April 2015, this man, 60-year-old, presents to his primary care physician with complaints of some fatigue, some weight loss. Primarily though, changes in the bowel movements and some blood in the stools. A workup follows, including a colonoscopy which shows a mass on the right side of the colon which was biopsied, then shows evidence of adenocarcinoma consistent with a colonic primary. The patient was staged. There was no evidence of any other disease. He was sent to the surgeon at that time, underwent laparoscopic right hemicolectomy, and he was staged at IIIA. So that&rsquo;s low-risk colon cancer with essentially a decision that followed to proceed with adjuvant chemotherapy. And based on the IDEA trial, the decision was to proceed with 3 months of capecitabine plus oxaliplatin, followed by close observation as per routine. The patient did fine with the capecitabine and oxaliplatin or the Capox with grade 1 neuropathy, relatively tolerable, very low hand and foot syndrome, but no major toxicities.

Thirty months later, that&rsquo;s April 2018, the patient started having some symptoms of abdominal pain, again some fatigue, some weight loss. Over 2, 3 months he lost about 10 pounds or so. The patient was overall not feeling well, so there was a concern that this could essentially be an element of progressive disease. He was scanned at this time. PET/CT shows evidence of both liver and lung metastases. To confirm the diagnosis since about 30 months have elapsed from the end of his adjuvant chemotherapy, a decision was to biopsy one of those liver lesions. Indeed, a biopsy suggested an adenocarcinoma which was consistent with colon cancer. His CEA [carcinoembryonic antigen] was on the rise at that time. Additional sequencing genomic sequencing suggests microsatellite stable tumor,

wild-type. So molecular testing was performed showing evidence of

The patient&rsquo;s ECOG [The Eastern Cooperative Oncology Group] performance status was 1, a little bit less than 1, still relatively active doing things, moving around. Patient is relatively symptomatic right-sided tumor, so the decision at that time was to start the patient on Folfoxiri plus bevacizumab, given the symptoms, given relatively a younger individual at now 62, 63. And then the goal was to expose the patient to about 2 to 3 months of Folfoxiri/bevacizumab and then transition to maintenance therapy.

The patient proceeded with 6 cycles of Folfoxiri/bevacizumab, almost complete resolution of the symptoms, getting closer to grade 2 neuropathy, I think some of the cumulative neuropathy from oxaliplatin and with the FOLFOXIRI. The PET/CT at that time showed near complete resolution of his lung and liver metastases with a dip in his CEA. At that time, we dropped oxaliplatin, continued with Folfiri for another 6 cycles, checked scans. Scans continued to look great. At that time, some fatigue, some elements of toxicity related to the chemotherapydiarrhea, and others led to stopping the irinotecan and the 5-FU [fluorouracil], continued the Avastin, although moving this to every 3 weeks, and then the patient was switched to oral maintenance chemotherapy with capecitabine, so capecitabine/bevacizumab, bevacizumab every 3 weeks, capecitabine daily, 5 days a week, Monday to Friday and then weekends off.

The patient did extremely well with the treatment for about 2 cycles and then started developing symptoms againfatigue, abdominal pain. His neuropathy was still grade 1 at this point. It actually went down from grade 2 to grade 1, but it was a grade 1 bordering on grade 2. And then the decision at that time was that this is a patient that remained with significant neuropathy, progressed within 2 months of stopping FOLFIRI on maintenance therapy, so it was time to switch to a new therapy.

Now, this is a right-sided tumor, so we understand that options are relatively limited. Decision at that time after discussions with the patient was to proceed with regorafenib, starting with a dose of 80 mg orally every day for the first week, with a goal to dose escalate 40 mg per week orally until we reach 160 mg within 3 weeks if there are no significant toxicities related to the regorafenib.

A 60-Year-Old Male with Relapsed mCRC

When the patient presented first with his early stage cancer, the patient was tested for microsatellite instability [MSI] which is pretty routine. The lymph node yield or harvest was adequate. We had a good idea about his projected prognosis. With IIIA, this is considered low-risk. Those patients survive at a rate of 80, 85%. It&rsquo;s not 100%. That&rsquo;s why we keep close observation. We know at least 15% to 20% of those patients ultimately will progress and will have disease recurrence. The choice of chemotherapy was primarily based on the results of the IDEA trial which asked the question of 3 month versus 6 month and the choice between Folfox and Capox, depending on the study that was included or physician choice.

From the IDEA trial, 2 things came about. One, that Capox is probably preferable over Folfox, and for low-risk such as stage IIIA, 3 months is not inferior to 6 months, especially with Capox. At that time, the decision was to essentially expose the patient to three month of chemotherapy and Capox specifically, based on those results, and then continue with close observation.

