you are a drug company you’re going to introduce a drug for a long period of time because that’s how you make your money. Then it is only once it is introduced that people start chipping away at really trying to find out what the optimal time range is,” she told those attending the conference.
FUNDING FOR HERCEPTIN
Since 2006 the AWHC has been closely following the debate surrounding the promotion and funding of various treatment regimes with Herceptin for women with HER2 positive breast cancer. During this time the Council has become increasingly concerned at how the debate has been constructed in the media and has failed to focus on the evidence currently available regarding the benefits and risks of the 9-week and 12-month courses of Herceptin.
The Council continues to advocate for an evidence-based approach to be taken regarding the use of Herceptin while the results from the drug trials are gathered and fully reported upon. The controversy over access to this drug and the best treatment regime being argued for by both the drug’s manufacturer and breast cancer groups continue to obscure the facts and has lead to a narrow focus on the cost of the drug for patients and the concurrent demand for public funding.
Sophisticated media campaigns continue to use stories of individual breast cancer patients, statements from patient support/lobby groups and selected comments from medical opinion leaders. Media coverage has rarely mentioned doubts about the claimed benefits of the 12-month course of Herceptin, the different outcomes for sequential as opposed to concurrent treatment regimes or the significance of the missing data from the clinical trials. Nor have they questioned the exorbitant cost of the drug.
A recent study undertaken at the School of Public Health at the University of Sydney examined the media influence on Herceptin subsidisation in Australia and revealed that the “claimed benefits of Herceptin often conflated cancer non-recurrence and survival and favoured quantification rhetoric which emphasised percentage increases in improvement rather that the more modest increases in absolute survival.”
As has happened in New Zealand, the Australian government’s financial parsimony was framed as responsible for the women’s plight, while drug industry pricing was never even mentioned. (1)
As the AWHC reported in its March and April 2007 issues of its newsletter, it is the interests of Roche, the manufacturer of Herceptin, to continue promoting the 12-month treatment regime as “the gold standard.” It is also hugely significant that Roche refuses to fund further larger clinical trials that aim to investigate the safety and efficacy of the 9-week concurrent treatment option.
Funding 12 months treatment
The AWHC does not support public funding for a 12-month course of Herceptin for the following reasons:
· There has been no new evidence presented that would indicate that a 12- month course of Herceptin is a great deal more effective than a nine-week treatment period of Herceptin administered concurrently with taxane.
· There is a reduced risk of cardiac toxicity with the shorter treatment period.
· The evidence published so far has revealed that administering Herceptin concurrently with taxane appears to be more effective than administering Herceptin sequentially after other chemotherapy.
· As Roche has not published the data from a key clinical trial and continues to withhold the results of this trial, the AWHC believes that it is very likely that the data on the missing women are being withheld due to the fact that including them would reduce the claimed effectiveness of administering Herceptin sequentially – Roche’s preferred treatment regime.
· The results of a small trial recently presented at the 2008 annual meeting of the American Society of Clinical Oncology showed that the addition of Tykerb to Herceptin improves progression-free survival in pre-treated women (2). This is further evidence to support the proposition that administering Herceptin for HER2 positive breast cancer concurrently is more effective than sequential therapy.
· Despite the small size of the trial, the FinHer study revealed an appreciable effect, where disease-free survival was statistically significant.
· In the context of the New Zealand health care system and the budget constraints faced by the District Health Boards a cautious approach to the funding of Herceptin is justified, particularly when faced with the withholding of important data from clinical trials and the resulting publication bias. (3)
Dr Susan Love’s visit
During her visit to New Zealand in October 2007 as the key note speaker at the conference held in Rotorua for breast cancer survivors, Dr Susan Love commented at the conference and subsequently on public radio, saying “I worry that as with many other treatments the way that we first introduce a drug is not the way that it ends up being the best done.
Chemotherapy for breast cancer was initially done for two years, then we found out that one year was better, then we found out that six months were actually better. So if you are a drug company you’re going to introduce a drug for a long period of time because that is how you make your money.” (4)
The AWHC notes that Dr Love was supportive of the decision NZ health authorities had made to fund the nine-week course of Herceptin.
