Metastatic CRC: Personalizing Patient Care Using Current Evidence and Innovative Therapeutic Strategies

We will go ahead and get started. Frontline treatment for metastatic colorectal cancer. We have a case presentation.

The next slide.

[00:09:34]

Case Presentation

This is a 59-year-old female, past medical history of hypertension, presented with rectal bleeding. No prior screening colonoscopy. We are glad that we have more and more options for screening nowadays, because colonoscopy does not have wide uptake above 55-60% nationally. The PCP refers to a gastroenterologist and finds a mass at the splenic flexure. This is left-sided. Biopsy comes back as moderately differentiated adenocarcinoma. CT scan shows multiple liver lesions and retroperitoneal lymphadenopathy. The upshot here is this really would not be resectable. You can see that dominant lesion there medially, which is bumping up against the inferior vena cava and the hepatic vein. This is not going to be a resectable case.

Next slide.

[00:10:29]

Case Presentation: What About pMMR mCRC?

The pathology sense for next-gen sequencing, MMR testing. The patient is RAS, BRAF wild-type. Proficient MMR. This is a pretty common situation. What should be offered for first-line therapy?

[00:10:44]

Randomized GERCOR Study: FOLFIRI Followed by FOLFOX6 vs Reverse Sequence in Advanced CRC

Let us go through some of the data on this 1. Indeed, this made me feel a little bit old because I was actually finishing my fellowship when this trial came out. It basically looked at starting with FOLFIRI and then pivoting to FOLFOX vs starting with FOLFOX and pivoting to FOLFIRI upon progression.

You can see there on the curve to the right, the overall survival curve, there was no difference in terms of what order you went in. This made people feel pretty comfortable about starting with either FOLFOX or FOLFIRI. Europeans tended to focus on FOLFIRI because irinotecan was off patent earlier, and had some cost advantages. I think some people also make the argument that FOLFIRI does not really have a cumulative toxicity like oxaliplatin does with neuropathy. Other people like FOLFOX, which is well-tolerated. People do not even lose their hair, they can continue working without a problem, etc. Those are some considerations as to why folks picked 1 or the other.

Next slide.

[00:11:50]

Randomized Trial of FOLFOXIRI vs FOLFIRI in Metastatic CRC

There have been various studies over the years. This is an example that was published in 2011 that suggested if you start with a more intensive therapy, you can have better outcomes. But I will say a lot of those studies the rate of second- and third-line therapy was not all that high. Of course, the decision in terms of whether to use a triplet like FOLFOXIRI vs a doublet like FOLFIRI or FOLFOX, there are often clinical factors that might drive that decision, such as how symptomatic the patient is. If the patient is really symptomatic with pain or something else where a response would relieve that pain, then certainly you might think about being more aggressive with the triplet. Or if you think you are only going to use 1 line of therapy, certainly the triplet would make sense. On the other hand, if they are not very symptomatic and you are pretty convinced you are going to be able to use multiple lines of therapy, it is reasonable to do a doublet.

Next slide.

[00:12:52]

STEAM: Phase II Study of Concurrent or Sequential FOLFOXIRI-BEV vs FOLFOX-BEV as 1L Therapy

This is an interesting study. I remember actually being at the poster presentation for this in the oral presentation at ASCO. A cool idea. The idea being what if you flip-flop between FOLFOX and FOLFIRI? You use FOLFOX for a month, FOLFIRI for a month, FOLFOX for a month, FOLFIRI for a month vs an intensive therapy of FOLFOXIRI plus bev and then the control arm, if you will, was FOLFOX-BEV. You can see there that the PFS was a little bit improved when you either use the triplet chemo or used all 3 drugs in a 1 vs the other vs the 1 vs the other vs the control group. But overall survival was pretty similar between all of the groups.

It seemed like a good idea at the time, but it turns out that flip-flopping between FOLFOX FOLFIRI and going back and forth really was not the way to go. This was a Phase II trial, actually. But people stopped looking at trying to pivot from 1 to the other in a planned fashion.

Next slide.

[00:14:02]

CALGB/SWOG 80405 (FOLFIRI/FOLFOX + Bev or Cetuximab): OS by Tumor Location (RAS WT)

80405, this was looking at FOLFIRI FOLFOX plus bev or cetuximab. What was surprising about this study was the left vs right story. If you take the cetuximab arm and you look at the blue, left-sided, vs the red, right-sided, you can see that cetuximab appeared to be detrimental for right-sided tumors. Now, why would that be? We are not totally sure. The left colon comes from the hind gut, and the right colon comes from the midgut during embryonic development. They actually have a different embryonic origin. The microbiome is quite different between the 2. These were some of the considerations as to why it might be so different. Then bevacizumab, which is green and purple, you can see there, there was not nearly as much of a difference between those 2 arms.

Next slide.

[00:14:59]

Role of Maintenance Strategy in mCRC

Maintenance. Maintenance is always an interesting question. Overall the initial study suggested that going with 5-FU and bevacizumab is a good maintenance strategy, but there have also been some other trials that have not really gotten as much press but have suggested you can actually take a treatment break. The upshot is that it is very reasonable to do maintenance therapy, especially if it is well-tolerated. But if you do have to take a longer break, as long as you are following patients carefully and getting regular scans, it is reasonable that you are not going to have an overall survival difference. You will have some PFS differences, progression-free survival, but you are not going to have overall survival differences if you take plan breaks.

