Welcome to An Intelligent Future – a special episode of The Oncology Podcast focused on targeted medicine in BRAF-mutant metastatic colorectal cancer.

This podcast explores how the treatment landscape for metastatic colorectal cancer has evolved, what options are currently available to patients, and the BRAFTOVI® (encorafenib) + cetuximab combination.

Our Host Rachael Babin is joined by Dr Lorraine Chantrill, Senior Staff Specialist Medical Oncologist and Medical Co-Director for Medical Oncology across the Illawarra Shoalhaven Local Health District in NSW, and Dr Jayesh Desai, Medical Oncologist from the Peter MacCallum Cancer Centre in Melbourne.

We discuss the BEACON study results, the optimal timing of treatment and much more so we hope you enjoy this informative episode.

ANNOUNCER: Hello. I’m Rachael Babin from The Oncology Network, proud producers of The Oncology Podcast. Welcome to An Intelligent Future. A special episode of The Oncology Podcast on targeted medicine in BRAF-mutant metastatic colorectal cancer. I’m joined by Dr. Lorraine Chantrill and Dr. Jayesh Desai.

Lorraine is a Medical Oncologist and Medical Co-Director for Medical Oncology across the Illawarra Shoalhaven Local Health District in New South Wales. Jayesh is a Medical Oncologist from the Peter MacCallum Cancer Centre in Melbourne, where he is Head of the Early Drug Development Trials Program.

In this episode, we explore how the treatment landscape for metastatic colorectal cancer has evolved, what options are currently available to patients, and the BRAFTOVI® encorafenib + cetuximab combination. Jayesh talks us through the BEACON study results and Lorraine discusses the optimal timing of treatment.

You’ll find links to the papers, bios, and Twitter handles in the notes on our website. For regular news and podcast updates, we invite healthcare professionals to join us at oncologynetwork.com.au. It’s free and only takes a minute.

I’d also like to thank Pierre Fabre for sponsoring today’s podcast. This podcast is intended for healthcare professionals only and contains discussion of Pierre Fabre Products. The opinions expressed are those of the speaker and do not necessarily reflect the views of Pierre Fabre. We hope you enjoy listening.

This is Rachael Babin and this is The Oncology Podcast.

R: Hi, Lorraine. Hi. Jayesh. Welcome to this special episode on BRAF mutated colorectal cancer.

L: Hi, Rachael.

J: Great to speak to both on this sunny day.

R: Thank you. I think Lorraine will be envious of your sunshine.

J: It's not sunny at all. It's Melbourne, come on.

R: So, I always like to start by getting to know our guests a little bit better. Lorraine, when did you decide to become an oncologist?

L: Well, I'm very lucky because I, in fact, did a science degree before I did medicine, and I worked in the field of genomic medicine in its very early days, I'm embarrassed to say. But I learned some very interesting techniques of PCR when it was being developed. So, then when I got the opportunity to do medicine, I saw that medical oncology was a great specialty that I could mix my scientific background, and my medical background because oncology is just the most amazing specialty where we see a lot of change and a lot of translational research involved in our decision making for medical oncology. So, it's a great fit for me, and I'm so happy that I chose it.

R: Thank you. And Jayesh, I'm hoping you can share your story too. What was your motivation for specialising in BRAF-mutated colorectal cancers?

J: Yes, so my research interests really were developed when I'd finished my training here, and I spent a few years overseas. In that time, it was the early days again, also showing my age here, where we were starting to develop molecularly targeted therapies. The prospect of being able to genomically characterise the patient's tumour, and to start to apply that by using molecularly targeted approaches was something that was really appealing. And that was in a broader context to start with. And then when I'd returned back, we'd started to do a lot more work in the laboratory and in a translational sense to start to characterise colorectal cancers in particular.

And BRAF was one of those really exciting early targets that we were starting to get a sense that maybe there's some importance in this and colorectal cancer. So, one of the first projects I did actually was looking at BRAF-mutant colorectal cancer in a large cohort of patients, and to better understand what that actually meant from a clinical perspective. And in parallel with that, the first clinical trials were starting with what was vemurafenib at that time, which is the first BRAF inhibitor. And that's how I really got involved at that point in time, and of course, the story has been a fairly long one since then, because it's been quite complex, to try and figure out what are the right combinations to actually use to start to have an impact in patients.

R: Such a fascinating balance between that, you know, it's a cliché, perhaps, but that art of medicine and the science behind it as well. It's a really great balance. Jayesh, could you please set the scene for us a little and tell us what treatments are currently available for BRAF-mutant metastatic colorectal cancer in Australia?

