ASCO 2012, Chicago, USA

President’s overview of ASCO 2012

Dr Michael Link – Stanford School of Medicine, California, USA


We were hearing this morning about a very unexpected topic – drug shortages. It seems hardy perennials like methotrexate, goodness knows what, paclitaxel, are in short supply. What is going on?

Well drugs have been in short supply for the last couple of years. There have always been shortages but in the last few years we’ve seen an accelerating incidence of shortages of many different generic drugs, mostly generic injectable drugs and of particular concern is the number of anti-cancer agents which are in short supply. At least 23 have been in short supply either now or in the recent past and these affect the curative therapy for many adult malignancies and many childhood malignancies as well.

It’s shocking to hear that this is happening even in America, so the rest of the world must also be in a bit of a predicament.

I think actually this is probably more of a problem in the United States than elsewhere and it’s not clear, that gives us some indication that it may be the economics of these generic drugs that are off patent that may be driving this shortage. There is simply not enough profit in that drugs are so cheap that there’s simply not enough profit to sustain industry’s attention to making these drugs. So when they run into a problem with manufacture and there’s a large investment required to fix the problem there’s not much incentive to do so.

So ASCO has identified this as something that needs fixing, what are you going to be doing about it?

This is not only a shortage of cancer drugs, this is a shortage of other antibiotics, anaesthetic agents, but the uniting theme is that these are basically drugs that are generics and injectables, that are difficult to make. So obviously we are most focussed on the oncologic drugs although our patient care is affected by the others as well. What we’re doing about it is we’ve had meetings with the Department of Health and Human Services; we’ve had meetings with the National Cancer Institute; we’ve publicised the problem with a media outreach to the press and I think that the problem is in play, we have certainly also put in what we would recommend in legislation that might resolve this problem and that remains to be seen as to what’s going to come forward.

Now you’ve got a paper presenting here, you and other colleagues, on Hodgkin’s disease. It’s very interesting to look at Hodgkin’s disease in a particular subset of patients, what do you make of the findings here, of using involved field radiotherapy with Stanford 5?

This is a study from our Hodgkin’s disease consortium of the Harvard Hospital, St Jude Hospital, Stanford and the main medical centre as well. We’ve collaborated to try to develop novel therapies. We’ve adopted the Stanford 5 chemotherapy regimen which is convenient, non-toxic and eliminates some of the major long-term side effects that we worry about for children which include cardiomyopathy from a lot of anthracycline exposure, infertility, those are problems that are not associated with this regimen. We use low dose involved field irradiation although we found out at this meeting that there is still a risk of breast cancer in women who are irradiated with low doses of irradiation, so even that is of continued concern. Our results are quite good, the survivals match those of other survivors. The event-free survival was not quite as good as we would have hoped so we’re still looking for novel regimens for children with high risks of Hodgkin’s disease.

And there’s a move away, though, from using radiation so what are your recommendations to clinicians at this point?

We try to avoid any of those interventions that lead to long-term side effects. One of the privileges of taking care of children, of course, is that when they’re cured they live for a long time; the downside is that you have all those years to develop the side effects and to see what occurs. So we are trying, in those patients where we can reliably improve that we can cure those patients with chemotherapy alone, to try to eliminate the irradiation from our regimen. We had a low intensity chemotherapy regimen where we took those patients that had a rapid and complete response and treated them without irradiation and proved that they did quite well. So we know that for at least a fraction of those patients who have low risk disease and are very responsive to chemotherapy that we can safely eliminate the radiation. I think that’s a trend that is going on in many paediatric centres.

Now EMILIA was a big study here, Dr Kimberly Blackwell presented on this immunoconjugate and it seems to be doing rather well. What are your thoughts about this finding?

There are two major ramifications of this study: a) this is very good news for women with breast cancer, another agent which is useful for patients with HER2 expressing breast cancers who have already developed disease recurrence or progression on the standard trastuzumab. So this is an agent that’s coupled, that delivers a toxin to the cancer cells and seems to work in those women as well. Good news for women with breast cancer. I think more important is the fact that this is proof of the principle of the technology: one can take an antibody, hook it to a toxin and deliver the toxin directly to the cancer cell, kill the cancer cell without having the collateral damage that one sees with routine chemotherapy. We’ve seen this effective in a drug last year that was useful for anaplastic large cell lymphoma and Hodgkin’s disease, so this is, I think, a technology whose time has come and there are other agents on the horizon targeting different targets but using toxins as a way of delivering the toxin to the cancer cell.

