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Standing Committee on Health
14/04/2014
Skin cancer in Australia

BROWN, Professor Michael Paul, Director, Cancer Clinical Trials Unit, Royal Adelaide Hospital

[13:48]

CHAIR: Welcome. I will go through some procedures before we start. Do you as a witness appearing before the committee have any objection to being recorded by media during participation in this hearing?

Prof. Brown : No.

CHAIR: Although the committee does not require you to give evidence under oath, I advise you that these hearings are formal proceedings of the parliament and warrant the same respect as proceedings of the respective houses. The giving of false or misleading evidence is a serious matter and may be regarded as a contempt of the parliament. The evidence given today will be recorded by Hansard and attracts parliamentary privilege. Would you like to make a short opening statement to the committee?

Prof. Brown : I am a medical oncologist by training, but before that I was a clinical and laboratory immunologist, so I have got a background that allows me—fortuitously probably—to take advantage of many of the changes that are occurring, particularly in the care of melanoma patients. The role I have at Royal Adelaide Hospital is to head the Cancer Clinical Trials Unit, which is the largest cancer clinical research unit in the state. We run a broad range of cancer trials—over 40 of them—mainly for patients with all sorts of cancer, including melanoma. Those trials vary across medical oncology, which is the use of systemic treatment for cancer, through radiation oncology—and we have run some gynaecological oncology trials as well.

My role as a clinician is that I am a senior medical oncologist at Royal Adelaide Hospital. I have been there for over 15 years. I see mainly patients with melanoma but also patients with lung cancer. It has been a very exciting time to start treating patients with melanoma, because of very recent advances, but unfortunately on that one end of the spectrum of care of patients, where they have disease that is not able to be treated by a surgeon, that is non-resectable disease. We need an approach that is based on systemic treatment. I will come to the major classes of systemic treatment, but that is what medical oncologists give as part of their professional role.

We are in a very fast-moving period of development of drugs, and I think some of the issues that are important are: based on continuing clinical trials and support of that, access to drugs, which can be in terms of making them available on the PBS in a timely manner so that they can exert their life-saving benefits; making them affordable—and there are various ways that have been put forward more recently about how that might be addressed, some of which I would agree with; and also making it easier to conduct clinical trials and to continue to foster that in this country. I think that is also very important, because that is how any drug that is eventually approved on the PBS got there in the first place.

It got there through these very rigorous processes, starting with bench work in the laboratory, through to an early phase trial, which is largely what I concentrate on, through to one that proves how efficacious it is and to a third phase which proves whether the drug knocks off a standard of care and replaces it or what its true role is. Then there are post-marketing or phase 4 trials, where further data can be collected about use and efficacy in the community. I think the example with the deal struck between Bristol-Myers Squibb for ipilimumab, a very expensive drug, and the Commonwealth government on them collecting survival data is a very important exercise. I would hope to see more of that, which will help properly inform the place of these drugs and how best they can be afforded. I think collecting more evidence is probably more vital and making evidence based decisions. That is what I have to say at this point.

CHAIR: You just talked about the recent exciting changes in drugs that are available. What sorts of changes have you seen? Could you get a bit more specific?

Prof. Brown : I think melanoma is at a place where some other cancers have been a few years ago, such as breast cancer, for example. It is the ability to define subsets of patients who will benefit more clearly from some sort of treatment more targeted towards the change in their cancer. That has been the case with breast cancer for decades and for prostate cancer, where treatments are based on the fact they carry hormonal responsiveness encoded in a receptor—the oestrogen receptor and the androgen receptor respectively in breast cancer and prostate cancer. So there have been many drugs that have led to control of disease—not cure, except perhaps in the adjuvant setting; that is, after surgery. Melanoma is really starting to be at that place. But what has also driven it is the new sciences of genomics and molecular diagnostics, which mean we can fairly accurately up-front now have the ability to diagnose patients with a particular molecular lesion. That would mean we could use a drug to specifically target that lesion and get the greatest effect—which may not be curative but it may lead to control of disease and actually may prevent death in the short term.