In my practice I tend to do some type of 5-FU and bevacizumab maintenance unless the patient has a lot of 5-FU toxicities. Then we think about just observation. Most of the trials have suggested that bevacizumab alone is not great as a maintenance regimen. There was 1 study that suggested it had some benefit, a German study. But overall, 5-FU seems to be 1 of a key aspect of maintenance therapy.

Next slide.

[00:16:17]

Case Presentation

All right. Let us go back to our case. Again, 59. This is a first-line patient, just got diagnosed, and similar, obviously, scan findings here.

Next slide.

[00:16:30]

Case Presentation

But now you can see that the mismatch repair testing, and this is testing for the presence of these DNA repair enzymes. I think of this as like a spell checker. Is your spell checker on your DNA working or not working? These are often dimerized. You often will see a loss of MLH1 plus PMS2 because you can see that you are not really getting much staining there. This patient appears to have deficient mismatch repair testing.

Of course, you can also look at the DNA. That is called microsatellite testing. The microsatellite should all be the same number of DNA bases, or at least very close. When you have microsatellite instability, you get multiple lengths of those microsatellites. That is why it is called microsatellite instability.

If you are looking at the protein, it is called mismatch repair. If you are looking at the DNA it is called microsatellite instability.

Next slide.

[00:17:33]

Poll 4: In your current practice, what would be your recommendation for this patient’s treatment?

This one is a deficient mismatch repair or MSI-high patients. Again, here are the options

You can see you have a traditional chemo option;

You have got immunotherapy singlet;

You have an immunotherapy doublet;

Then we see immunotherapy plus chemo; and

There is also a BRAF-directed option here as well.

Paul: Poll is open. Please vote. Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

Dr Messersmith: Okay. We had a vote for traditional chemotherapy, FOLFOXIRI plus bevacizumab. Then we had a vote for pembro plus FOLFOX. All right.

[00:18:44]

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

Well, let us look over some data. This is actually an active area during the last 2 ASCO meetings.

The ASCO before last KEYNOTE-177 was presented. This is single-agent pembrolizumab. You can see here that in the first-line setting, there was an advantage to pembrolizumab over chemotherapy with a pretty good hazard ratio of 0.6. The PFS was 16.5 vs 8.2 months.

Kind of interesting on KEYNOTE-177, if you look all the way at the beginning of the curve, the first few months, the chemo arm does a little better because immunotherapy takes a little longer to work. But then the curves quickly flip by the 4-month mark, and there is an advantage to single-agent PD-1. Pembrolizumab or nivolumab would be reasonable.

CheckMate 8HW. This was presented at the ASCO GI Symposium as well as the ASCO annual meeting. Just showing that there was a market advantage to nivo-ipi. This is just 4 doses of low-dose ipi. Ipilimumab being a CTLA-4 inhibitor with nivolumab just showing a very impressive difference here with the hazard ratio of 0.2. It is not often we see hazard ratios that are so low, 0.2. Again, this is PFS.

Next slide.

[00:20:10]

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

This is again on CheckMate 8HW, which was presented, and this was the curve in patients with centrally confirmed. Some of these trials are more real-world where as long as it is locally confirmed, you are okay, then this is the curve for centrally confirmed. You can see really good response rate. Nivo plus Ipi 71%, nivo alone 58%. Really good disease control rates. You can see the progressive disease is all the way down at the 10-20% mark. This is basically singlet vs doublet chemotherapy. 8HW is a very large study. There were some first-line and some second-line patients. It looked at both single-agent and doublets.

Next slide.

[00:21:01]

CheckMate 142: OS

CheckMate 142. This is another study looking at Nivo plus or minus Ipi. Again, the Nivo plus Ipi arm seemed to have better overall survival at 5-year follow-up, 68% vs 46%. Fairly impressive. The median survival was not reached, and I think many of us have these patients in our clinics with deficient mismatch repair who are doing extremely well long term. It is really nice to see those curves flatten.

Next slide.

[00:21:39]

General Recommendations for Treatment of irAEs

Now, what about immune related adverse events? I think this is something that folks are getting more and more comfortable with as we use immunotherapy in more and more settings. For mild grade 1, we can generally follow patients. As you start getting into your grade 2 and grade 3, we start looking at steroids and stopping treatment. It seems to be the case that as long as you are 10 mg or less of prednisone, for instance, that you can go ahead and restart immune therapy and still get responses. Then as you get into your grade 3s and 4s, that is where we start giving high dose IV steroids and start getting our specialists involved and often have to use multiple agents to get control of this.

These are rare. If you look at the clinical studies, pretty rare to have severe adverse events with these agents, but nonetheless, it can be a pretty scary experience. It can take quite a while to improve for the patient. When it does happen, it can certainly be a problem clinically for the patient.

Next slide.

[00:22:47]

Management of Immune-Related Hepatobiliary Toxicities: AST/ALT Elevations

This 1 is specifically on immune-related hepatobiliary toxicity, so ALT/AST. The main issue here is as you get into the grade 3, so 5-20 times upper limit of normal, that is where you are definitely going to want to involve your hepatologist, start the higher dose inpatient steroids. You often admit the patient. This is often a slow recovery from this hepatotoxicity. But it does generally recover, and controllable as long as you are on it as soon as it starts to develop.

