Thank you, everybody, for taking time out of your day to talk about colorectal cancer and non-small cell lung cancer in the context of BRAF V600E.

I am Chris Lieu. I am a GI Medical Oncologist at the University of Colorado and very excited to do this, especially with a thoracic oncologist. We are very thankful to have Dr. Riely here. You do not always get to do webinars with people in different disease states. So this is pretty exciting.

Case 1: Patient With mCRC

We already went through a pre-test question about one patient with metastatic colorectal cancer. I am going to ask a similar question regarding another patient. This is one of my patients, a 60-year-old female who underwent right hemicolectomy for T4N1 cecal adenocarcinoma. Postoperative ctDNA testing was positive. We gave this patient adjuvant chemotherapy with six months of FOLFOX and the ctDNA cleared, but it was only transiently cleared.

It was unfortunately positive at the end of adjuvant FOLFOX. This is actually an increasingly common clinical situation where we really do not know what to do with these patients that are ctDNA positive. We obviously would love to offer this patient a trial.

Six months later, CT imaging revealed unresectable peritoneal metastases. The patient did note some mild abdominal pain. At that time, she was started on FOLFIRI and bevacizumab with resolution of her pain and three weeks after initiation of chemotherapy. She seems to be doing fairly well on FOLFIRI-bevacizumab. The next-generation sequencing return showing that the patient's tumor was microsatellite stable, and there was a BRAF V600E mutation in the tumor.

Poll 3

Another polling question. In your current practice, what would be your recommendation for this patient with metastatic stage IV colorectal cancer on FOLFIRI-bevacizumab. Your options are now that you know that the patient has a BRAF V600E mutation, are you going to:

1. Continue what you are doing with FOLFIRI-bevacizumab;
2. Switch to dabrafenib-trametinib;
3. Switch to encorafenib-cetuximab; or
4. Switch to encorafenib-cetuximab in combination with FOLFOX chemotherapy.

Let us see what the group says. Let us see what the results are. We have a majority of the group wanting to switch to encorafenib, cetuximab and FOLFOX.

Okay. We are going to talk a little bit about that data that really guides that decision. It seems like a majority of you want to make the switch.

BRAF V600E Background

Okay. A brief background on BRAF V600E in colorectal cancer. Across all stages, it ranges from about 8% to 12%. We are really are specifically talking about this one mutation. We know that there are other class II and class III BRAF mutations that are different than the V600E mutation.

This signals through the MEK/ERK activation pathway. It is an early event in colorectal cancer. When you test the primary site and a metastatic site in colorectal cancer, the concordance rate there is extraordinarily high.

Just like our patient, the association of these tumors are right-sided tumors, higher grade in older age adults and female. There is a correlation with these tumors being also MSI-high and we are going to talk about the impact of BRAF mutations in the MSI-high population, and it is accelerated as opposed to a tubular adenoma pathway.

CRYSTAL: First-line FOLFIRI ± Cetuximab for mCRC

Now it is wild that I get to show you data from 2011. This is really old data. This is the CRYSTAL study looking at front-line FOLFIRI with or without cetuximab for patients with metastatic colorectal cancer. What you are seeing on the top two solid lines are the impact of FOLFIRI in combination with cetuximab in a BRAF wild-type population.

Really what I am trying to drive home with this graph is what happens the natural history of our patients that have the BRAF V600E mutation. In the CRYSTAL study, you are looking at median overall survival being a little bit over two years. When you look at the BRAF-mutated population, this is the V600E-mutated population, the prognosis for these individuals is very poor.

Whether or not you receive chemotherapy alone or chemotherapy in combination with the EGFR inhibitor, we are looking at median overall survival that are roughly one year, basically half of what they saw in the other population. This is very aggressive biology.

Simplified Advanced Colorectal Cancer Guidelines

What I am showing you here is really how we treat metastatic colorectal cancer across lines of therapy. I would say there are two main take-home points. Number one, there are a lot of words on this slide, which means that we have a lot of options.

When you look at the response rates as the second major take-home point, they drop really precipitously as we go from front-line to second-line, and certainly in third-line, where the response rates are really in single digits, even though those agents do have a median overall survival benefit.

It really points to the fact that we really need to be doing our best, obviously, in the front-line setting and really giving patients the best shot to have the best response possible. Because when you get into the second-line setting, particularly in individuals that have KRAS mutations, FOLFIRI in combination with bevacizumab really has a response rate around 15%, which is really low.

CRYSTAL: First-line FOLFIRI ± Cetuximab for mCRC

This really drives home to this next point that when we look at how our patients are treated across lines of therapy, there is a significant amount of drop off as we go from front-line to second-line to third-line.

When you think about all the patients that receive front-line therapy and the majority of patients currently receive FOLFOX and bevacizumab in the frontline setting, as we think about sequencing the next treatment in the second-line and third-line settings, you can see that there is a tremendous drop off, particularly as we get into the third-line setting.

Again, it speaks to this idea of giving the best therapy that we have in the frontline setting, because there is no guarantee, even with patients with great performance statuses that they are actually going to make it to the second-line setting.

What Influences Treatment Choices in mCRC?

What influences the treatment options for our patients with metastatic colorectal cancer? Certainly, a lot of this is the health of our patients. How are they looking? How are they feeling? What is their ECOG performance status?

Obviously, the tumor burden is also something that we consider, particularly when they are having symptoms from their cancer. If you think about our 60-year-old female with metastatic colorectal cancer, that peritoneal disease was causing her symptoms. The idea of being able to shrink cancer and make the patient actually feel better is obviously a very critical goal for that patient and for many of our patients.

Of course, the molecular characteristics of this disease is really what we are talking about, and it certainly changed the landscape for, I would say, colorectal cancer and non-small cell lung cancer.