I would like congratulate the Australian government through its committees and agencies on the Medical Benefits Schedule listing of BRAF mutation testing, for example, and particularly the way it has been done, where the diagnosis is really based on detection of mutation rather than using a particular test to diagnose a mutation. This is in contradistinction to what happens in the United States, where drugs are approved based on clinical trial data, where they are tied to the particular diagnostic test used in the trial to diagnose the mutation. That is how the drug gets approved. The drug is approved along with a companion diagnostic. Here it is different. We have got a process that allows up-front mutation testing on the standard diagnostic material that is actually used to make the tissue diagnosis of melanoma. It also allows in the wording that pathologists are able to perform reflex testing. So, instead of having a requirement from a clinical practitioner to say, 'I want this test done because I want to know if they have this so that I can treat them with this drug,' the pathologist automatically can do this testing. That means there is no further delay. There is no attempt by any other practitioner to have to retrieve a block tissue from some pathologist out in Woop Woop, which they may not want to do, they are not getting paid for it, and it can lead to enormous delays. I think this is a critically important advance in improving care of melanoma patients who have got advanced unresectable disease.

That is, for any of us in medical oncology, where it starts. We need to know what the particular genetic change is and then what drug we would then use. It is the beginning of a decision tree, if you like. So if a patient has a BRAF mutation we can then decide, 'They will be eligible for this drug and that drug,' and if they fail they may be offered this trial or that trial, and at the hospital we can get other mutations besides BRAF mutations detected, which might allow us to ask a company for access for a drug that is not approved for the specific indication of melanoma, which is available off label but approved for other indications in this country. To give you an example, there is a rare mutation called a KIT mutation—two per cent of melanoma—and we can approach one of the companies for their drugs and say, 'Would you be happy to look at some shared funding arrangement or free access for the patient so that they can get potential benefit from this drug.'

The other advantage of this up-front mutation testing is that we can then more accurately allocate patients to arms of clinical trials based on the mutation status in their tumour. If they do not have any of these mutations then we can default to a standard PBS-listed treatment, which is ipilimumab, or Yervoy, the trade name—which is an immune therapy. The two major classes of therapy that I alluded to earlier—there are three, really—are targeted therapies, which are drugs directed towards specific molecular lesions in the melanoma; immunotherapy, or immune based treatments, and the only registered and approved PBS listed one is ipilimumab but there will be others coming which we can talk about; and cytotoxic chemotherapy—which, until 18 months ago or less, was the standard treatment for melanoma. It still has a role but there is now probably a role later in sequence to these other treatments.

Dr SOUTHCOTT: I would like to ask you about the tyrosine kinase inhibitors—the ones that are useful in people who express the BRAF mutation. My understanding is that while they do perhaps increase the period that you are symptom free, they have a period where they will work and then eventually people will acquire some sort of resistance to the tyrosine kinase inhibitors. So thinking forward to the future they have got a role in the treatment of advanced metastatic melanoma but what can we expect their place is going to be?

Prof. Brown : The first thing to say is that many of the data in this area are not very mature, so we actually do not have long-term follow up —and by long-term I mean beyond two years. It is hard to say actually how many people will ultimately benefit from this class of molecules. To contrast that with the PBS-listed medication Yervoy or ipilimumab, of the starting population that you treat, really only one in 10 will ultimately benefit. Most patients will fail the treatment. That data certainly goes out now to four years post start of the treatment. It could be that when the data is mature for these kinase inhibitors that you might get similar rates of maintenance on this treatment. I have quite a few patients who have been on it for two to three years who are getting benefit just from one of those kinase inhibitors. It is likely that when two get applied—which is likely to be the case this year, hopefully, for PBS listing of GSK's Mekinist, trametinib, and Tafinlar, or dabrafenib, which they have already listed—this will, on current indications, extend that progression-free survival interval where they do not have evident disease by another 50 per cent. So it could be that you will have a tail to the survival curve or a plateau of patients who are on long-lasting treatment, because we do not understand the heterogeneous biology of many of these tumours. So there could be a small proportion who actually do continue to derive benefit. By saying that I am not saying that that represents a cure; I am just saying that it could represent in a small subset—maybe as large as that who benefit from ipilimumab. It is a meaningful proportion of patients who get benefit.