Next slide.

[00:23:30]

Case Presentation: What About BRAF V600E–Mutated mCRC?

What about BRAF V600E? Same case, same CT scan. What we are doing is just altering the molecular findings. In this case this patient was proficient MMR with BRAF V600E mutation. I will just pause there and say if the patient has both deficient MMR, MSI-high and BRAF, because BRAF mutations often have a secondary hypermethylation of MLH1, which basically shuts down that gene and makes someone have deficient mismatch repair. But if you have both, it seems as though focusing on the immunotherapy is going to get you the best outcome just because of those nice long survival times. The flattened survival curves showing just a nice long benefit vs going after the BRAF V600E. We generally prioritize the immunotherapy. But in this case the patient is proficient MMR. They are basically a normal mismatch repair.

First-line therapy, let us look at some options.

Next slide.

[00:24:39]

Molecular Alterations in mCRC

This is actually just showing the molecular alterations that we have to look at. That purple there at the bottom is the V600E population, so roughly 8%. You can see the most common of course is RAS mutations. MSI-high is certainly an important consideration. Of course, HER2 in black. We will talk about HER2 a little bit later as well.

Next slide.

[00:25:13]

Considerations for BRAF V600E–Mutated mCRC

Basically the first-line chemo plus Bev, for instance, seems to be a little bit less effective vs some of the other ways of approaching this. There is a key trial looking at encorafenib and cetuximab, which we will look at, which is in the pre-treated population. Then more recently we had BREAKWATER presented at ASCO and also published, looking at FOLFOX plus encorafenib and cetuximab. I would just note that FOLFIRI plus encorafenib and cetuximab is also being tested. There is a little bit of a drug interaction with irinotecan. That took a little longer to get off the ground but does seem to have promising initial results. But we will focus on BREAKWATER the FOLFOX arm, initially.

Next slide.

[00:26:09]

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

BREAKWATER at the end of the day, it is basically looking at those bottom 2 boxes, the blue encorafenib plus cetuximab and FOLFOX-6 vs standard of care chemotherapy. The encorafenib + cetuximab just doing the targeted arm, that was actually stopped early just because they were not seeing the efficacy that they were looking to see, whereas the chemo arm was doing quite well. Essentially, it is a comparison between the blue and the orange there.

The statistics are a little bit complicated. This is part of an FDA project to try to avoid a lot of single-arm studies. Basically, you start the trial, you have co-primary endpoints, and you take some early interim looks, and therefore you are able to get the comparative data without having to just have a single arm.

Next slide.

[00:27:10]

BREAKWATER: ORR With Chemotherapy + Anti-BRAF Strategy

This looks at the response rate. Again, this is 1 of the coprimary endpoints. You can see that encorafenib and cetuximab had a higher response, actually, even just without chemotherapy vs standard of care. But you got almost an additional 20-30 points of response when you combine the targeting agent against V600E, which is the cetuximab and encorafenib with the chemotherapy.

Then the PFS, you can see the encorafenib cetuximab FOLFOX-6 arm had a longer PFS, 12.8 months vs encorafenib plus cetuximab or standard of care chemotherapy. The combo did better than either single strategy.

Next slide.

[00:28:00]

BREAKWATER: Interim OS With Chemotherapy + Anti-BRAF Strategy

This was the interim overall survival. Again, you have 3 zeros in your P value there with a hazard ratio less than 0.5. Just showing a nice improvement. Median of 30 months vs 15 months. Basically, doubled survival. That is despite the fact that many of these patients are getting BRAF-targeting agents in the second- and third-line setting. We do not have a full data set on that. But initially, it looks like a lot of them did.

The idea here is that if you hit the cancer hard because upregulation of MAP kinase pathway signaling, for instance, is 1 of the ways that tumors can try to survive chemo. When that pathway is trying to be upregulated, you are hitting it as well, the MAP kinase pathway with encorafenib cetuximab. The idea is you are hitting 1 of the pathways that tumors use to try to get around chemo. Hit it hard, hit it early, and you seem to have a nice survival benefit.

Next slide.

[00:29:11]

BREAKWATER: Most Frequent All-Causality TEAEs

These are the adverse events. Sorry. The title over the blue there got a little cut off, but it is encorafenib plus cetuximab plus FOLFOX. The blue bars standard-of-care chemo, which was a doublet, is on the right. You can see that despite the fact that patients on the left side, the blue side, got twice as much therapy because the PFS was so much longer. The toxicities are not all that different. Certainly, we are seeing a little bit more on the GI side. Of course that depends on the standard of care chemo, whether you are using FOLFIRI or FOLFOX. Joint pain is a class effect with RAF inhibitors, so, not surprised to see arthralgia much higher. Also, of course, rash. That is a class effect when you are looking at BRAF and cetux, of course, you are going to see rash as well. Otherwise, there were not really major safety signals here. In the encorafenib and cetuximab you can see the grade 1 and 2, grade 3 and 4 adverse events put there on the side.

Next slide.