Molecular Alterations in mCRC

These are some of the actionable molecular alterations in metastatic colorectal cancer. I am going to get to show you this pie chart, which certainly looks better than the pie chart that I was showing about seven or eight years ago. Dr. Riely gets to show a pie chart that is much more impressive.

In colorectal cancer, we aspire to non-small cell lung cancer. You can see here that we have patients that are totally wild-type. We know that those patients should start with an anti-EGFR inhibitor in combination with chemotherapy. We are obviously going to spend a lot of time looking at the data for BRAF V600E. Then you can tell that a lot of these smaller pies like MSI-high. It is great when we see them, but of course still represents only about 4% of our patient population.

BEACON CRC: Encorafenib + Cetuximab ± Binimetinib for BRAF V600E–Mutant mCRC

Of course, the actionability of BRAF V600E in colorectal cancer really started with this BEACON study. This was the second-line and beyond study. Patients with BRAF V600E-mutated metastatic colorectal cancer were randomized in the second-line setting to receive either:

• Binimetinib, a MEK inhibitor; encorafenib, a BRAF inhibitor; and cetuximab, anti-EGFR; or
• Encorafenib-cetuximab without the MEK inhibitor; or
• Investigator's choice, FOLFIRI; or irinotecan in combination with cetuximab.

BEACON CRC: OS With Triplet and Doublet vs Control (All Randomized Patients)

Of course, these were the overall survival benefit. Certainly, when you look at the triplet versus the doublet, those curves look fairly equal. That is why we have moved on with encorafenib and cetuximab without binimetinib, because the overall survival is essentially the same. We just did to have to give another MEK inhibitor in addition to the doublet. Certainly, these are the median overall survival improvements that we want to see.

The median PFS in this setting was still 4.3 months. We know that resistance develops in the second-line setting and beyond.

BRAF Inhibition In The Frontline Setting? Encorafenib + Cetuximab + Chemotherapy

Then that really brings us to where we are today. What does BRAF inhibition look like in the frontline setting when we combine encorafenib-cetuximab and chemotherapy?

BREAKWATER: First-line Encorafenib + Cetuximab + Chemotherapy vs SoC for BRAF V600E–Mutant mCRC

That was the purpose of the BREAKWATER study. Again, patients with BRAF V600E-mutated metastatic colorectal cancer. Here, this is in the frontline setting, so patients who have not previously received treatment were randomized to receive targeted therapy only; encorafenib, cetuximab and chemotherapy or standard of care investigator's choice chemotherapy.

The co-primary endpoints here are overall response rate, as well as progression-free survival with a key secondary endpoint of overall survival.

BREAKWATER: Baseline Characteristics

When you look at the baseline characteristics, this is essentially who we see in clinic. I will note that there is a high percentage, as we would expect with BRAF mutations of having right-sided cancer. Again, right-sided colon cancers have a tendency to be more aggressive. We also know that a majority of these patients had multiple organs involved as well as liver metastases.

BREAKWATER: PFS by BICR

When you look at the BREAKWATER progression-free survival, the difference between encorafenib-cetuximab and FOLFOX versus the standard of care is really striking, a near doubling of median progression-free survival of around 13 months with encorafenib-cetuximab and FOLFOX.

Keep in mind that with the CRYSTAL data that I was showing you, that was the overall survival was around 12 months. Here, the progression-free survival was 13 months.

BREAKWATER: Interim OS

When you look at the overall survival, this is the interim overall survival that was reported out last year. Encorafenib-cetuximab plus FOLFOX resulted in a doubling of overall survival from 15 months to 30.3 months.

What is hidden in this overall survival is the fact that when you look at the standard of care arm, a percentage of those patients went on to receive encorafenib and cetuximab and still had a really poor overall survival, which means that doing this treatment upfront really does seem to significantly prolong overall survival and, in this case, a doubling of overall survival.

BREAKWATER: OS by Subgroup

When you look at the subgroup, there is a lot of numbers and words here. What I really want you to look at is on the last column of these hazard ratios, whether the patients were younger or older, male or female, performance status is zero, one or even tumor sidedness or liver metastases. The survival benefit was consistent across all groups.

BREAKWATER: Response

When you look at the responses, it is really impressive when you look at encorafenib-cetuximab-FOLFOX of having a response rate of 65% or 66%. The other interesting thing on this graph is actually the response rate of encorafenib and cetuximab without the chemotherapy, which is 45%, which is still higher than the standard of care response rate of 37.4%, but a really impressive response rate, again, critical for our patients that have symptomatic disease in particular.

BREAKWATER: Most Frequent All-Causality TEAEs

I do want to really show you what I think are the critical adverse events. We are going to talk a little bit more about adverse event management in just a bit. I really want to highlight rash. That is what we always worry about with anti-EGFR inhibitors.

I want to point to the fact that only 1% of the patients receiving FOLFOX-encorafenib-cetuximab had grade 3 rash. To put that in perspective, in the CRYSTAL study of chemotherapy with cetuximab, the grade 3 rash event rate was around 16% to 19%, which means that with the combination of encorafenib and cetuximab, you have dropped that down to 1%. There really is an interaction between encorafenib, the BRAF inhibitor, and cetuximab, the anti-EGFR inhibitor, where the BRAF inhibitor actually helps mitigate the rash that is caused by anti-EGFR therapy. That is a critical point.

It actually reactivates ERK in some of the normal cells. So it actually has a protective effect over the skin. The rash here is actually much more tolerable than what we typically expect to see with cetuximab.

BREAKWATER Cohort 3: First-line Encorafenib + Cetuximab + FOLFIRI for BRAF V600E–Mutant mCRC

Just recently reported last month, FOLFIRI in combination with encorafenib and cetuximab.