I think overall that the patient was treated adequately. He was staged adequately. He was low-risk, but, unfortunately, because of his right-sided tumor, I suspect his chances of recurrence were much higher than if it was on the left side. We know that, I mean we knew that even before all the right versus left discussions. In the metastatic setting started, we know from actually early in the 2000s or even a little bit the 1990s, that a lot of the adjuvant trials suggested that the right-sided tumors generally do worse than the left-sided tumors. And chemotherapy itself, at least in the earlier stages, does not seem to change the time course much of those right-sided tumors at the same level than the left-sided tumors.

The patient responded extremely well to Folfoxiri/bevacizumab, almost near complete resolution of the lesions. I mean, he still had few lesions left. They were not amenable to any locoregional therapy, and thus the decision was to continue with systemic chemotherapy. The question is what do you do after 3 months of Folfoxiri plus bevacizumab, 3 to 4 months of Folfoxiri plus bevacizumab. You can go straight to maintenance strategy with capecitabine plus bevacizumab or you can do what we call de-escalation. Since this patient had a significant neuropathy, the logical thing was to drop the oxaliplatin. And I think the reason why this patient had even worse neuropathy than I would expect for 3 month exposure is because he had prior exposure to oxaliplatin in the adjuvant setting. Usually 3 to 4 months should be fine without having major issues with neuropathy.

So the decision was to drop with Folfiri/bevacizumab. Although equally I think consider it would be to go to capecitabine plus bevacizumab maintenance. So he continued on Folfiri/bevacizumab for another 6 cycles which seemed to maintain a good response. And then after that you start having significant issues with toxicities such as this patient. Then it makes sense to go to what we typically do is capecitabine daily plus bevacizumab. In my clinic, I choose not to go daily, meaning nonstop, because especially in our US-based population, we have significant issues with hand and foot syndrome. A little break in between actually helps, and I find the 5 days continuous capecitabine and weekend breaks very helpful in terms of cutting down significantly on the risk of hand and foot syndrome. And that was the choice for this patient.

Treatment Overview of a Patient with Relapsed mCRC

There are multiple factors that go into the equation when thinking about our patients with metastatic colorectal cancer, specifically for first-line but also beyond first-line. One is, is the tumor left-sided or right-sided, age of the patient, comorbidities, genomic factors,

, HER2 amplification, microsatellite stability [MSI]. And there are other factors: patient preference and physician preference. Overall, we know that left-sided tumors, and RAS wild-type, BRAF wild-type,

, and nonamplified may actually do a little bit better with an EGFR inhibitor versus bevacizumab versus an anti-VEGF inhibitor.

On the right side, it does appear that regardless of the mutational status, but specifically the RAS wild-type, BRAF wild-type, tumors do not seem to respond wellat least from the CALGB 80405 abstract&mdash;well to EGFR inhibitors. So we know that in this particular group of patients like this gentleman, despite the fact that they had a RAS wild-type, BRAF wild-type tumor, his likelihood of responding to the EGFR inhibitors is not only low, probably inexistent, but at least from the CALGB 80405 abstract, there were signs that we actually may induce some detriment. Now, again, this was not a randomized question, so we have to be careful about how to look at this. But the survival was actually the lowest we&rsquo;ve seen in colorectal cancer for the last decade.

So a word of caution about this. The other things we look at, of course, especially on the left side of the tumor, is this patient RAS wild-type, BRAF wild-type, and HER2 nonamplified. I think these are important. RAS wild-type, BRAF wild-type tend to respond well to EGFR inhibitors. If HER2 is amplified, then there&rsquo;s much more likelihood of responding to EGFR inhibitors. That&rsquo;s why I think it&rsquo;s very important to check that

also opens up other doors for us. We&rsquo;ll discuss those later.

The other important element is microsatellite instability. The presence of microsatellite instability at high levels would predict favorable outcomes with immune therapies, and so that also completes the picture. Of course, age and comorbidities, so let&rsquo;s say someone has a recent history of a myocardial infarction, or has angina, or had a stroke 3 months prior or 6 months prior, then you would avoid a VEGF inhibitor. You may favor, in the right patient, an EGFR inhibitor. There&rsquo;s, of course, patient preferences. Some patients would rather not have the rash. Actually, most patients don&rsquo;t like the rash. It&rsquo;s an offender to the quality of life of patients. It increases the risk of diarrhea.

Now, the other thing that was important in these patients to think about is this patient was getting very symptomatic very quickly, was losing weight, was having a lot of pain, and you needed a response. Now, on the left side, let&rsquo;s say this was a left-sided tumor, RAS, BRAF wild-type, HER2 nonamplified, one could certainly consider an EGFR inhibitor plus chemotherapy. There may be a little bit of an improvement in response. My personal choice would still be Folfoxiri plus bevacizumab for many reasons in these patients. 1) very high response rate, probably higher than what you get with chemotherapy doublet plus EGFR inhibitors, 2) You would get your best response in the first 2 to 3 months of therapy and you can deescalate maintenance or to Folfiri/bevacizumab such as happened in this patient.