[00:30:28]

Considerations for Initial Therapy of mCRC

As we look at these different groups of patients, so proficient mismatch repair microsatellite stable patients, we are looking at chemotherapy, often with bevacizumab. You can use doublet or triplet backbones. This is at the top for patients appropriate for intensive therapy. If they are left-sided RAS wild-type, you are going to be thinking about an EGFR inhibitor such as cetuximab and panitumumab. The first-line setting again with the chemotherapy backbone of your choice.

Going to the third column. Microsatellite stable proficient mismatch repair. V600E mutated. We are thinking about encorafenib plus cetuximab and FOLFOX based on the BREAKWATER study that we just looked at. NCCN guidelines and others, they are really ecumenical about whether you use cetuximab or panitumumab. In the study they use cetuximab, but there is no reason to think panitumumab would be any different. That is why it is included in most of the guidelines.

Microsatellite-high, you are looking at doublet vs single-agent chemotherapy. You can see there you have a lot of different choices. If you are both MSI-high and BRAF, we tend to focus on the immunotherapy side of things just given the just remarkable results we get with immunotherapy in this patient population.

Then finally, the third column, if you have a patient who is HER2-amplified, it looks like it is saying HER2-negative and then amplified, but it is HER2-amplified. For those patients, we are thinking about HER2-directed therapies such as trastuzumab plus pertuzumab, trastuzumab plus tucatinib, which we will look at in just a minute.

Next slide.

[00:32:27]

Posttest 1: A patient was recently diagnosed with mCRC, including multiple liver lesions and retroperitoneal lymphadenopathy. Their molecular profile is: pMMR/MSS, BRAF V600E mutation, HER2 negative, KRAS wild type. What would be your recommendation for this patient’s treatment?

Patient recently diagnosed with colorectal cancer, again not operable, liver lesions, retroperitoneal lymphadenopathy. The patient has a BRAF V600E mutation. This would be appropriate for the BREAKWATER trial that we just talked about. What would be your recommendation for the treatment? Again, we have our traditional chemo, which many people had chosen initially. Two dabrafenib options. We have the 2 encorafenib options that we just reviewed and then vemurafenib, which was another early version of a RAF inhibitor.

Paul: Poll is open.

Dr Messersmith: Make a choice.

Paul: Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

[00:33:44]

Dr Messersmith: All right. Great. We really had a nice flip there because I do think there is good data to support this. Many folks picked FOLFOXIRI plus bev initially. But you can see here we are flipping over to encorafenib plus cetuximab and FOLFOX. As mentioned, encorafenib plus cetuximab was an arm of the study. But that arm was closed because they just were not seeing the activity, and there are some other results that came out suggesting you need the chemo part of it as well.

The correct answer is (E) encorafenib + cetuximab and FOLFOX. There is an FDA approval for this. It is really the preferred strategy just given the survival benefit. Hit it hard and hit both pathways, chemo pathway and signaling pathways as well.

Next slide.

Treatment for Metastatic Colorectal Cancer After Disease Progression

[00:34:37]

All right. Let us start going into some of the second- and third-line options.

Next slide.

[00:34:46]

Case Presentation: What Are Options at Progression?

This is a patient you can see on the CT scan. On the right side, lots of liver lesions. Again, not a resectable patient. You see some effusions there as well. This patient has progressive disease after triplet plus bev. What are some options for therapy following this?

Next slide.

[00:35:11]

Poll 5: In your current practice, what would be your recommendation for this patient’s treatment?

We have fruquintinib, regorafenib, TAS-102, encorafenib plus cetux plus FOLFOX. This patient is not BRAF-mutated and pembrolizumab. This patient was proficient mismatch repair. Which of these would you choose? We will go and open the poll.

Paul: Poll is open. Please vote. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr Messersmith: Okay. Folks picked encorafenib plus cetux plus FOLFOX. Again, this patient does not have a V600E mutation. I probably should have made more of a big deal of that. They are BRAF wild-type. We would not use BRAF-directed therapy here. But we will talk through some of the options and loop back on that.

Close the poll. Next slide.

[00:36:32]

Considerations for Second and Subsequent Lines of Therapy of mCRC

This looks like a busy slide. But it is actually not too complex here. On the column all the way to the left, if you have gotten both irinotecan and oxaliplatin like this patient has, you have a couple of different options. You can look at fruquintinib, you can look at regorafenib and you can consider TAS-102, which is that trifluridine and tipiracil. Just remember, trifluridine was actually synthesized way back in the 1960s, but it has a 15-second half-life. The tipiracil is a metabolic inhibitor, so the trifluridine can stick around. That is how TAS-102 is formulated.

Those are the 2 middle columns there. If you have gotten oxaliplatin, you can obviously use an irinotecan based regimen. If you have got irinotecan, you can use a FOLFOX or CAPEOX based regimen. Notice that there is no option for oxaliplatin alone. That is because oxaliplatin really needs 5-FU to work. Because irinotecan can work on its own. Never use oxaliplatin alone. Then, obviously, if they have not gotten irinotecan or oxaliplatin, then you would go ahead and use those combination regimens as well.

If they are RAS wild-type left-sided, you are going to be looking at EGFR inhibiting monoclonal antibodies such as cetuximab or panitumumab if they have not received that previously and their left-sided. If it is right-sided, of course you would not use cetuximab or panitumumab.

Next slide.