BREAKWATER Cohort 3: Response

This data was presented at ASCO GI showing that the response rate again, really consistent across FOLFOX-encorafenib-cetuximab and FOLFIRI-encorafenib-cetuximab. The overall response rate here was 64.4% compared to 39% in the control arm.

BREAKWATER Cohort 3: Safety

Again, similar adverse event rate, but again, when you look at rash, which is towards the bottom of your screen, there are actually no grade 3 rash adverse events in the FOLFIRI-encorafenib-cetuximab arm.

Take-home Point

Really, the take-home point is truly that patients with newly diagnosed metastatic colorectal cancer with a BRAF V600E mutation, they really need to start with chemotherapy if they are eligible for it with encorafenib and with an anti-EGFR inhibitor. The data shows that on average you are going to be doubling overall survival.

If you have a patient, that many of us do, we start our patients on FOLFOX-bevacizumab. When we get that molecular information, we need to make the switch because it is such a critical survival issue for our patients.

Let's Return to a Question From Earlier in the Program

Posttest 1

We will return back to our patient. This is a post-test from the pre-test that you have. Same patient with metastatic colorectal cancer. Molecular profile is BRAF V600E microsatellite stable. Your options are here:

1. FOLFOX-bevacizumab;.
2. Dabrafenib-trametinib;
3. Dabrafenib-panitumumab;
4. Encorafenib-cetuximab;
5. Encorafenib-cetuximab-FOLFOX; or
6. Vemurafenib-bevacizumab-FOLFOXIRI.

Let us see what our poll results show here. Okay. I am convinced at least a decent number of you to treat this patient with FOLFOX-encorafenib-cetuximab.

It is interesting, the FOLFOXIRI data. Actually, there has been reports and some clinical trials showing that FOLFOXIRI plus bevacizumab has had some impact, particularly in right-sided cancers, maybe in BRAF-mutated cancers, but that survival benefit has always been pretty minor. The absolute overall survival difference that we are seeing with the BREAKWATER study really does show that if we are able to give the targeted therapy, we should proceed with that.

Posttest 1: Rationale

This is now FDA-approved to combine encorafenib-cetuximab with FOLFOX for this patient population.

Hitting Biology in Earlier Lines of Therapy: MSI-H/dMMR and BRAF V600E mCRC

Phase III RCTs of Immunotherapy vs Chemotherapy as First-line Therapy for dMMR/MSI-H mCRC

I want to touch very briefly on this idea of BRAF mutations in the setting of MSI-high disease. I am showing you data here looking at pembrolizumab versus chemotherapy and nivolumab and ipilimumab versus chemotherapy. It is unfair to put these curves beside each other. It is important to note that these patients with MSI-high disease, many of you on the call know we start these patients with immunotherapy just because it works so much better than chemotherapy.

I will tell you that, in these studies, BRAF V600E status was not a negative predictive biomarker for immunotherapy efficacy, which means that if you have MSI-high and a BRAF mutation, you should still feel comfortable starting with immunotherapy giving these outstanding results.

CheckMate 8HW: Nivolumab + Ipilimumab vs Nivolumab or Chemotherapy for MSI-H/dMMR mCRC

The latest update on here, of course, is the CheckMate 8HW, which compared doublet immunotherapy, nivolumab and ipilimumab, versus nivolumab alone, again, for MSI-high metastatic colorectal cancer.

CheckMate 8HW: PFS (Primary Endpoint)

You see that these progression-free survival curves for both arms is really just outstanding. You can see that there is nearly 70%, 36-month progression-free survival rate for nivolumab and ipilimumab. I will tell you that, again, there is no detriment to having the BRAF V600E mutation.

Take-home Point

The take-home point here is really that patients that are MSI-high should still start with immunotherapy. Now there is a trial of immunotherapy plus a BRAF inhibitor ongoing. Right now providers should feel comfortable in the MSI-high setting. So go ahead and continue using immunotherapy. Of course using chemotherapy and the BRAF inhibitor therapy in the second-line setting after immunotherapy would be something that providers should really consider.

Real-World Considerations

I am going to wrap up here. Just some real-world considerations, the cetuximab versus panitumumab matter. Obviously no data to tell us one way or another. Those of you who live in the southeast certainly know that you do not use cetuximab anyway. So panitumumab certainly would be a reasonable switch.

What do you do if you start FOLFOX-bevacizumab, and then two weeks later you get the NGS? That was actually the question that I really posed to you. That patient was getting FOLFIRI-bevacizumab. Do you make the switch?

I would strongly encourage you to go ahead and make that switch again, just to hit that biology early and very hard.

In terms of biomarker testing, that is certainly something that we need to talk about. Can ctDNA help provide a faster next-generation sequencing result?

BREAKWATER: BRAF V600E ctDNA Analysis

I am going to show you, and I am sure Dr. Riely is going to touch on this too. The ctDNA concordance to tissue is actually really good. I want to point to, in the BREAKWATER study, there were no false positives with ctDNA testing. Now there are some false negatives because if the tumor does not shed ctDNA, nothing you can do about that, right? Essentially, 90% concordance with no false positives. If you see BRAF mutation on ctDNA testing, you can believe it.

Real-World Considerations

I am going to wrap up with just the maintenance strategies. We say to get FOLFOX-encorafenib-cetuximab. When do you drop the oxaliplatin in the study? You could drop it after four months. That is what we typically do in practice.

I would encourage you for a maintenance strategy just to continue hitting the biology. Use 5-FU with encorafenib and cetuximab. We do not have a lot of data with capecitabine, unfortunately.

In borderline patients, I do think that the idea of giving encorafenib-cetuximab in patients that are not eligible for chemotherapy is actually a reasonable option, and that is also in the NCCN guidelines as well.