A lot of excitement in the field is looking at combinations of immune therapy and kinase inhibitors. That largely is in the province of early phase clinical testing. There was a trial that combined ipilimumab with Roche's drug vemurafenib the which is TGA approved but not PBS listed. That was stopped because of unacceptable liver toxicity. To my knowledge there is a trial still ongoing of GSK's drug dabrafenib and ipilimumab. That is still recruiting, so there must be something that has not stopped it. What the ultimate result will be I do not know. This company GSK is looking at combinations with their kinase inhibitors with the anti-PD-1 drugs, which are probably the most promising class of these immune checkpoint inhibitors in which ipilimumab is included as an immune therapy. I think we have yet to see the answer on this but I think there is a lot of hope and anticipation that there may even be a breakthrough in this area by the combination.

Dr SOUTHCOTT: At the moment you are buying some time which previously was not possible with the pre-existing drugs.

Prof. Brown : Absolutely. That is vital because things can always be different in six months or 12 months. One of the companies is looking to likely have an access program for their anti-PD-1 molecule. So if I can keep someone going for another six months, and they fail—the disease becomes resistant and they progress—maybe I can give them the opportunity of accessing that drug. Maybe I will have a new trial that I can put them on. People do live longer as a result of these things, including trials. There is even evidence for phase 1 trials of molecularly targeted agents that on the whole the patients who are in them do better than historical controls. They are not randomised control trials but some of these new molecules are very promising. I think having the whole mix available is actually very important for patients.

Dr SOUTHCOTT: Do you have access at the moment to any anti-PD-1 drugs?

Prof. Brown : I do not right now. One of the major sponsors has had two trials at our site and they are close to accrual. These trials are popular. They are global trials and they are competitive. So we do not have any access right now to an anti-PD-1.

Dr SOUTHCOTT: The access at the moment is through clinical trials?

Prof. Brown : That is right.

Ms RISHWORTH: I was going to ask a couple of questions. Firstly, you mentioned that the standard treatment has changed quite significantly in 18 months and you are obviously very closely connected with the clinical trials. Would you say that oncologists right around the country have been as quick as you to move into this fast moving space? How are the new treatments, the new things on offer, best communicated so that they become standardised treatments that every patient is getting, no matter who their oncologist is?

Prof. Brown : I am at a centre, as many of my colleagues are, where we are the major centre in the state. When there was a lot of excitement earlier on, particularly with the BRAF inhibitors, we would get referred patients. Now that they are on the market I do not get so many referrals, at least for that reason. It is a fairly small community, so people are often aware enough as medical oncologists if there is something good. There are ways of communicating formally and informally with colleagues to let them know what trials you have and people will be put on trials if they are eligible. So there is nothing different there.

Once these drugs are out on the market, though, you are right—there is a continuing need to inform practitioners about their availability, the best use and safe use of them. I have been invited to head a steering committee for one of the companies which will have a whole day session for exactly this purpose in July. So it will invite oncologists from around the country for just this purpose. While there is a company sponsoring it, it is untied in terms of mentioning other drugs and so on.

In the profession we are very aware of what is new, because that is actually the case for nearly all of the tumour types. Things are moving so quickly. It is not just melanoma—they are all moving so quickly. We all have to try and keep abreast of many changes happening right now.

Ms RISHWORTH: Of course, if you are talking about prolonging someone's life for six months, as soon as it is available it is so important for all oncologists to be onto it as quickly as possible.