J: Yeah, so the treatments for BRAF-mutant colorectal cancer have evolved, fortunately, and actually, quite dramatically in the last year or so. There's been data for some key trials that have really started to change practice for this particular patient group. And perhaps the most direct impact for oncologists like Lorraine and I, are not having to rely on chemotherapy alone. But we can now start to apply a more personalised, molecularly targeted approach to this particular colorectal cancer subset.

So, we've now got the availability of targeted combinations based on data from the BEACON trial, which compared chemotherapy to targeted approaches using the BRAF inhibitor encorafenib combined with EGFR and MEK inhibition. And the other things to know, perhaps even more sub characterise that BRAF mutant population. So, there's a group of BRAF-mutant tumours, for example, that are MSI high. And looking at how we can incorporate immunotherapy into that particular patient group, again, with some really important data becoming available in the last year or so, is starting to refine practice for this patient population. These are drugs that are also fortunately available in Australia as well.

R: Wonderful. Thank you. Lorraine, how has the treatment landscape changed in your practice over the years?

L: Well, it's actually changed enormously. And it actually wasn't that long ago, maybe about 15 years ago, where we had access to oxaliplatin, which was a relatively new agent in the treatment of bowel cancer. And that was added to the backbone of all chemotherapy for bowel cancer, which is 5- fluorouracil. And that addition of oxaliplatin actually did have an incremental change in survival for patients with metastatic bowel cancer. Soon after that, we had trials using bevacizumab, a VEGF inhibitor, which were positive studies and again, enhanced the effectiveness of chemotherapy for those patients.

But as we've been saying, what has revolutionised the treatment more recently has been to better subdivide bowel cancer into a number of different molecular subsets based on some as yet fairly limited molecular testing. So, at the moment, we can use in practice RAS testing, RAF testing, and mismatch repair testing. We would like to see other sorts of molecular tests incorporated as well, not probably currently in routine clinical practice, but we will see those come into effect soon, we hope, as we start to test for things like HER2 and other drivers of cancer in metastatic bowel cancer.

R: Are you hopeful for the future?

L: I'm very hopeful for the future. But the future is maybe a little bit more complicated. But as I say, to my patients, it's more intelligent. And I think it will be a better treatment for our community as well, because we won't be giving people unnecessary treatments. The idea will be to give the best treatment to the person at the best time and that will also be in the long run more economic value for our community. So, I think the future is very hopeful, yes.

R: Wonderful. Thank you. Now Jayesh, I'd like to move into molecular drivers specifically now. Could you please give the listeners a brief explanation of the molecular drivers that dictate growth and proliferation for BRAF-mutant metastatic colorectal cancer?

J: Yes. So, BRAF in itself is actually a key driver, right? And we know this, when we look at what happens in patients who have BRAF mutations, particularly in patients who have metastatic disease with BRAF mutations and what we've learned over the years is that there are a few key things that happen. One is that unfortunately, the survival of a patient with the BRAF-mutant tumour is less than what it would be if they didn't have a BRAF-mutant tumour. That's probably because we find that the response to chemotherapy, so the conventional chemotherapy drugs we've been using for many years, their effectiveness wears off really quickly.

So, in the first-line setting, chemotherapy still do work for a period of time, perhaps not quite as well, but certainly they do have some effect. But once we get beyond that first-line setting, we find in fact that the response to chemotherapy is really poor. For that reason, of course, we've been looking to see if we can find better ways of treating that particular patient group.

There are a few other things that happen as well. So, I've talked about the lower response that we see with chemotherapy. But in fact, in someone who has a BRAF-mutant tumour, the biology of their disease is often quite different as well. The tumours metastasise in different ways. We see high rates of peritoneal metastases, for example. We see patients develop brain metastases at a higher rate than what we might expect for someone who doesn't have a BRAF mutation. That sort of tells us that this is not just driving their cancer to grow, but it's also driving their cancer to behave in different ways as well. And there probably are other factors behind this too. Patients with BRAF-mutant tumours more commonly have right sided tumours, for example.

So, there may be some anatomical reasons for this, that go beyond just the biology alone. And we're starting to understand that more and more, and I think we need to still understand that more and more as well. The other thing that I think is really important to understand is that, although BRAF is a key driver, when we target BRAF using a targeted therapy, what we've learned, of course, for a long period of time is that there is a lot that changes dynamically. And in fact, it's not just that BRAF drives that tumour, but when we inhibit BRAF, there are other things that get switched on, in some cases almost instantly. So, EGFR, for example, gets activated very quickly in response to BRAF inhibition. But there probably are some other factors at play as well. I think that sort of comes back, really well to the point Lorraine made which is, as much as we're optimistic, we also understand that this is actually quite complex. And we're going to have to keep working really hard to understand that complexity more and more, so we'll come up with better approaches to treating the patients that we're treating.