That was a rapid fast-paced move through colorectal cancer. I am going to turn it over to my colleague, Dr. Riely, to talk about non-small cell lung cancer.

Applying Evidence With Precision: Advancing 1L Treatment Selection in BRAF V600E–Mutant mNSCLC

Dr. Gregory Riely (Memorial Sloan Kettering Cancer Center): Thanks, Dr. Lieu. I really appreciate it. As you said, we do not often do cross disease medical education events. For me, I have learned a lot already. Thank you so much.

We will move next to lung cancer. When we think about lung cancer, it really is, as Chris hinted earlier, a disease where we think about a lot of oncogenic drivers and it is important for us to target some of those.

Today, we are going to focus on this BRAF as in the context of non-small cell lung cancer.

Pretest 2

Before we dig in, I will ask a couple of questions. The pre-test two question. It is a pretty generic one, but we will try. In my current practice, I am confident in my ability to apply the latest evidence and guideline recommendations for the first-line treatment of patients with BRAF V600E-mutant non-small cell lung cancer. Your choices are:

1. Strongly disagree;
2. Disagree;
3. Neither disagree, nor agree;
4. Agree; or
5. Strongly agree.

We will wait a second for you to answer these questions. Looks like we have a little bit of opportunity to make things better here.

Poll 4

Our first poll question. In your current practice, what do you recommend as first-line therapy for a patient with metastatic non-small cell lung cancer with BRAF V600E mutation and PD-L1 that is zero.

1. First choice is dabrafenib-trametinib;
2. Second choice is encorafenib-binimetinib;
3. Third choice is immune checkpoint inhibitor monotherapy;
4. Fourth choice is immune checkpoint inhibitor plus chemotherapy; and then,
5. Finally, nivolumab plus ipilimumab.

Give people a second to think about that as first-line treatment for a patient with metastatic, BRAF V600E non-small cell lung cancer. It is PD-L1 zero.

Okay. Yes. It looks like we have a variety of takes here and look forward to taking you through the data.

Lung Cancer Molecular Subtypes With FDA-Approved Agents

This is the classic lung cancer pie chart. It is really amazing how it has changed over the past 20 years. We are actually 22 years from the first approval of erlotinib, the discovery of EGFR mutations. We have learned so much since the original EGFR days. We see a large range of oncogenic drivers, some with many drugs to treat them.

Importantly, what you are seeing here is mostly drugs that we can consider first-line therapy for metastatic non-small cell lung cancer, with the exception of the KRAS G12C targeting drugs, sotorasib and adagrasib. All of these mutations, if we find them, then we typically are acting on them in the front-line and regardless of PD-L1 status.

If you find a patient has, for instance, an EGFR mutation and a high PD-L1, you are still going to target the EGFR. That stands by contrast to what you heard from Dr. Lieu about BRAF mutant MSI-high tumors.

These are the broad range of things, but we are going to focus now on BRAF V600E-mutant lung cancer.

The Current Approach to Treatment of Patients With Advanced NSCLC

This I alluded to a moment ago, which is just a reminder that when we are thinking about first-line treatment of patients with metastatic lung cancer, we really bring together histology assessment because that is critical to understand the chemotherapy backbone and how important molecular testing, molecular analysis and PD-L1 testing is.

We developed three pathways here. The most important one is finding out whether there is a gene mutation or gene rearrangement. Then if you do not have one of these first-line ones, like I mentioned earlier, then you make your decisions based on PD-L1 status, whether it is high or low.

That puts us into these three bins, where, on the left, if you have a mutation or gene rearrangement that has got approval for first-line therapy, then you will go straight to targeted therapy. Sometimes we add in some chemotherapy, but mostly it is just targeted therapy.

If you do not have one of those and it is a first, we decide about the mutation and then we look at the PD-L1 status, even though that is not the order in which these results come back. If you do not have a targetable alteration, then you are making your decision on chemotherapy or chemotherapy with immunotherapy or immunotherapy alone. Typically, if the patient has a very high PD-L1, you are going to do immunotherapy alone.

Just a reminder that the mutations we are focused on here are these what I have referred to as first-line mutations or gene rearrangements. These include:

• EGFR;
• ALK;
• ROS1;
• BRAF V600E, the topic of our discussion today;
• MET exon 14;
• RET; and
• NTRK.

There Are Many Types of BRAF Mutations

Let us focus in on BRAF-mutant lung cancer. Before we spend too much time talking just about the V600, it is a useful reminder that in patients with non-small cell lung cancer, there are a variety of BRAF mutations that are identified. There is a system of organization people have come up with, or there is class I, class II, class III. I do not want to dwell too much on these individual classes, except to point out that in lung cancer, about half the time when you find a BRAF mutation, it is not a V600E.

What is important to know is that all of what we are talking about here today does not apply to the non-V600E-mutant lung cancers. If you identify V600E mutation, then what we are talking about applies.

For all these other class II and class III mutations, the use of encorafenib, binimetinib, dabrafenib, trametinib, it is not appropriate and not likely to be effective. There are case reports and there are hints of various things, but we do not have approvals in those diseases yet. So this really is about half of BRAF mutations which are the V600E mutations.

Single-Agent BRAF Inhibitors in Patients With BRAF V600E–Mutated NSCLC

Now BRAF V600E mutations, interestingly, were identified before EGFR mutations were in non-small cell lung cancer. They were targeted around the same time in melanoma, first with the BRAF inhibitor, vemurafenib. That was the first drug to come to this space. It showed great results in melanoma, so people started moving it forward in other diseases.

