First-line bevacizumab plus chemo and cetuximab plus chemo provide similar survival benefits in metastatic colorectal cancer

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Published: 1 Jun 2014
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Dr Alan Venook; Prof Gordon McVie

Dr Venook (UCSF, San Francisco, USA) discusses his work with ecancertv's Prof McVie (European Institute of Oncology, Milan, Italy) at ASCO 2014. Specifically, they discuss the results from a large federally funded phase III study which demonstrate that four common first-line treatment regimens – bevacizumab plus chemotherapy and cetuximab plus chemotherapy – are equally effective for patients with metastatic colorectal cancer and no KRAS mutations.

Read the article or watch the press conference for more.

Dr Venook, thank you very much for telling us about this really, really significant trial, at least in my view. You and a lot of very important oncologists in the United States of America got funding from the State, which is the first good achievement because there’s not so much funding around for clinical trials, and you managed to do a comparative trial which involved new agents from two different pharmaceutical companies, and that’s another big plus point. Tell me first of all about colorectal cancer in the United States; I’m from Europe, so what’s it like here?

It’s more of a problem than we think it should be. It is, of course, mostly preventable if people would be screened and if we could reach out and get colonoscopy or sigmoidoscopy in the broad population. We do better than we used to; we still cure more patients than we don’t with colorectal cancer but over 120,000 people will get colorectal cancer at one stage or another in a given year and while many are cured there are still 40-50,000 patients a year who have metastatic colorectal cancer.

And it’s that last group that you’re looking at with this trial.

That’s correct. This trial took patients who were diagnosed with advanced metastatic colorectalcancer who had not had chemotherapy or other treatment before that.

And then the issue of the KRAS status was dealt with?

So this study is the study I will present, that I’m presenting, 80405 as we present it will be only on the KRAS wild-type patients. The study was initiated in 2004 when we didn’t know about KRAS so there was an earlier component of the trial, those patients will not, in total, be discussed, are not being included in this analysis.

So there are 1,000 patients in the study, which is a fairly significant lot, but if you hear that there are 50,000 patients in the United States who might have been eligible for this sort of question, that puts it into perspective, it’s 2%, I suppose. You had a very clever design, I think, because you took account of the fact that there are two popular chemotherapy cocktails, there are FOLFOX and FOLFIRI, and then what did you do?

Correct. We believed that the complexity of randomising patients to a study made it difficult enough to do a single randomisation and we felt that doing two randomisations would make it prohibitive. In the United States, for reasons that are more detailed than I can talk about now in this given timeframe, FOLFOX is favoured by many practitioners and we believe that we had to go with the flow and give practitioners the option of using FOLFOX although other practitioners might favour FOLFIRI. So we gave it that the physician and the patient would agree to which chemotherapy independent of this study. As they enrolled on the study the decision was made, you will get FOLFOX or FOLFIRI, and then we moved on.

And that was an institute decision?

Correct, it was generally... we were neutral on how they decided to do that.

So that took care of that and that’s very important because that’s the practical way it is in the practice in oncology in the United States and that’s really important.


Then the question was, what? Two antibodies?

The question was two antibodies. When we designed the study you had cetuximab, which is an epidermal growth factor receptor inhibitor and antibody, and you had bevacizumab which inhibits anti-vascular endothelial growth factor, the angiogenesis inhibitor. Each was available and in use in colorectal cancer although cetuximab was not approved for first line, bevacizumab was. Each of them works better with chemotherapy than without. So the issue really was is there a first line treatment we should be doing? Does it matter if you start with one, do you lose ground or do you gain ground and are you better off? That’s a fundamental question – where do you start. Patients, of course, want to know where we start and what we’re going to do next in the same visit, they ask that question as well,but this was asking where do we start.

So you had uncertainty about which antibody?

Correct, and they have different toxicities, very different toxicities. They’re both really pretty safe but bevacizumab causes mild hypertension, a few toxicities, some nephrotic, some protein in the urine, things that aren’t usually game stoppers. But it turns out that cetuximab causes a severe skin rash, an acne rash that people just plain don’t like. So the issue is is one better than the other and at what cost would patients take one versus the other?

And the answer? 1,000 patients, you must have an answer.

Yes, we do, we have an answer in that, in fact, the patients do... in this study as we defined KRAS wild-type, the patients do the same. But what’s noteworthy is that they live almost 30 months, both groups of patients live almost 30 months, 21⁄2 years. When we first designed the study the average patients with this advanced disease lived 22 months.