L: Yeah, I think the BRAF story in colorectal cancer has been a fascinating one. And you will all remember, probably, that the BRAF story came first from melanoma, and BRAF inhibitors were used in melanoma as a single agent and were reasonably successful on their own. That led to trials in BRAF-mutant bowel cancer. And interestingly, they didn't work as Jayesh said, unfortunately, the EGFR pathway was upregulated. And so, without EGFR inhibition, the BRAF inhibitors don't work in bowel cancer. Isn't that an amazing illustration of the complexity of cancer biology? That just because an agent works in one cancer, it doesn't necessarily work in the next.

J: Yeah and you know, Lorraine, I think one of the other really fascinating things and I think we're going to see this more and more as we're starting to target, you know there are certain KRAS clones. So, KRAS G12C for example, where there are now drugs that are showing some level of activity in that. But what's fascinating there is EGFR seems to continue to play a really important, it's almost there in the background, and it continues to influence how signaling pathways work in colorectal cancer either per se, or in response to us targeting something like BRAF, for example. I think, again, we're going to have to continue to work to overcome those challenges, because there's not going to be a sort of one-shot approach on a lot of things, but we're probably going to have to come up with combinations, sort of clever combination strategies, because there will be more than one pathway at play, for example.

R: Thanks, Jayesh. Can you please talk us through the BEACON CRC study results now?

J: Yes, so the BEACON trial has really been a seminal study in the context of how we treat BRAF-mutant colorectal cancer. So, leading up to it, as we've talked about, we've known that BRAF inhibitors play an important role here and BRAF and EGFR combinations, in fact, are really important as a step towards effectively treating patients with BRAF-mutant disease. So, leading up to the BEACON trial, there were a number of trials done that looked at using different BRAF inhibitors, and I'd argue that encorafenib is the best in class from that perspective. And then combining that with EGFR and also looking at targeting the pathway, even more forcefully by adding in a MEK inhibitor as well.

That led to the BEACON trial, which was a randomised phase three trial that compared standard of care chemotherapy, in a second or third-line setting, in patients with metastatic BRAF-mutant colorectal cancer to two active groups or two experimental groups. One was looking at a combination of BRAF and EGFR, so encorafenib and cetuximab, and the third was adding in a MEK inhibitor to that with binimetinib, to see whether we might be able to lead to even more forceful results.

What we've learned from BEACON is that, in that setting, the combination of encorafenib and cetuximab improved the overall survival of patients from about six months to about nine and a half months, it's improved the progression-free survival. So, tripling that from about one and a half months, which is often the interval between two scans, and about four and a half months and also improving the response rate as well. And I think because of that, that's now become the standard of care in many parts of the world, and, you know, available in many parts of the world as well. Looking a little bit beyond that, perhaps some of the other key points to make is, the safety of the BEACON doublet, as we call it, it's actually pretty well tolerated in patients. There are some toxicities that we need to be aware of as GI oncologists. It can cause diarrhoea in some patients, some patients get some skin toxicity, and fatigue and so on. So, it's important that we are aware of that and obviously manage that really actively.

In the context of the BEACON trial, with active management of those toxicities, most patients actually tolerated it really well. And over 90% of patients were able to continue their treatment with, you know, careful supportive care to go along with their trial treatment as well. Interestingly, with the BEACON trial, which as I described, looked at chemotherapy versus the doublet or triplet approach. It was actually, the triplet was not shown to be any better than the doublet across most of the key endpoints looking at overall survival or looking at progression-free survival in particular. And, as a consequence of that, it's the doublet regimen with encorafenib and cetuximab, that is the approved regimen in Australia, and in fact, many other parts of the world as well, and that is what's considered standard of care in most regions now.

R: Did you have anything you wanted to add there, Lorraine?

L: Yeah, so I would agree with Jayesh. I think that the doublet is very well tolerated. I do have some patients who get some muscle aches and pains. That was kind of a little bit of a surprising side effect for GI oncologists. It's not something that we experience with many of our other treatments, and so that's taken a little bit of learning for us to manage. But the patients who I'm treating, are actually saying, look, it's a thing, but it's not too bad and I'm feeling so much better from all sorts of other symptoms that I used to have, from my very advanced bowel cancer now that the treatment is working. So, my patients are mostly feeling better on treatment, but have some of these relatively unusual side effects.