You see here two single-arm trials. On the left is a phase II study of vemurafenib. This is in patients who had had prior therapies with non-small cell lung cancer. You see the response rate is 42%. On the right side is another BRAF inhibitor, dabrafenib, phase II study in patients who have had prior therapy. You see the single-agent dabrafenib, response rate was 33%.

These are both similar efficacy drugs. They were interesting and they were certainly provocative for us back then.

The melanoma field had zoomed ahead already, and we knew that we could do better than just single-agent BRAF inhibitors in patients who had BRAF V600E-mutant melanoma. People began to explore that in non-small cell lung cancer.

Targeting BRAF is Best Done With Combined Inhibition of BRAF and MEK

The idea was that, just like in melanoma, we could target both BRAF and MEK. Combining both BRAF inhibition and MEK inhibition, sometimes referred to as vertical inhibition in the magical thinking way that this is a single pathway.

It is useful to think of it that way. If you can block both the BRAF and then the MEK, you can overcome a variety of feedback pathways. It is useful to note, as Dr. Lieu mentioned, with regard to cetuximab and encorafenib where the encorafenib improves the tolerability of cetuximab. We see the same here where the combination of BRAF inhibitor and MEK inhibitor actually improves the tolerance of these drugs.

I will show you the data to show that it improves the efficacy, but it also improves tolerance.

Dabrafenib (BRAF Inhibitor) + Trametinib (MEK Inhibitor) for BRAF V600E–Mutated mNSCLC

This is the first set of data that we got looking at a combination of BRAF inhibitor and MEK inhibitor. This is the combination of dabrafenib and trametinib. I am showing you two waterfall plots. On the left are those patients who are treatment naive. On the right are those patients who were previously treated.

These are the waterfall plots we like to see in non-small cell lung cancer. The vast majority of patients having tumor shrinkage and high response rates. Here you see 64%, 68%. This really tells us that this combination approach is a more effective strategy for patients with BRAF V600E non-small cell lung cancer.

Dabrafenib + Trametinib: Safety

Of course, combining drugs does come with toxicity. I will spend just a moment here looking at the toxicity tables from this study that incorporated dabrafenib and trametinib.

You see that grade 1/2 events. The most common were pyrexia, nausea and diarrhea. There were grade 3 pyrexia events as well as a little bit of grade 3 diarrhea. The big one was pyrexia that hit grade 3. It is important to recognize too, that these grade 1 and 2 adverse events are nothing to ignore. Grade 1/2 diarrhea can be very limiting for people.

Grade 2 diarrhea is multiple bowel movements a day. That is oftentimes something that prevents people from going to see the movies, prevents people from going to theater, prevents people from getting on airplanes. We always have to be mindful of that as an adverse event. I would just note it here.

The remainder of the adverse events are pretty low grade: fatigue, peripheral edema, dry skin, anorexia, but certainly things that we know about and we keep an eye on.

PHAROS: Encorafenib (BRAF Inhibitor) + Binimetinib (MEK Inhibitor) for BRAF V600E–Mutated mNSCLC

The second combination of BRAF inhibition and MEK inhibition to come to the market is this combination of encorafenib and binimetinib. This is again studied in a very similar way to the data we saw for dabrafenib-trametinib. This took patients who none of them had had prior BRAF or MEK inhibition. These were patients who may have had chemotherapy on the right side or were treatment-naive on the left side.

What you see here is maybe a higher response rate than what we saw with dabrafenib-trametinib, particularly in the treatment naive group with a response rate of 75% and an amazing median duration of response of 40 months. Median duration of response in the previously treated group was also almost a 1.5 year, with a response rate of 46%.

It really shows us that these drugs shrink the cancer and they are able to prolong disease control for quite some time.

PHAROS: PFS With Encorafenib + Binimetinib for BRAF V600E–Mutated mNSCLC

These are the most recent data looking at progression-free survival for patients who have BRAF V600E-mutated non-small cell lung cancer, who get the combination of encorafenib and binimetinib. On the left are those patients who are treatment naïve. As I mentioned earlier, they had a long median duration of response and that median progression-free survival is 30 months. So very long durations of progression-free survival for treatment-naive patients.

On the right are those patients who were previously treated, where you see there that the median progression-free survival is certainly shorter. So identifying these patients upfront is certainly the way to go. This is very much analogous to what you heard from Dr. Lieu about what we see in colorectal cancer, where the earlier we bring these therapies, the higher the response rates. That is definitely something to identify as early as possible.

PHAROS: Safety With Encorafenib + Binimetinib for BRAF V600E–Mutated mNSCLC

Now, looking at the toxicity tables for the encorafenib-binimetinib data. The one big difference is pyrexia. You see that the treatment-related events of pyrexia were all grade 1 or 2 and occurred in just a handful of patients. It did occur on both arms of the trial. It was much lower rate than what we have seen in dabrafenib-trametinib. That is a bigger improvement.

We continue to see some toxicity. You see here grade 1 and 2 nausea, a little bit of grade 3/4 nausea, a little bit of grade 3/4 diarrhea. For the most part, adverse events are grade 1 and 2. You see the relatively similar in a lot of ways to what we saw with dabrafenib and trametinib.

For Patients With BRAF V600E–Mutated mNSCLC, Standard Initial Therapy Is BRAF + MEK Inhibitors

When we think about our patient with identified BRAF V600E mutation with metastatic non-small cell lung cancer, the standard initial therapy is that combination of BRAF and MEK inhibition. You have a choice of dabrafenib-trametinib or encorafenib and binimetinib. No randomized data has really compared this either combination to the other.

Importantly, unlike with a lot of other oncogenic drivers, we do not have randomized data comparing targeted therapy to chemotherapy or targeted therapy to chemotherapy and immunotherapy. That is a bit of a gap in our prospective clinical trial knowledge.