[00:38:09]

SUNLIGHT: Efficacy With TAS-102 (Trifluridine–Tipiracil) ± Bevacizumab

This is the SUNLIGHT trial. This looked at trifluridine-tipiracil ± bevacizumab. As with many of these studies that have this 5-FU type of drug, TAS-102 is not exactly like 5-FU, but it is in the same class here. It combines really nicely with bevacizumab and had an improvement over the TAS-102 alone. For this reason, if we can, we often use bevacizumab with the TAS-102.

Next slide.

[00:38:45]

FRESCO-2: Fruquintinib vs Placebo in Patients With Refractory mCRC

Fruquintinib. This is the FRESCO-2 trial looking at fruquintinib vs placebo. The curves do not flatten like they do in immunotherapy but nonetheless there is a 34% benefit for overall survival. Bigger benefit for progression-free survival. I call these peacekeeper drugs. They do not have high response rates, but they can really keep things from growing for long periods of time. That is also a very reasonable option.

Next slide.

[00:39:19]

CORRECT: Regorafenib for mCRC Following Progression After Standard Therapy

Regorafenib. This was the CORRECT trial. Hazard ratios are a little bit higher if you look at overall survival. This 1, you do need to be very mindful of toxicity. I do not use regorafenib as much anymore, when fruquintinib came out. Regorafenib is multi-targeted, fruquintinib really is focused on EGFR signaling. But nonetheless, regorafenib is certainly an option, FDA-approved and it is on guideline.

Next slide.

[00:39:54]

CRC: A Molecularly Diverse Entity

With colorectal cancer, you just have to remember what the slides are really trying to show you is that some of these are overlapping markers and some of them do not overlap. For instance, pretty rare to see both a RAS mutation and a BRAF mutation together. Why is that? Because if you have a RAS mutation, there really is no selection pressure to get a second mutation in the same pathway. In other words, the light is already turned on, the signaling is already going. Not surprisingly, you do not really have 2 mutations in the same pathway at once. Whereas deficient mismatch repair, that is a totally different mechanism. As I mentioned, BRAF V600E, you often get hypermethylation of MLH1. You have that overlap between BRAF and deficient mismatch repair.

HER2 is really more common in RAS wild-type, but it can happen for RAS-mutated. It makes sense, if you are RAS mutated, you do not have that selection pressure to upregulate that HER2 pathway. But it does happen occasionally. You can see there that KRAS G12C, which we will talk about in a minute, is only 3% of the RAS mutations. We certainly are hopeful that there will be some other drugs coming into this space that hit the other RAS mutations, such as G12V, G12D, Q61R, etc, etc.

Next slide.

[00:41:28]

Considerations for Second and Subsequent Lines of Therapy of mCRC

Looking at each of these columns are these different molecular subsets that you will see. I mean, it has become very clear at this point in time, that you cannot treat colorectal cancer without molecular profiling because there are just so many different things you might pick up. V600E, we talked about encorafenib plus an EGFR-targeting monoclonal antibody such as cetuximab or panitumumab with chemo.

HER2, we will talk about this in a minute. But trastuzumab and pertuzumab or lapatinib and tucatinib. Tucatinib being the most recent 1. HER2-amplified, you have trastuzumab deruxtecan. G12C, we have our G12C inhibitors sotorasib and adagrasib. But main pivotal trials are in lung cancer, but they are on guideline for G12C-mutated colorectal cancer. Entrectinib, very rare that you will see this. But, of course, we have these drugs, entrectinib, larotrectinib. Then for RET fusions, selpercatinib.

Next slide.

Current Data for Anti-HER2 Therapies in mCRC

[00:42:27]

Let us go through HER2. Next slide.

[00:42:31]

HER2+ mCRC: A Distinct Subset

HER2, it is a distinct subset. Tends to be left-sided, tends to have lung metastases and a higher incidence of brain mets. It is enriched in RAS/RAF wild-type tumors, which makes sense because there is some overlap in the signaling. We are not totally sure about prognosis. It is 1 of these things where it might have a little bit of a more aggressive biology, but once you are able to target it, like breast cancer, then patients can actually do fairly well. It seems to be a negative predictor for cetuximab or panitumumab efficacy.

Next slide.

[00:43:12]

MOUNTAINEER: Tucatinib + Trastuzumab for CT-Refractory, HER2-Positive, RAS Wild-Type mCRC

The MOUNTAINEER trial. This is a cool story because John Strickler started this out of Duke as an investigator initiated trial, and then the data looked good, and the company took it over. You can see the combination of trastuzumab plus tucatinib, which is an oral HER2 inhibitor. You are hitting the pathway from above and below vs tucatinib alone was also an arm here.

Next slide.

[00:43:42]

MOUNTAINEER: Efficacy With Tucatinib + Trastuzumab

You can see that the response was seen across all age groups. 40ish percent response patients with a better performance status did a little bit better here. But whether it was left or right seemed to be better for left-sided patients, which is what you see more commonly. These are pretty good response rates, 29%. Tucatinib alone did not have much of a response. Upregulation of the receptor, upregulation of HER2 is a common way that these tumors can get around these inhibitors and so blocking that by giving the trastuzumab is an important component of the therapy. You can see a 38% response rate vs 3.3%.

Next slide.