R: Interesting. Thank you. Lorraine, I'd like to bring you now to the timing of treatment. At what point in a patient's treatment do you prefer to use the BRAFTOVI and cetuximab combination?

L: Thank you. So, I prefer to use it second line. There are a couple of reasons for that mainly because we like to capitulate what the clinical trial has done, but also because the reality is that currently in Australia, I often have patients referred for treatment, I want to treat them quickly and I don't have all their molecular pathology yet. BRAF testing is a little bit easier because we can often see BRAF mutations by using immunohistochemical test rather than a genomic test. But I often am waiting for that full sort of genomic panel in order to inform their second-line treatment, but I'll often be starting their first-line treatment with FOLFOX. And if they are right-sided tumours as Jayesh has said - most of these patients are, if they're right-sided tumours, I'll usually be combining their FOLFOX with bevacizumab in the first line setting, and then moving to the combination of cetuximab and encorafenib in the second line setting. After progression on the first-line treatment.

R: Jayesh, why do patients fail to respond to systemic treatment in the first-line setting?

J: So, for the most part, patients will respond to treatment and then develop progression rather than not responding at all. You know, even with BRAF-mutant disease. You know, there are some patients who don't respond to chemotherapy at all, but most patients actually still would respond to first-line chemotherapy. So, for me, perhaps the key message is that if I know someone has a BRAF-mutant tumour, I suspect they have a tumour, as Lorraine has talked about, I would actually follow those patients really carefully. I have a high degree of anxiety around how they're going to respond to treatment, and how long their treatment would continue to work for. So, I tend to, for example, do scans more frequently in that patient population, and certainly tend to follow them more closely. My main reason for doing that is that I know I want to pick up resistance or progression of disease as early as possible so that I can intervene with the BRAF inhibitor combination rather than leaving things to a point where that patient's cancer is really having a major impact on them.

R: So, in that second-line setting, you would tend to use it as quickly as possible. There is an urgency from your point of view?

J: I tend to, and again, my feeling is that if I can treat someone with less bulky disease, I feel that they're more likely to benefit from that treatment. And, you know, there's a simple principle that if you've got effective therapies for someone, and you know that their cancer is progressing, and is going to – if it's not causing trouble now, it will cause trouble soon - my feeling is that I would like to intervene sooner rather than later in that setting.

L: Yes, and of course, the patients are very pleased to not be on a treatment that's not working. But secondly, to not be receiving chemotherapy, which has significant side effects. In most patients I treat, the side effects from the BEACON doublet are much less than the side effects from FOLFOX chemotherapy, for example. So, I think patients also are very keen to go on a less toxic regimen, especially if it's going to work better.

J: Yeah.

R: Yeah, definitely a win, win. Lorraine, how do we get access? So, is the combination available on the PBS now?

L: Yes, it is. So, it is available on the PBS and the testing is also available. So there's no reason why you can't treat your patients with BRAF-mutant bowel cancer in this way now.

R: Fantastic. Your experience of testing, how's that been? Do you typically wait a long time for results?

L: It's got a lot better with time. I think now that our centres are used to the fact that we're going to order RAS, RAF and BRAF and mismatch repair on every patient we have with metastatic disease, our pathology labs are getting a lot more slick at doing it, and testing times are coming down. The gap in our system is the fact that the test has to be requested. So, we have to know that the patient has metastatic bowel cancer in order to request it for it to be done. So that's probably where the gap still could be narrowed a little bit, is that time to requesting the test.

R: Okay, thank you. The purpose of today's podcast is to explore the nuances of this new treatment combination in detail. So, with that in mind, do either of you have a final question or comment for each other?

L: Oh, I've got a bunch. I'm sure Jayesh can answer them.

R: Wonderful

L: I think as we see patients have this combination for a long time, we're starting to see some of the emerging side effects that patients complain of that we may not have been used to seeing before. The eyelashes, the change in the eyelashes is really interesting. So, people's eyelashes become longer and curlier, and that can be great for some people, but not so good for others. We do see some changes around the nail beds, which I have to manage quite actively. As I said, you know, this mild myalgia, which I recommend occasional nonsteroidals for it, but I'd be interested to hear what Jayesh’s management is for that mild myalgia that we sometimes see.

J: Yeah, I agree. And I think that's certainly something that is seen with BRAF inhibitors. And again, it's not something we've been familiar with until recently. So, both myalgias and actually arthralgias are the other thing that patients complain about as well, and my approach has been to use nonsteroidals. But occasionally, I've needed to use a low dose of steroids, 5 or 10 milligrams of prednisolone a day. That's actually been really effective. It's one of those things that fortunately, hasn't been too recalcitrant to treatment.