Prof. Brown : Right. If you are also alluding to access and equity of access, I think that is a separate and related question. In our country this is a real issue. In this state we certainly see it. Many of the patients at Royal Adelaide Hospital—outpatients and in-patients—come from the country. There are very small hospitals in the country. There are very few hospital based specialists in those country hospitals, and so most of the referrals for any treatment are to city specialists. So it is something we wrestle with all the time. It is not easy to do this, but we do our best to try to get people treated as close to home as possible.

Ms RISHWORTH: Do you work in a multidisciplinary team?

Prof. Brown : Yes.

Ms RISHWORTH: You do. Who makes up that team?

Prof. Brown : I chair the one at Royal Adelaide Hospital. It is made up of the diagnostic disciplines—the pathologists, the nuclear medicine physicians, the radiologists—and the surgeons. There are dermatologists, the skin specialists, as well as medical oncologists and radiation oncologists. So they are the main groups who are involved. We discuss five to 10 cases every fortnight and attempt to come to a consensus management.

Ms RISHWORTH: Do you have social workers or people who support the patient and the family through it?

Prof. Brown : Individual units might have those services. It is not appended to the multidisciplinary meetings that I have chaired. It would be a great idea. It would be good to have a coordinator. Some of the multidisciplinary clinics do. Lung cancer I am familiar with. It does have funded coordinators and I think that sort of role is probably the most important ancillary role for a multidisciplinary team meeting.

Ms RISHWORTH: Thank you.

CHAIR: Mr Wyatt?

Mr WYATT: Thank you, Chair. There are a couple of things I want to ask about. I want to ask about the genomic studies. I want to ask about that because I went to a presentation by the Garvan Institute in which they suggested that we should not distinguish between the cancers and we should just call it 'cancer', because of some of the proteins and because by locking in a specific cancer we sometimes create a mindset that a drug will only work on that cancer when in fact research is showing that that particular drug may work on three or four.

Prof. Brown : Sure.

Mr WYATT: How far have you progressed work in that area in what you have done in terms of both the pox virus based vaccine and your novel antibody work?

Prof. Brown : I think they are separate programs.

Mr WYATT: I know they are separate.

Prof. Brown : I collaborate with a group and I am a member of the Centre for Cancer Biology, which is now a formalised alliance between SA Pathology—the main pathology provider and the University of South Australia. The centre has an Australian Cancer Research Foundation, ACRF, funded genomics facility. So it is actually quite a sophisticated facility. There are probably only three or four in the country. And it has some of this sophisticated equipment you are alluding to, that allows sequencing of tumour genomes to know what sort of mutations are present that you might use to guide therapy.

I agree with you; I think it is important to be agnostic about what can be in a particular tumour and what drug you might use. The difficulty will then be getting access to that drug; that would be the problem. Our system does not really allow for that to easily happen. Often what you might then have to do is, if you do find such a mutation—for example, the BRAF mutation made famous by melanoma is in a whole lot of weird and wonderful diseases—we have to go to a company and say, 'What do you think?' and we get compassionate-use access for this drug, which of course is a cost to the company. They are probably never even going to apply for a listing if it is a rare disease unless they have some global strategy to do that for a rare disease.

So this is the kind of problem: once we know what might be responsive and what might allow tumour control, how do we actually get the drug? And who will pay for it? So that is not solved, to my knowledge. If it is indicated, that is fine, but it only got there because of all the tumour-specific testing. That is how all drugs get approved; they get approved for an indication in a specific tumour type, not for tumours with BRAF mutations, or whatever they might be. They do not get approved that way. So, unless the system changes, we will not have a way of addressing what these genomics initiatives can throw up.

Mr WYATT: That will be part of the challenge that I would seek advice from you on. If that does throw up that a particular drug will have an impact—it does not matter what degree that is—if it has a generic impact in slowing down the growth of a tumour or reducing it, what would your advice be to this committee? What change is required to allow that—without putting a drug company back through a protracted process, and given you have evidence in the genomic work you are doing?