[00:44:33]

MOUNTAINEER: Final Efficacy Analysis

This is the final efficacy analysis, just showing 24-month median overall survival. NGS patients seem to do the best. They are in the middle tissue NGS. If you looked at immunohistochemistry and FISH, that seem to do pretty well in terms of the response rate, 41% vs 10%. As I said, NGS was 50% vs 0%. That was really good at picking up patients. Then blood a little bit, not quite as good, 42% vs 25%. The NGS testing did quite well. You do not need to order separate IHC FISH, although it is usually included on the panels, but if you get the NGS panel.

Next slide.

[00:45:23]

MOUNTAINEER: Safety

Safety. Kind of expected. With a lot of these combinations, a fair bit of GI side effects, diarrhea, nausea, etc. Really, there was not anything that was surprising. You can see that the red bars there, which are grade 3 or 4, pretty rare. Those red bars are pretty low. Overall, it is fairly well-tolerated. As with any oral drug, with tucatinib, you can hold it and then restart at a lower dose if need be.

Next slide.

[00:45:58]

DESTINY-CRC02: T-DXd for HER2 Amplified mCRC

What about trastuzumab deruxtecan? This is an interesting study because when it first came out, people were using the 6.4 mg dose. It had some potentially fatal pulmonary toxicity. They did a separate trial looking at 5.4 mg. What they found actually was quite efficacious, and they did not have any of those grade 5 events.

Next slide.

[00:46:24]

DESTINY-CRC02: Efficacy With T-DXd in HER2-amplified mCRC

This is the efficacy here. You can see 5.4 mg, 31% response rate, 6.4 mg had an 11% response rate. The lower dose, those patients seem to do better, and despite the fact that you had similar numbers of cycles, etc. This made us much more comfortable using the 5.4 mg. When we came back from this conference, we told our pharmacist, let us change the dose from 6.4 mg down to 5.4 mg because it seemed to perform a little bit better.

Next slide.

[00:47:02]

DESTINY-CRC02: PFS by BICR With T-DXd in HER2 Amplified mCRC

This is the PFS by blinded independent central review. Again, showing the 6.4 mg vs 5.4 mg. You can see very similar median progression-free survival, 5.5 vs 5.8 months.

Next slide.

[00:47:23]

DESTINY-CRC02: OS With T-DXd in HER2-amplified mCRC

This is the overall survival, again, looking at 5.4 mg vs 6.4 mg. We had a little lab printing thing there. But the overall survival, and this is in previously treated patients, was 13.4 months, and the 5.4 mg dose level.

Next slide.

[00:47:46]

DESTINY-CRC02: Adjudicated Drug-Related ILD/Pneumonitis

Pneumonitis, when you use that lower dose level, you get rid of grade 3, 4, 5 interstitial lung disease. Whereas the 6.4 mg, they did have the grade 5 event. Most of the time this is grade 1 or 2. We will talk through how to manage that, especially when it is grade 1.

Next slide.

[00:48:22]

Pretest 3: After progression on first-line chemotherapy + bevacizumab, a patient with mCRC starts T-DXd. On his most recent scan, his right lung shows signs of asymptomatic ILD. In your current practice, how would you manage this patient’s grade 1 ILD?

There we go. All right. This is a question. Progression on first-line therapy, a patient with metastatic colorectal cancer starts trastuzumab deruxtecan. Then, on the most recent scan, his right lung shows signs of asymptomatic interstitial lung disease. In your current practice, how would you manage grade 1 interstitial lung disease?

You can continue at the same dose with close monitoring;

You can reduce the dose;

You can hold until grade 0 and then restart if it resolves in less than a month;

You can hold and restart at a reduced dose; or

Permanently discontinue. In addition, initiate high dose steroids.

Polling is open.

Paul: Please vote. Five more seconds. All right. Thank you. Close the poll and share the results.

Dr Messersmith: Okay. Everyone did the right thing by holding it. Then the question is whether you restart the same dose or reduced dose.

Next slide.

[00:49:55]

Managing ILD/Pneumonitis With T-DXd

Okay. This is a somewhat busy slide, but it gets to the bottom line here, which is you have to, first of all, monitor. Make sure the patient knows to call if they get a cough, or shortness of breath, or fever. Step 1 is really making sure that the nurses and everyone in clinic are looking out for this kind of thing.

High-resolution CT is the most common way this is diagnosed. Obviously, low threshold to get pulmonary involved. You want to do an infectious workup, and you can consider pulse ox, of course, as a vital sign. Pulmonary function tests can be considered as well. Then if you are in a clinical trial situation, you could look at PK. But otherwise you are going to interrupt the dose, and you want to wait until it is resolved to grade 0. If it is grade 2 or higher, you are definitely going to be starting steroids. Certainly at grade 1, it can be considered. But if it resolves, in less than 28 days, then you actually can maintain the dose. If it takes more than 28 days, then you would generally reduce a dose level. If you are at 5.4 mg, you would go down to 4.4 mg. Again, in colorectal cancer we use the 5.4 mg dose level. If you had a gastric cancer patient, for instance, then it would dose reduce from 6.4 mg to 5.4 mg. You do not re-escalate. That is another key point.

Next slide.

BRAF V600E–Mutated Therapy for Later Lines

[00:51:42]

What about later-lines of therapy?