1L Treatment With ICI ± Chemotherapy May Be as or More Effective vs Targeted Therapy (Retrospective Analysis)

I would highlight this recent publication that I was one of, I do not know, there is probably 25 authors on this paper. So you can recognize that it is not one that I was a big part of, but we definitely contributed some data to.

This is a retrospective analysis looking at overall survival outcomes in patients with BRAF V600E-mutated non-small cell lung cancer, who received either frontline BRAF plus MEK inhibition or checkpoint inhibitor with or without chemotherapy. This is a real-world analysis asking the question of what is the best first-line treatment for patients with BRAF V600E.

What you see on the left side is that the patients who got checkpoint inhibitor plus chemotherapy might have done a little bit better than those patients who got just targeted therapy. There is always a lot of bias built into these retrospective analyses, but it is certainly provocative and tells us that maybe a trial comparing these two would be useful.

Now, I would note on the right side here that if you look at the groups of patients who seem to do better or worse than others on this forest plot. Look at the bottom of the forest plot, you see the things that are toward the left are those patients who did better with checkpoint inhibitor plus chemotherapy. On the right are those patients who did a little bit better with BRAF/MEK inhibition.

Notably, the patients who were never smokers or those patients who had very low PD-L1 scores, those were the patients who were more clearly on the right side of this forest plot, telling us that those patients really definitely should get first-line BRAF/MEK inhibition. I still think that very much is the standard of care, but it is provocative to think about this retrospective analysis to think about how we can design the next generation of clinical trials to understand best care for these patients.

Discussion Points

I am just going to close for a second with a couple discussion points. We can probably have a whole webinar on the best practices for biomarker testing for both colorectal cancer and non-small cell lung cancer, because these questions are so important for decision-making for our patients.

I am in clinic today and saw patients this morning. I said, “This is a very difficult diagnosis, and I wish I could tell you how we are going to treat this, but we have got to wait another 10 days until the results from this molecular testing comes back.” That is hard. But it is incumbent upon us to work closely with our pathologists to develop workflows so that we can get these results done as quickly as possible.

I know that locally we have an NGS platform that we have discovered, essentially takes too long to get working results. We developed a small platform that we use so that we can get the quickest answer possible for patients with newly diagnosed disease. Just as importantly, in patients who have early-stage disease where we are thinking about induction therapy approaches. That is a big factor in trying to get the right treatment for our patients.

The second point here, the question is, are there factors that would sway you toward one targeted regimen or another or an ICI for patients with BRAF V600E-mutant non-small cell lung cancer?

I would say I generally today use encorafenib-binimetinib. That is largely because of my experience of putting patients on trial with encorafenib-binimetinib and finding that that lower rate of pyrexia is certainly a notable difference between these regimens. So I typically use encorafenib-binimetinib.

Now, if a patient comes in and they have a heavy smoking history, I might think about using immune therapy as a first-line, particularly if they have a high PD-L1 score. If they have a high PD-L1 or a heavy cigarette smoker, I might lean towards using checkpoint inhibitor rather than targeted therapy in that patient.

I would say you are going to have to push me to get away from targeted therapy. That is maybe more of a cultural statement than it is anything based on data today. This is an interesting time for patients with BRAF-mutant non-small cell lung cancer as well as a variety of other diseases.

I will turn it over now to Chris to go back through a little bit of data. Well, actually, before I turn it over, Chris, I have to do some question from earlier.

Let's Return to a Question From Earlier in the Program

Posttest 2

This is our pre-test questions. Now our post-test question. Now I am confident in my ability to apply the latest evidence and guideline recommendations for first-line treatment of patients with BRAF V600E-mutant non-small cell lung cancer. Same choices:

• Strongly disagree;
• Disagree;
• Neither disagree, nor agree;
• Agree; or
• Strongly agree.

I will let you answer that question now. We did move the needle a little bit. People are a little bit more confident. I am glad I could show you some data and help you get to that point.

Maximizing Treatment Continuity: Coordination of Care and Management of AEs With BRAF Inhibitors

Now I will turn it back over to Dr. Lieu to take us through maximizing treatment continuity.

Dr. Lieu: Thanks so much, Dr. Riely. Just a phenomenal presentation. When I was in fellowship a long time ago, who knew that we would just be jealous on the GI side of the thoracic oncologists and how far you have gone with non-small cell lung cancer. It is really cool to see that data. Thank you for that great talk.

Case 2: Patient With Colon Cancer Receiving BRAF + MEK Inhibitor Therapy

Okay. We are going to wrap up with a discussion on adverse events. This is probably something that we always worry about. Many of us that treat colorectal cancer and have a lot of experience with anti-EGFR inhibitors certainly understand that the toxicity management can be difficult, right?

Even though Dr. Riely and I have both discussed the attenuation of some of the toxicities that we see with anti-EGFR inhibitor with the BRAF inhibitor, this is still a very important topic to discuss, mainly because our patients are going to have some side effects. So how do we manage those?

Just a quick reminder to those that are attending the webinar, please feel free to put in any questions that you have in the Q&A that should be at the bottom of your screen. Feel free to ask us anything that you want, whether the questions are easy or hard.

This is a case, a patient with colorectal cancer getting here, I would say, BRAF and anti-EGFR inhibitor therapy. This is a 63-year-old female with right-sided colorectal cancer, liver metastases and has a BRAF V600E mutation. The treatment that was initiated was encorafenib-cetuximab-FOLFOX, which is what a majority of you have chosen to treat this patient with.

At week three, the patient presents with grade 2 acneiform rash on the face and chest and grade 2 fatigue. She is anxious and wants to potentially stop therapy just because of the rash that has developed.