The principle has been advanced in fact long ago, so now you feel it is finally proved?

The idea of the magic bullet was certainly an idea from the beginning of this century. The initial forays into this field using toxins and antibodies, once we had monoclonal antibodies, were less than successful because of the lack of specificity of the toxin, not having a linker that could reliably keep held to the antibody until it was in the cell. Now I think this technology has come of age where we have all the components, plenty of antibodies directed at good targets, a good toxin that is really toxic to the cancer cell and a way of making certain that it is delivered to the cancer cell.

And the main message for busy cancer doctors coming out of EMILIA?

I think the two messages again, there’s hope on the horizon for new, very highly targeted agents, and specifically for breast cancer this is a new agent that is available for women with HER2 expressing tumours. I think where this molecule will end up in the complete spectrum of breast cancer care remains to be seen but I think that hopefully this will be moved even further up to patients with earlier stage disease.

Another buzz word here has been regorafenib, George Demetri discussed fast-tracking this agent for use in GIST, gastrointestinal stromal tumours. That again looks very interesting, doesn’t it?

Yes, this is a group of patients when they do… of course, we’re thrilled with their responses that we have seen to imatinib and its relatives in this disease but now we have yet another agent for patients whose disease is refractory to that class of agents. Really they did not have many alternatives at that time and now we have a new alternative for them. So, again, rare disease but we see these agents that are specifically highly targeted that work in tumours that were once felt to be incurable. I think this is great news for that group of patients.

And there is quite a good extension of life, isn’t there?

An excellent extension of life for a group of patients who really had a very poor prognosis because their tumours were already refractory to front line agents.

What about this principle of fast-tracking promising agents?

That is a hope now. We are now having very, very highly targeted treatments so we know that these treatments should be very effective for subsets of patients. So what we need to be able to do is enrich the trials of these drugs with the right patients who have the right target who then may be the most likely to benefit. Then when we can see those major benefits, we hope that the regulatory agencies will move them forward so that they will be available to patients in the clinic.

Now bendamustine is an old agent and a very interesting one because it was a neglected agent because, we were hearing here at the ASCO meeting, it was developed in former East Germany and therefore largely neglected. But we also heard from Mathias Rummel that it works extremely well in indolent lymphomas and he recommends it more than CHOP, what do you think?

Of course the standard in North America certainly is rituximab associated with CHOP chemotherapy, an old standby but a regimen that’s actually associated with a fair amount of toxicity, especially for elderly patients who are the ones that have these indolent lymphomas. So one of the difficult problems associated with R-CHOP was the toxicity and patients’ ability to tolerate the regimen. Bendamustine, in association with rituximab in a head to head study, proved to be at least as good or perhaps better than the old standby at number one and, number two, actually associated with fewer side effects and better tolerance. So, on both those counts, I think this should emerge as a new standard for elderly patients with indolent lymphomas in North America.

Finally, looking back over your year as President of ASCO, what do you think about the steps forward that have been made? What are the highlights for you, just very briefly?

This has been an amazing year for me but if I think of the things that have come out during this year, we celebrated the fortieth anniversary of the National Cancer Institute in the United States and have been able to mark clear progress in those four decades in terms of the numbers, in terms of the decrease in the cancer mortality and the increase in the number of survivors of cancer so that there are now twelve million cancer survivors in the United States and improvements in their quality of life as well. I think we’re on the verge of this entirely new paradigm for cancer care, the idea that we’re getting a return on the investment into understanding the biology of tumours; we have the drivers identified and the ability to develop specifically targeted agents which are highly effective and associated with much less toxicity. This is the future. A very interesting part of my presidency as a paediatric oncologist is to see that some of these targeted agents, perhaps developed for lung cancer like crizotinib, turn out to work in paediatric cancers as well like neuroblastoma and anaplastic large cell lymphoma. Maybe not too surprising, but it establishes a whole new level of collaboration; tumours that have had nothing to do with each other and physicians that don’t usually collaborate together are now really brought together in developing these new agents for a variety of tumours. It’s an exciting time.

And what do you think are the immediate targets for the future and the hopes for busy oncologists in the next twelve months or so?

I think that the prospect for the development of new, highly targeted agents, there’s a crescendo of new things that are being developed for our patients. The key thing, I think, for our oncologists in practice – how to keep up on this new information. And that’s really what is part of our mission at ASCO is to make certain that we have the facilities out there to keep physicians abreast of new developments and hopefully the idea of learning from every patient as well - the new developments in harnessing what’s available in the electronic medical records and health information technology.

Dr Michael Link, thank you very much.