Next slide.

[00:51:45]

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

By the way, you can see here that on the chat they put in the downloadable slides there. You can create an account and get those slides there.

BEACON. If the patient has not had BRAF-directed therapy. Let us say you treated them first-line prior to that study coming out. This looked at bini plus encorafenib plus cetuximab as a triplet, or the green box here, encorafenib plus cetuximab alone. Then finally the control arm FOLFIRI/cetuximab. Triplet, doublet vs standard of care.

Next slide.

[00:52:21]

BEACON CRC: OS and ORR

What was interesting about this study on the next slide is that there was not much difference between the triplet and the doublet. You can see the shapes of those curves and the hazard ratios are quite similar between the 2. Hazard ratios of 0.6 for the triplet, hazard ratio of 0.61 for the doublet. Not much of a difference, and yet lower cost and toxicity.

Next slide.

[00:52:54]

BEACON CRC: QoL Maintenance (EORTC QLQ-C30)

This is looking at triplet vs doublet vs standard of care chemo in terms of maintaining quality of life. You can see here, that very similar between the doublet, the triplet and then seem to be an advantage over the control arm.

Next slide.

[00:53:17]

KRAS G12C–Mutant mCRC

The bottom line there is if you have a patient who has not received BRAF-directed therapy in the first-line setting, you can use it in the second-line. We use that same doublet that we used previously with encorafenib and cetuximab.

KRAS G12C-Mutant mCRC

[00:53:34]

All right. Let us talk about G12C mutated colorectal cancer.

[00:53:37]

KRAS Mutational Landscape in Colorectal Cancer

Glycine gets substituted by cysteine. Here are the common RAS mutations in G12C, which is the fourth 1 down. Only a 3% overall prevalence. This is not something you are going to see every day in your practice. If you look at all KRAS-mutated patients, it is roughly 7%. But of course that is only about half the patients, so it ends up being 3%. These are the common mutations that you see. Of course, 1 big question in the field of RAS inhibitors is: Is it better to go pan-RAS and hit all of them vs making inhibitors against specific mutations?

Next slide.

[00:54:19]

CodeBreak 300: Sotorasib + Panitumumab for Chemorefractory KRAS G12C–Mutant mCRC

CodeBreak looked at sotorasib. I just remember the O-code and then soto. That is how I remember CodeBreak. But sotorasib panitumumab for chemorefractory G12C mutant colorectal cancer. You can see they had 2 different dose levels there. The standard of care was TAS-102 or regorafenib.

Next slide.

[00:54:44]

CodeBreak 300: PFS and OS Sotorasib + Panitumumab for Chemorefractory KRAS G12C–Mutant mCRC

You can see that, especially the 960 mg arm, there is some controversy about what dose of sotorasib is ideal. But in this study, the 960 mg seemed to do better when combined with panitumumab vs the control. You had a 30% response rate at the 960 mg dose level. You can see improved PFS vs the standard of care.

Next slide.

[00:55:17]

KRYSTAL-1: Adagrasib + Cetuximab for Chemorefractory KRAS G12C–Mutant mCRC

KRYSTAL, on the other hand, and I just remember that one has the A in it, so KRYSTAL and adagrasib. Adagrasib plus cetuximab for G12C-mutant colorectal cancer. There was a phase I and then a Phase II. We will look at the efficacy in the next slide.

[00:55:36]

KRYSTAL-1: PFS and OS Adagrasib + Cetuximab for Chemorefractory KRAS G12C–Mutant mCRC

Slightly different patient populations in terms of pretreated. You really cannot compare the trials head-to-head. You have to be careful there. But again, you see a PFS of 6.9 months, median overall survival, and pretreated patients of 16 months. Not too bad for a later-line type of therapy.

What was clear from both these trials is that, again, because you have that compensatory pathway to signal through receptors like EGFR, it really helps to have the monoclonal antibodies such as cetuximab or panitumumab on board. A little bit similar to the HER2 story, tucatinib does better when it is combined with trastuzumab.

Next slide.

[00:56:24]

CodeBreak 300 and KRYSTAL-1: Safety With Sotorasib and Adagrasib in KRAS G12C–Mutant mCRC

This is the safety data. Just showing low magnesium is fairly common with sotorasib. You tend to see skin toxicity and GI toxicity in both of these.

Next slide.

[00:56:42]

TKIs for mCRC With Tumor Agnostic Indications

These are some of the other TKIs. The first 3 are for NTRK. It is not often you see NTRK, but 1 of the good things about getting these large panels through many of the common testing companies is you probably will pick it up when you do see it. You can use NTRK inhibitors. Then finally, for RET fusions, you have selpercatinib there, and which had a tumor-agnostic cohort. Granted the small numbers, 13 patients, but pretty active with the response rate of 30%.

Next slide.

[00:57:18]

Posttest 2: Based on current guideline recommendations, which of the following patients with mCRC could be considered adagrasib or sotorasib plus an EGFR inhibitor?

All right. Posttest. Here we have a patient who is going to be treated with adagrasib or sotorasib plus an EGFR inhibitor. What is the molecular alteration that you are looking for? You see the choices there. We will go ahead and vote.

Paul: Poll is open. Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

[00:58:06]

Dr Messersmith: Awesome. You guys scored 100%. That is great. G12C, we are going to be using adagrasib or sotorasib.