Prof. Brown : I do not know that the genomic work itself represents sufficient evidence. Just finding a mutation does not mean 'two plus two equals four'. Again, I can turn to BRAF as an example. There are many colorectal cancers, bowel cancers, that have BRAF mutations in them, probably four or five per cent. If you just give a BRAF inhibitor, it will not work because it actually has a way of looping back and stopping it working. You have to apply another drug, an EGFR inhibitor, to get them both to work together. The only way you are going to find that out is by doing a clinical trial. So you cannot escape the rigour needed to find the patients who will truly benefit in the clinical trial. I think what is more important is enabling that process and getting industry—perhaps—and government on board to make that easier and to make the regulation of that easier.

I do not think it is going to be simply a matter of saying, 'We've got a list of mutations we've seen in your tumour. Therefore we know there is a list of drugs that could work.' You would want a bit more information on that besides just giving the money over. That is the process, even if it is a laborious one. That is the process currently used: hand the money over to ultimately give to companies to get the drugs for mutations, because you have the clinical evidence for it. I do not see why you would not try to have the same due diligence applied, if you like, for rarer mutations in a wider range of tumours. I think the system does need to be fixed, but maybe not just to allow a diagnostician to say 'Tick' on this mutation or this drug. It needs to be about accumulating the clinical evidence through trials.

Mr WYATT: The other point they made is that there are drugs that we prescribe for an individual that are the standard and yet they do not work on them because of particular proteins or enzymes that they have. There must be an easier way in which we can also look at how the collective wisdom and knowledge of the medical profession within your field could derive a set of solutions in the long term that governments should be more responsive to.

Prof. Brown : That is called research and that is the challenge. It just does not happen that quickly or that easily. This is a general plea to make sure that funding is at least maintained for medical research if not increased. If health spending is going to increase, some relationship or formula needs to apply to medical research to make sure it also increases to address the very things you are raising.

Mr WYATT: How much of the NHMRC grants give a focus on key areas of medical research in this area of health need?

Prof. Brown : Probably not as much as you might like. There are at least a couple of strains of thought about this. One is not to have curiosity-driven or discovery based research and the other is to fund more translational research. I do not think they are mutually exclusive. I think they are related to each other. It is very important to fund areas in curiosity-driven or discovery based research on which we are internationally competitive. That is vital. We might lead to some breakthroughs that other people can copy instead of the other way around, but we need to tie it better to practice. The NHMRC already has a category called clinical practitioner fellowships where some time is bought from the public health service, for example, to allow a practitioner to spend more time on translational research; that is, taking it from the bench to the bedside. More initiatives like that are important rather than prescribing the actual kind of research that needs to be done. There is some irritation amongst scientists that they are required to give some clinical rationale for what they are doing. I am in two minds about that. I do not think it is a bad thing. It certainly focuses you on what is important and probably gets you to talk to clinical colleagues, if they are available. That is the point: you have to have career paths for clinician scientists who are strong to enable them to participate and have the time to do it. That is vital. More can be done in that area.

Ms RISHWORTH: One of the biggest things is facilitating more clinical trials. You alluded to some current barriers. What are those barriers? Obviously more money was the response to actually do this research, but are there any other structural barriers that prevent clinical trials from going ahead, where can you see more ability to conduct clinical trials, including things such as connecting clinicians with the ability to do research?

Prof. Brown : One is infrastructure and funding infrastructure, which is more money. It is not otherwise funded. It is about making sure you have the right information systems and the linked information systems. This is a big idea, and NHMRC is attempting to address this through the Research Translation Faculty, for example. But we need much, much better data linkages to Commonwealth databases—for example, the MBS and PBS. People are crying out for this, as you well know.