As well as supporting an approach that ensures the health and wellbeing of women is the highest priority rather than the vested interests of the drug companies, the Council believes that the research currently being done will result in answers to the questions about the optimum duration and the sequencing of Herceptin treatment.
Until the issues that still need to be resolved regarding the long-term efficacy of the various treatment regimes for Herceptin, the comparative clinical effectiveness of 12 months versus shorter treatment periods, and assessment of toxicity and adverse events, etc, it is entirely appropriate that health authorities resist both public pressure and the private pharmaceutical companies’ demands for scarce health dollars to be spent on what is very likely to turn out to be unnecessarily prolonged treatment periods with a vastly overpriced drug that carries an increased risk of adverse effects.
Until further research whose results are not controlled by the drug company reveals whether 12-months is actually more effective than the nine-week course of Herceptin, the AWHC supports the subsidising of treatment with Herceptin for HER2 positive early breast cancer patients when it is administered for nine weeks concurrently with taxane.
1. Ross MacKenzie et al. “Media influence on Herceptin subsidization in Australia: application of the rule of rescue?” Journal for the Royal Society of Medicine 101:305-312 2008.
2. J O’Shaughnessy et al. “A randomized study of lapatinib alone or in combination with trastumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy.” Program and abstracts of the 44th American Society of Clinical Onoclogy Annual Meeting: 30 May – 3 June, 2008; Chicago, Illinois. Abstract 1015.
3. Scott Metcalfe et al. “Trastuzumab: possible publication bias.” The Lancet. 17 May, 2008.
(4) Dr Susan Love. Commenting in response to a question posed at the conference for breast cancer survivors and on public radio: October 2007; Rotorua, New Zealand.
DR SUSAN LOVE ON HERCEPTIN
At the end of October 2007 New Zealand’s first conference for breast cancer survivors was held in Rotorua and featured Dr Susan Love as the key note speaker.
Dr Love is a world renowned breast cancer specialist and researcher, and at the end of her presentation she was asked about her thoughts on the New Zealand government’s decision on funding for Herceptin. She told the 450 women attending the conference that the funding and trial of a 9-week course of Herceptin for women with breast cancer in this country is to be applauded, and that there was not enough research to conclusively prove 12 months of Herceptin was more effective at treating breast cancer than three courses of the drug over nine weeks.
Her comments caused an audible gasp from the audience.
In July 2007 Pharmac made the decision to fund Herceptin over a 9-week course for a total cost of around $6 million compared to $30 million for 12 months. Dr Love said a trial over nine weeks is necessary to test the drug’s effectiveness.
“The first study ever done on it was done on giving Herceptin for a year and showed some beneficial results. I worry that as with many other treatments the way that we first introduce a drug is not the way that it ends up being the best done. Chemotherapy for breast cancer was initially done for 2 years, then we found out that one year was better, then we found out 6 months were actually better,” she said.
“So if you are a drug company you’re going to introduce a drug for a long period of time because that’s how you make your money. Then it is only once it is introduced that people start chipping away at really trying to find out what the optimal time range is.”
Dr Love said she wouldn’t be at all surprised if a 9-week course of the drug is eventually found to be as good as 12 months.
“There is data from a small study from Europe to suggest that it is. It would not surprise me at all if that were the case – and I think it would be better – because the long term side effects are likely to be less.”
Dr Love says Herceptin is good drug but shouldn’t be seen as a miracle one. She is a strong advocate of early detection of cancer cells and her research is currently focusing on this. Dr Love says fluid can now be sampled from breast ducts and analysed to find a cause of the cancer. She believes that better early detection is probably more realistic than finding a cure for cancer.
THE TRUTH ABOUT HERCEPTIN AND THE FINHER STUDY
At the beginning of the year another round of public controversy hit the headlines when Pharmac announced it was considering funding a nine-week course of the breast cancer drug Herceptin for women with Her2 positive early stage breast cancer.