Pretest 3

For this patient, in your current practice, which of the following would you recommend? Would it be:

1. Topical steroids and antibiotic;
2. Topical steroids, antibiotic and hold the treatment until grade 1 or less;
3. Oral steroids, antibiotic and treatment hold until grade 1 or less; or
4. Oral steroids and antibiotic and treatment discontinuation permanently.

Let us see what the poll shows. Most of you want to do topical steroids and oral antibiotic and treatment hold until grade 1 or less. Okay. We will take down the poll and we will go through the mitigation strategy.

Mitigation and Management of Dermatologic AEs

Dermatologic AEs. Dr. Riely and I both showed you the adverse events rates for several trials. Grade 1 and 2 rash is an adverse event that does happen, obviously with BRAF and anti-EGFR obviously MEK inhibition as well.

In terms of prophylaxis, obviously this goes along with the chemotherapy teaching that we give to all of our patients. We tell them to be careful in the sun. Broad spectrum sunscreen and then thick creams, not lotions starting on day one. It will be interesting to hear if many of you are actually starting with prophylactic antibiotics or not. I will tell you that most of the time, because I am not necessarily sure what the rash might look like in my patient, that I am not necessarily starting the antibiotic on day one, but that does remain an option.

Certainly for a patient with grade 1 or 2 rash, in addition to the antibiotic, you can add on the topical steroids and the topical clindamycin gel. Many of us have experience with this exact regimen. Sometimes we do this prophylactically, but I usually start when I start to see grade 1 rash with all three of these agents.

For grade 2 for encorafenib, if there is no improvement in two weeks with this regimen, because you do not necessarily have to stop at that time. You can initiate these therapies and continue on with the patient with the therapy. If there is no improvement in two weeks, we would withhold the BRAF inhibitor until grade 0 or 1. Then if it is the first instance, you can actually resume at the same dose. If it is multiple instances, obviously at that point you are definitely going to do a dose reduction.

For dabrafenib, you would withhold it for up to three weeks. If improvement is noted, you would resume at a lower dose.

For grade 3, obviously we are doing oral antibiotics and a dermatology consult at that point. In rarely rare instances, I have actually used oral steroids as well, but that is not necessarily something that is absolutely recommended. For encorafenib, we would withhold the BRAF inhibitor until grade 0 or 1 at the same dose if first occurrence, and then reduce the dose if it is recurrent.

For dabrafenib, same thing that you would do with grade 2. You are going to dose reduce that patient.

Mitigation and Management of Other Key AEs

There are gastrointestinal side effects. We treat this as we would almost any other chemotherapy or targeted therapy drug. For nausea, we are obviously going to give plenty of anti-nausea medications. With encorafenib, some patients seem to tolerate it better with or without food. You can tell your patient to try it with or try it without to try and mitigate some of the nausea adverse events.

Then for ocular toxicities, for encorafenib in particular, there is actually no routine prophylactic exam needed unless the patient is symptomatic. The rare ocular toxicity that you are going to see with a BRAF inhibitor is uveitis. If the patient does complain of blurred vision or photophobia, obviously, you are going to stop the drug and have a rapid referral to ophthalmology, but only if the symptoms arise. They do not routinely need ophthalmologic exams.

If for cardiac, we usually get a QT or EKG at the beginning of treatment just to get a baseline QTC. You can get periodic EKGs, but this is just some additional monitoring that you can provide, but it is not necessary except for that initial EKG to have as a baseline study.

Dose Modification Strategies

In terms of the dose modification strategies, you are essentially going to reduce by 25%. For encorafenib, you are starting at 300 milligrams daily and you can reduce down to 225 or 150. Dabrafenib, same thing, just essentially dropping by 25% with each dose reduction.

Then obviously, many of you are very familiar with what causes these adverse events. Rash and hypomagnesemia, still likely to anti-EGFR therapy. Arthralgias and nephrotoxicity. We are obviously checking creatinine some patients with BRAF inhibitors. And any visual changes we are looking at the BRAF inhibitors as the causative agent.

Then nausea and diarrhea certainly can be both drugs. Of course, if we are giving these agents with chemotherapy, like we are in colorectal cancer, that is obviously a overlapping toxicity with chemotherapy as well.

Discussion Points

In terms of some discussion points just in terms of real life practice. Some practitioners really like to start everybody on prophylactic antibiotics. Like I said, in my own practice, this is not necessarily something that I have done up front, unless a patient is deathly afraid of having any acneiform rash at all. In those patients, I would be fine with some prophylaxis.

Again, when you look at the BREAKWATER study, not every single patient even had significant rash, given that I usually like to start when I actually see it.

We talked a little bit about this in the BREAKWATER data. You saw the data with FOLFOX-encorafenib-cetuximab. If a patient is not eligible for chemotherapy either because of bone marrow suppression or performance status or age and you are really worried about giving somebody FOLFOX or FOLFIRI, could you start with encorafenib and cetuximab.

Like I said, this is actually in the NCCN guidelines. Given that the initial response rates of encorafenib-cetuximab was around 45% in the BREAKWATER study, I still actually feel comfortable starting with targeted therapy to encorafenib and cetuximab in patients that just are not eligible for chemotherapy.

If patient has significant toxicity, the question of treatment holidays always comes up, right? There is not really a good answer for this. If you can continue somebody on 5-fluorouracil for colorectal, obviously, encorafenib and cetuximab and the patient is tolerating that well, certainly that is the ideal state because obviously you have to target inhibition. You still have some chemotherapy to kill off any resistant clones that are coming up.

At the same time, sometimes our patients really do need a break. We obviously need to monitor those patients closely because this is just an aggressive disease.