We need to make sure that we have a pool of trained coordinators who have a career path, and these are the people who collect the data. It is a bit fly-by-night at the moment in the way they are organised. Linking some of the clinical research units in this country together in more formalised ways might help—getting them to talk to each other, to pool resources in some way. There has been an attempt to nationalise the ethics submission processes. That has a good and bad side. It actually makes it very cumbersome until you are used to it. It also puts an extra burden on the site that initiates the process, because then they have to take all the reporting for all the adverse events for the entire country. Are they properly funded for that? Probably not.

The other aspect to it is the research governance aspect. It is only recently in many institutions that that has been separated from the ethics review process. This is also a highly cumbersome process that I think should be streamlined. It has really been at state level. To me it has been an inhibitor and has put companies off placing their trials because it may take them three or four months or longer. It used to be two months but now it is three, four, five or more months and counting sometimes to get a trial started. Some of the stuff is purely bureaucratic. It is creating an audit trail rather than being forward-looking. It is making sure we have got all the paperwork in case something does go wrong. It is good to be safe, but you can maybe collect that at the same time as the ethics submission process is occurring. I do not think some of these processes are well integrated or coordinated.

Ms RISHWORTH: So the ethics process is a national coordination but the other processes are state based?

Prof. Brown : It is institutional and organised largely out of SA Health, which is now in this state a centralised entity anyway—no hospital boards or anything. It is all run out of SA Health. I am not speaking on behalf of SA Health, by the way.

Mr WYATT: No. It varies from state to state. Having worked in two jurisdictions, I know that it is problematic. There are also Indigenous ethical processes in place that are problematic—I am not saying the Indigenous process is problematic, but the time factor becomes pushed out.

Prof. Brown : And you also have to recognise that a lot of the work of the people on these ethics committees is voluntary. It is not funded. It is out of the goodness of their hearts that many people are doing this work. I actually serve on the ethics committee at the Royal Adelaide in a very limited way in looking at haematology trials. My haematology colleagues look at oncology trials. It is a big burden; it is a lot of work. So ways that help people stay in the game and allow them to make a commitment, and maybe some sort of funding scheme that allows them to devote a bit of extra time—something like that that is competitively based—might be helpful. Having good people who know what they are doing and who are experienced is very important on an ethics committee. I am not saying that we should cast off any of the processes—they are all important—but just make them work better and more efficiently.

CHAIR: Professor Brown, I have a question, which I think is a bit relevant, about a drug called Zelboraf. Do know about that drug and what stage it is at?

Prof. Brown : If that is the one I mentioned earlier, it is known by its generic name, vemurafenib. It is the Roche drug. It is TGA approved but not PBS listed. As far as I can work out, this seems to have been based on the company making two submissions to PBAC and then ultimately not being satisfied with the price that was being discussed and withdrawing from the process.

CHAIR: So it is only the price that is—

Prof. Brown : That is my understanding. And the drug that is competitive that they could subsequently list at the price would have been lower.

CHAIR: I have a note from someone who actually had a positive outcome from using it.

Prof. Brown : It is the same sort of drug as dabrafenib, or Tafinlar, which is a GSK drug, and there really is much of a muchness. The two drugs differ a bit in their side-effect profiles, but their efficacy is almost identical.

Mr WYATT: You mentioned adverse events in the early-stage trials. How do we handle those in Australia?

Prof. Brown : They are reported locally to the ethics committee, which is the first port of call. The sponsor of the trial, which is usually a pharmaceutical company, will also have a mechanism for rapid reporting of adverse events, which is typically now done online; much of the data gathering for clinical trials is online. The other organisation that needs to know is the Therapeutic Goods Administration. But once it is a trial they are typically not involved; it is only really with a registered drug that they would be involved. So, the trial reporting mechanisms are first local, the ethics committee, and then the sponsor.

CHAIR: Professor Brown, thank you very much for taking the time to come to talk to us. I know how busy you must be. I am sure that if we have any further questions we will send them through to you from the secretariat. If you have been asked to provide additional information, please forward it to the secretariat by Monday 28 April. And if you think of anything further that you think we may need, please feel free to submit it to us.

Proceedings suspended from 14 : 27 to 14 : 41