So, as you'd expect, I'd want to continue the anti-cancer treatment, with the BRAF inhibitor and cetuximab and add in those supportive care measures. So, escalation tends to be with nonsteroidals, and sometimes including a short course of oral steroids, steroids that I've found has been pretty effective, actually.

L: Yeah, thank you.

J: You know, if it's an older patient population, I mean, the obvious points about making sure we're not missing something else that might be going on. I had a patient last year who had polymyalgia rheumatica, which, again, I thought was just drug related to start with, but it became pretty clear that there was something else going on, as well, in that particular patient.

R: Yeah, that's really important. And the $64,000 question, of course, is, what do you do after, you know, the BEACON doublet doesn't work anymore?

J: Yeah. I mean, that's a really challenging one, isn't it? I think, if we think biologically about what's going on, we're starting to understand that resistance is probably because you've got other clones that are developing, and so on. So, it's sort of resistance to the targeted approach, rather than resistance per se. So. the best-case scenario is to try and cycle back to chemotherapy. And occasionally, you know, I know of some anecdotes with myself and colleagues who have treated patients who have sort of really cycled between a targeted therapy combination with encorafenib and cetuximab going back to chemotherapy, and then even potentially coming back to a targeted approach again.

But the reality is that, you know, once we find resistance starts to develop, those other treatments and the effectiveness of them becomes lesser and lesser, and that's part of my reason for wanting to treat early and treat when someone doesn't have overly bulky disease as well, because I think I can have a greater impact that way, rather than trying to catch up at a later time point.

L: Thank you.

J: Lorraine, I was actually going to ask you a question and to get your thoughts on, you know, there's this BRAF MSI subgroup, right, you know, that we well and truly recognise now. What's your approach to that particular patient group? Thoughts around that?

L: So, I think right now, today, I would probably, if someone was MSI high, I would probably give them pembrolizumab first-line, as it's funded on the PBS as first-line therapy, and I would probably give them, you know, a BEACON doublet, you know, second-line or beyond. And, you know, maybe reserve chemotherapy for after that, possibly. I think that's what I would do. We've had the availability of immunotherapy for metastatic bowel cancer now only for a short time. It's absolutely fantastic that we have another medication that we can give patients, albeit a relatively rare subgroup, but nevertheless, people who are really benefiting from treatment.

J: Yeah, I would follow exactly the same approach. And, you know, that sort of comes back to that really important point you made earlier about, again, the molecular characterisation of patient’s tumours, and in some instances, that has a very direct benefit for a patient, but in others, I think it gives us insights into what's going on with their disease, even if there isn't necessarily a treatment you might have for it. I think we need to keep chipping away in that way so we can sort of start to, again, you know, individualise treatments, right? I mean, take a true precision medicine approach in what we're trying to do with our individual patients who we're treating.

L: Absolutely.

R: Okay. So, just before we wrap up, Lorraine, do you have any take-home messages for listeners, or resources, perhaps you might want to mention?

L: Look, I think the take-home message is look for BRAF-mutant patients in your patient population, make sure you're doing the test, make sure you're ordering the tests early on, if you can, and, you know, consider it as a treatment after failure of first-line chemotherapy for these patients, because we really feel they'll benefit. So, thank you, and thank you for listening.

R: Thank you. And you, Jayesh, any final thoughts? Pearls of wisdom?

J: I’d completely reinforce the comments that Lorraine made. I think it's just so critical that doing a test triggers a thought process and the fact that we can act on some of that thought process, I think, as, you know, as clinicians is really important. So again, I'd reinforce that point around testing. And again, I'd come back to,you know, I think earlier intervention is always important as well and if you're not going to intervene early, make sure you're following things really carefully as far as your patient is concerned.

R: Wonderful. Well, thank you both very much for your time today. It's been a real pleasure sharing this conversation with you. So, thank you.

L: Thank you.

J: Bye.

L: Bye.

ANNOUNCER: You’ve been listening to The Oncology Podcast. For oncology news and podcast updates, join The Oncology Network at www.oncologynetwork.com.au. It’s free for registered healthcare professionals.

Just a reminder that today’s episode is sponsored by Pierre Fabre. This podcast is intended for Health Care Professionals only and contains discussion of Pierre Fabre Products. The opinions expressed are those of the speaker and do not necessarily reflect the views of Pierre Fabre. If you enjoyed this episode, please share with your colleagues. Thanks for listening…. This is Rachael Babin and this is The Oncology Podcast.

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