Next slide.

[00:58:24]

Posttest 3: After progression on first-line chemotherapy + bevacizumab, a patient with mCRC starts T-DXd. On his most recent scan, his right lung shows signs of asymptomatic ILD. In your current practice, how would you manage this patient’s grade 1 ILD?

Okay. After progression on first-line chemo, now we are going to be using trastuzumab deruxtecan. We talked about interstitial lung disease. Right lung asymptomatic interstitial lung disease. How would you manage this grade I?

You could continue at the same dose level;

You could reduce the dose;

You could hold it until it resolves to grade 0 and restart if resolved at less than 28 days; or

You can dose reduce even if it is resolved in 28 days; or

Permanently discontinue.

This is for grade 1 interstitial lung disease. We will go ahead and open the poll.

Paul: Poll is open. Please vote. All right. Thank you. We will close the poll and share the results.

[00:59:32]

Dr Messersmith: Great. Yes. You restarted the starting dose if it is less than 28 days. All right. You guys are scoring 100%.

All right. Next slide.

[00:59:39]

Poll 6: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

I think it is the last. I know we are coming up on time here. All right. Do you plan on making any changes to your clinical practice based on what you have learned in today's program? We will go ahead and open the poll.

Paul: Poll is open. Five more seconds for incoming answers. All right. Thank you. We will close the poll and share the results.

Dr Messersmith: Great. All right. 75% said yes. That is fantastic.

All right. Next. I think this is the last slide.

[01:00:30]

Poll 7: Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

I know people have places to go. Go ahead and take a moment and enter 1 key change that you plan to make that could be around immunotherapy, it could be around BRAF, it could be around G12C. Whatever that might be, go ahead and put that in there.

Paul: Poll is open. Again, you do have the option of scanning the QR code on the screen or typing in a quick comment in the poll. We will just give you a couple of seconds here to complete that. All right. Thank you. We will close the poll.

Dr Messersmith: All right. Well, I know we are 2 minutes over, so I will just briefly note this. We are definitely getting better survival rates. When I started my career, it was 1-2 years, we are now exceeding 3 years.

Clinical trials obviously can be an issue for community oncologists. I think all the academic centers are trying to partner with community centers and really get trials up. Some of the community centers are some of the best enrollers, actually, because folks in the community are seeing so many patients.

Barriers, we are trying to get better about enrollment criteria, trying to make them easier and more generalizable. Then, obviously, we need to think about what molecular testing results, as we think about later lines of therapy. Then finally there is a variety of online resources, etc, that can be helpful in educating patients or caregivers. It is interesting to think about what are best practices from an educational standpoint.

But I will turn it back over to the moderator, because I do think we are at time. I am not sure we have time for a lot of discussion here just because folks might have places to go.

Q&A

Lisa: Yes. We are now taking any questions that you may have for Dr Messersmith. Please use the Q&A function to submit those. While you do so, as Dr Messersmith pointed out, there are links in the chat panel. We will also put up a couple of QR codes momentarily. One will lead to the downloadable slide deck from today's presentation so you will have that as a resource. Then the other will be to the program evaluation link that you will need to complete to claim your credit. You will need to log in to or create a CCO account, and please claim your credit within 30 days from today, as it will expire afterward.

Dr Messersmith, I do see a few questions. I will be happy to read those out to you.

Dr Messersmith: Yes. Sure. Please do. Yes.

Lisa: All right. The first is any tricks you use to support adherence for patients on oral agents with GI side effects?

Dr Messersmith: Yes. I would say 1 of the main things I try to do is not blow people out of the water on the first try. If it is someone who just seems to be very sensitive to therapies, I will sometimes start at a little bit of a lower dose and then work my way up. Those patients that just seem to get side effects to everything, or maybe I am worried about borderline performance status, or they have some baseline adverse events going on. Then I always tell them, please, if they are in doubt, stop taking the drug and wait till we can touch base. Usually, after a few days it will get better, and we will start at a lower dose. Because what is a killer is if they start getting severe diarrhea or something on Friday evening, they do not want to call over the weekend or something. Then by Monday morning it is a grade 3 or grade 4 toxicity.

Those are the 2 things I do. I started a lower dose for patients who fail the eyeball test or have had a lot of problems with drugs that really should not be as much of an issue. Then also just being very aggressive about saying, look, if you cannot get in touch with me or you are on vacation or you are traveling or it is Friday night, just stop the drug, wait till the side effects get better, and wait till we can talk, and we will probably start at a lower dose. Those are the most common things that we do.

Lisa: Okay.

Dr Messersmith: The second question looks at the patient who starts with encorafenib-based therapy. Yes. Second-line, for the most part, we do not really use BRAF-directed therapy. If they started with FOLFOX and encorafenib plus cetuximab, for instance, I would probably switch over to FOLFIRI and bevacizumab. Because as far as we can tell, continuing the BRAF-targeting agent, does not have a role. I think there will be some other studies coming out with potentially other BRAF inhibitors or other ways to inhibit the pathway. But basically, if the tumor progresses on a BRAF-directed strategy, then typically the tumors learn to get around it. I am just going to hit it with a totally different thing, such as FOLFIRI and bevacizumab for instance, or 1 of the oral agents.