Then sequencing. When we treat patients with chemotherapy-encorafenib-cetuximab, we know with anti-EGFR inhibitors that we can sometimes rechallenge patients, and we will learn more about this as time goes on. In patients that have progression on FOLFOX-encorafenib-cetuximab, move on to, say, FOLFIRI-bevacizumab, we can check ctDNA and look for any resistance mechanisms.

We are going to start learning more about what rechallenge with encorafenib-cetuximab looks like and what the response rates look like in that setting as well.

Case 2 Revisited: Patient With Colon Cancer Receiving BRAF + MEK Inhibitor Therapy

We are going to close up with our case again. This is our patient with grade 2 acneiform rash. We are going to ask you what you want to do for this patient? Again, your options are:

1. Topical steroids and antibiotic;
2. Add that with a treatment hold;
3. Add on steroids with a treatment hold; or
4. Add on steroids and do a complete treatment discontinuation.

Let us see what the polling says. We still have a majority of people wanting to do a treatment hold. Honestly, that is a totally fine regimen, particularly given that we are leading you with the fact that the patient is obviously very anxious about continuing on therapy. I would say for grade 2, you can obviously do topical steroids and antibiotic if the patient is not already doing those treatments and continue dosing, if you want.

Obviously, if you have a treatment hold and you institute some of these treatments, you can actually restart at the dose that you had started at, assuming the patient has a reduction in their adverse event to grade 1 or grade 0.

Poll 5

Great. Then we have some backup questions or post-test questions for you as well. Poll number five is, do you plan to make any changes in your clinical practice based on what you learned in today's program? Very easy.

1. Yes;
2. No; or
3. Uncertain.

We will see what everybody says. Okay. We are not going to see the results for this, so just answer honestly.

Poll 6

Then we will wrap up with our last polling question, which is, we would love everybody to text in one key change here that you are going to make in your clinical practice based off of this webinar. It can be in colorectal cancer, non-small cell lung cancer and toxicity management. Again, we would not be showing answers for this polling question either. Feel free to put in anything that you want. This will just provide great feedback for the organizers of this webinar.

Q&A

Thank you guys very much for filling out all those polls and those questions. I do not see any questions or answers coming through at our end here. Feel free to put in anything that you guys want in the Q&A. Dr. Riely and I would be happy to answer them.

Dr. Riely, one thing that you and I had talked about before the webinar was this question that you had brought up about what biomarker testing looks like, right? We are struggling with the same thing. You have a patient in front of you. This is the reason why in GI medical oncology we start so many patients on FOLFOX-bevacizumab because that is not a biomarker-directed therapy. You can start somebody on it but would love to hear best practices on your end. How you guys have managed trying to get biomarker testing back in an efficient manner?

Dr. Riely: Yes. I have to say, this has been a struggle over the past 20 years as we have learned that we need to. I will tell you that the biggest breakthrough in getting biomarker testing moving actually was not any cool mutation results or anything like that. It was instead the great results we saw with checkpoint inhibitors and finding out that the checkpoint inhibitor trials. The checkpoint inhibitors did not really work for EGFR and ALK.

Then people had to pick their first-line therapy, and they had to know EGFR and ALK status to be able to give first-line therapy. That really drove people to do this better.

What does better look like? Getting the piece of tumor and getting it to the right people to do the test. That is a huge challenge. All of us recognize that. I was really pleased to see your data talking about circulating tumor DNA because it is a cheat code, if you will, right, for molecular testing. It is not the best answer. It is not the answer we would all pick if we had a choice. But it is fast and it is pretty sensitive, not nearly as sensitive as we need it to be.

If you can find a result there, then you can feel comfortable. There is still a lot of folks. When I meet a new patient, unless I know for sure that their NGS results are very near, like just on the horizon, I am going to send off plasma just in case. Otherwise I sit there a week later and say, “I wish I would have drawn the plasma”, and then I am in a tough spot.

In lung cancer, that is what we do. I will say that even then, we still have a group of patients where the results are not back. They really want to start therapy. Maybe sometimes they even need to start therapy. For those folks, we will start with just chemotherapy and we will exclude the checkpoint inhibitors. We will not give any targeted therapy. We will just use the chemotherapy backbone. Then when we get the results back, then we can make a change.

I will flip that around and ask for in the colorectal world. My perception is that a lot of times this is recurrent disease after a prior surgical resection, is there a move to try to get more biomarker testing done on resected disease so that you have that data in hand when they recur?

Dr. Lieu: Yes, it is a great question. It is an area that is evolving over time. The concordance rates between primary and metastatic sites is very high. So we can feel comfortable at least testing the primary. The more recent the data is, the better, right? If we have a metastatic site biopsy, sending that off for molecular testing is always preferable as long as you have enough tissue to run it.

I used to not honestly be a huge believer in ctDNA testing upfront for a patient with metastatic disease. I am now. The data that you can get in terms of MSI-high and BRAF, like you said, it is not perfect, and there is a false negative rate that we are going to see. That is why the tumor tissue testing is always so critical.

There are really two take-home messages. That is, number one, with ctDNA testing, if it is positive, it is there and we can trust it. The second thing is that when we send off tissue, we get results back in three weeks if that is how long it takes. It is to act on those results. Sometimes our patients just do great on FOLFOX-bevacizumab. What the data is really showing us is that especially with BRAF, the sequential treatment is just not going to be as effective as just hitting that biology hard and giving the best treatment upfront.

I really believe that we need a way to get those results back on hundreds of patients that we are going to see right in a week or two weeks and be notified about that and then make the treatment change.

Dr. Riely: Sounds great. Yes. No, this will be a perennial challenge for us is to constantly improve our biomarker testing. Thanks so much, Dr. Lieu, for this presentation. I learned a lot. Thanks everybody for joining us today.

Dr. Lieu: Thank you everybody.