So that’s a big shift.

So it’s a big shift and we think it reflects a different approach to patients and critically, at least in this study, it didn’t matter what order you did the treatments in. Now this is important because it’s in contrast to another study that has been presented recently, and more data will come out at the meetings here, called FIRE-3, which is a study from Germany, which found that the antibody against the epidermal growth factor receptor, cetuximab, appeared to be better than bevacizumab. That was with a different... every patient in that study had FOLFIRI, in our study most had FOLFOX, and we think there may be some issues of subsequent therapies that may have changed the outcome. But our take-home message is that patients really do have choices of how to be treated and that we do much better than we used to do. Most remarkably, I think, we have about 10% of the patients actually, at one point or another, are rendered free of disease in our study with surgery after chemotherapy and in that group, a select group, the average patient lives almost six years. So what we believe we can do is see that there’s a subset of patients who do very well. The real message we hope will be in six months or a year, we will be doing a really comprehensive molecular analysis of all these tumours and all the data and we will try to put a picture together to say how should we treat which patient and how do we get the best result.

But it’s a very important clarification for the practitioner, and there are many in the United States, who have to treat these 50,000 new patients a year and it’s a bit, big public health issue.

Correct and it also gives patients some control because they can make a choice based on the toxicities, what they’re willing to put up with. So we think this is really a big step forward; we now will analyse it and it may be that there will be a subset of a subset that does very well and won’t that be great, but that is for another day.

We’ll have to wait for that. In the study, just a detail, if I were in the study and I got an unbearable rash from the cetuximab was I allowed to transfer over to the bevacizumab?

You could come off study and, in fact, about 20% of patients came off for that reason.

In the cetuximab arm?

Correct, and you could get bevacizumab by your practitioner, it was commercially available. Thestudy did not mandate any second line but, because these are all available, there was really common exchange for most patients.

And patients who had hypertension from bevacizumab could stop, go off study and get cetuximab?

That’s correct.

Are you following those people?

We are, we are.

And when do you reckon you’ll get a glimpse of that because that would be quite interesting looking at them in sequence?

There are many patients who are still alive, probably 30%; there are 10% where we’re still waiting to bring in new... finalise the data. So distinguishing all of this will take time. The data was only released two months ago to me and so I’ve had a group of incredibly dedicated associates, statisticians and data managers, who have been crunching the numbers pretty much endlessly, as have I. So we’re hoping in the next couple of months to get it all put together and then, as we do the molecular analyses, we hope in a year, maybe, or two years, we’ll actually be able to say that these are patients who we should treat this way, these are patients that we should treat that way, that would be a big difference.

So the take home message is clearly FOLFOX versus FOLFIRI, that’s not an issue, there’s already a choice element there for doctor and patient alike.


And cetuximab, with a set of cutaneous toxicities, and bevacizumab, with hypertension, some kidney problems, these actually are, in terms of you reaching thirty months, are equivalent?

It appears to be, yes.

Is there a cost difference in terms of the government who paid for this trial? Are they going to have to pay more for one arm or the other?

Yes, that’s a great question. Actually, insurers paid for the bevacizumab because that was part of the standard of care. The cost element, the drugs are about the same cost, although the way cetuximab is administered in the study was weekly and bevacizumab was administered every other week so the costs of administering the drugs are different so the cetuximab patients would cost a bit more.

Because of the frequency?

Because of the frequency of the injection. Otherwise it’s almost a wash.

Good, well that’s also an important result.

Yes, absolutely, and we have a detailed pharmaco-economics component that we’ll be doing but I won’t be presenting that.

Congratulations to you, Dr Venook, and to all your team of oncologists across the States. I think a message to the funders of this important study is that it is feasible to do these large population-based trials and get answers which will benefit a large number of people.

And this is... we need to do these trials because if the pharmaceutical industry is doing it they will very much be particular about who they treat and how they treat. This result is generalizable across broad populations and this is what we need to do, we need to clarify the standards.

I hope that the pharmaceutical companies watching this video will take note and realise that there is indeed benefit in doing this kind of study.

I think they will.

Thank you very much for the interview.

Thank you so much.

Thank you, I appreciate it.

You’re welcome. Thank you, thanks for having me.