Once again the facts were obscured by reporters, clinicians and lobbyists who were quick to voice their condemnation of the decision to fund a nine-week course of the drug rather than the 52-weeks recommended by the Herceptin manufacturer Roche. The managing director of Roche NZ, Svend Petersen, said he was going to seek an urgent meeting with Health Minister Pete Hodgson in an attempt to get the decision over-turned, stating “this has the potential to be this Labour government’s unfortunate experiment.”
The truth is far less clear-cut than the news media and the pharmaceutical giant Roche are prepared to admit.
The Herceptin drug trials
Out of a total of 13,609 patients who have been involved in eight clinical trials regarding the anti-cancer drug Trastuzumab (otherwise known as Herceptin), 8,724 were treated with Herceptin. Of these just under half were given the drug after their chemotherapy treatment (sequentially), and just over half received the drug during their chemotherapy (concurrently). The difference between these two groups is very important, because the data reported so far from the eight studies have revealed that sequential treatment is significantly less effective than concurrent treatment, although the latter carries greater risks of toxicity including damage to the heart.
Sequential Herceptin studies
There are two large studies on the effectiveness of 12 months treatment with Herceptin after chemotherapy. One study of 1694 patients (HERA/1 year) showed some benefit, the other study involving 985 patients (N9831 arm B) did not. A third study involving 1694 patients (HERA/2 year) has yet to be reported, and another study (N9831 arm A) is missing. Roche has said it is unable to supply the full data for the missing arm of N9831. This is a significant and worrying issue given the amount of money involved and the need for full disclosure by drug companies of all the results of drug trials.
Concurrent Herceptin studies
There have been five studies on the effectiveness of Herceptin given concurrently with chemotherapy. Three of these involved 52 weeks of concurrent treatment with Herceptin, one of which is a study of 840 patients (N9831 arm C), a fourth study (FinHer) involved 9 weeks of concurrent treatment with Herceptin, and the fifth study (Sledge) involved a comparison of 52 weeks with 10 weeks of concurrent treatment with Herceptin.
The data on the 116 patients in the FinHer study is for 3 years of follow-up and reveals that short duration concurrent treatment with Herceptin is effective at preventing recurrence of disease. In Finland both the 52-week course of concurrent treatment with Herceptin and the nine-week course are available to women. However Finnish doctors prefer the 9-week course because there is less likelihood of cardiac damage and because the doctors were involved in the FinHer trial and saw for themselves the benefits to their patients of the 9-week course. This experience makes a big difference when doctors are making recommendations to their patients on best treatment options.
The data on the 227 patients in the Sledge study is for 5 years of follow-up and it showed no difference in survival rates between those who received 10 weeks of concurrent treatment with Herceptin and those who received it concurrently for 52 weeks.
It is obvious that the issue of concurrent treatment with Herceptin versus sequential treatment is at the core of this debate. The results of these studies revealed that concurrent treatment with Herceptin results in significantly better efficacy than sequential treatment with the drug, all of which casts grave doubts on the superiority of the sequential treatment regimen being promoted by Roche.
The pharmaceutical industry is an extremely powerful lobby group that has a vested interest in the outcome of drugs they produce and market. As a recent article in the Sunday Star Times revealed, the reason other countries have not opted for the 9-week course of Herceptin is because in places like Britain it is the drug manufacturer who decides what treatment period they will request for their new drug, and of course in the case of Herceptin, Roche put forward the more expensive 52-week course of treatment.
The international trials just described have raised important questions about the optimum duration and sequencing of Herceptin treatment. A further trial is being planned to find the answers. It will be headed by Professor Heikke Joensuu of the University of Helsinki in Finland, who headed the FinHer trial and who has extensive international experience in trial design and management.
Roche of course is not interested in funding further nine-week trials of Herceptin. The interests and position of drug companies around issues such as research choices, length of treatment and treatment sequencing, not to mention pricing, do not always align with the public interest or even patient safety. The promotion and marketing in New Zealand during the 1970s of fenoterol for asthma, and HRT during the 1980s for women during the menopause are powerful evidence of that.
Meanwhile Pharmac has indicated funding support of NZ$3.2 million should the trial proceed. New Zealand’s participation depends on Herceptin funding decisions and on support from New Zealand oncologists to recruit patients to the study.
Roche of course will be doing all it can to ensure that other countries don’t follow suit.