Now, on the right side, you don&rsquo;t have a choice. EGFR inhibitors are not an option on the right side, regardless of the genomic profile. The right-sided tumors don&rsquo;t respond to them, and so naturally you would be either a doublet or a triplet plus bevacizumab. In a younger patient that&rsquo;s very symptomatic, I think a triplet makes sense. Those patients have a worse prognosis overall. Thus, the choice in this patient to proceed with Folfoxiri plus bevacizumab. As I said, within 3 months, you should reach your maximum response, and that&rsquo;s why this patient was exposed to 3 months of the regimen.

Determining First-Line Therapy for mCRC

Unfortunately, with the right-sided tumors, we know that these tumors have a very poor prognosis regardless of their genetic profile. And so they tend to progress early. Most patients will start with a doublet, usually Folfiri or Folfox plus bevacizumab. And then when they fail, their second-line would be the other regimen. So, if they started with Folfiri, they go to Folfox. If they started with Folfox, they go to Folfiri and we continue the bevacizumab. In this patient we chose to go with Folfoxiri plus bevacizumab because of the high tumor burden and symptom burden. And so we needed a higher response rate, and we went with Folfoxiri/bevacizumab. So, technically, when you fail Folfoxiri/bevacizumab, then your next option would be either regorafenib, or TAS-102 [trifluridine/tipiracil], or an EGFR inhibitor. If you went with say Folfiri/bevacizumab in the first-line, your second-line would be Folfox/bevacizumab. Then your third-line, you assess the same options.

Now, how do you choose between all theseregorafenib, TAS-102, and EGFR inhibitors. Now, again, we&rsquo;re focusing on the right-sided tumors. If this was a left-sided tumor, and I started with bevacizumab in the first-line, then my second-line is going to be an EGFR inhibitor. If I started with an EGFR inhibitor, my second-line would be bevacizumab. On the right-sided tumor, as we discussed, those EGFR inhibitors have to fall down the line of therapies.

And so the question, do you introduce it in the second, third, fourth-line? Where exactly is the right point? Remembering that this was a RAS wild-type, BRAF wild-type tumor. Most of these are

mutated, and therefore this would not even be a discussion. But, specifically in the RAS wild-type, BRAF wild-type right-sided tumors, where do we introduce these EGFR inhibitors, whether it&rsquo;s cetuximab or panitumumab? The answer is frankly not clear because most of our knowledge is really in the first-line, to a lesser degree in the second-line.

There are some hints that in the refractory settings, there may still be some benefit from EGFR inhibitors. There&rsquo;s an interesting study that was presented and now about to be published called REVERCE study which essentially looked at a sequencing question. Start with regorafenib followed by cetuximab, start with cetuximab followed by regorafenibso REGO/CETUX or the reverse, CETUX/REGO. The primary endpoint of the study was survival. This was a Japanese study, so in some ways it may not apply to what we do in the United States or may not apply to our patient population but, nonetheless, gave us very intriguing finding. And that finding was that if you actually start with regorafenib followed by cetuximab, the survival benefit is a few months higher than if you start with cetuximab followed by regorafenib, regardless, by the way, of side, whether you are right or left.

So, on the right side where there is a big question mark about the role of EGFR inhibitors, I take this study a little bit more seriously. Although, again, I think it needs to be reproduced at a larger level in the US, and it&rsquo;s in the works. So we will have more answers hopefully in the next couple of years on this. But, at this point of time, I just look at this, I look at the data say from CONCUR that suggest that regorafenib may actually have a little bit more of a benefit in patients who are less pre-exposed to biologics, i.e., VEGF and EGFR inhibitors.

And you put all this knowledge into works and from my standpoint, it would make sense to start with the regorafenib and push cetuximab, panitumumab to later lines, in fact I would say even after TAS-102. So my sequence in my colonic would be regorafenib followed by TAS-102. And then EGFR inhibitors would still be used, but I&rsquo;d use them in much later lines of therapy, just because, again, on the right side, there are big question marks about the value of these inhibitors.

Once patients go through multiple lines of therapy to one or 2 lines of extensive therapy, so in this patient, Folfoxiri/bevacizumab or sequentially Folfiri, Folfox, bevacizumab, those patients, as they get to the third, fourth-line, so the more refractory setting, they&rsquo;re pretty fatigued. They&rsquo;re tired of their chemotherapy. Their cancer burden continues to grow on them and makes it much more difficult for them to tolerate further chemotherapy. So they start off with a very difficult journey, perhaps much more difficult than they&rsquo;ve had it in the first and second-line which makes treatment challenging. If we look across the board, whether it&rsquo;s regorafenib, TAS-102, whether it&rsquo;s Folfiri, Folfox in second-line and beyond, for most of these patients the benefit at the median is small.

Although for the patients who benefit, they tend to benefit for a meaningful amount of time. But, for most patients, the benefit is actually small, and that&rsquo;s because they start coming from behind because of essentially what they had to deal with from the prior chemotherapy. But mostly, because as we get through multiple lines of therapy, the cancer burden and I call the level of aggression become much more noticeable, and those patients have a harder time overall to withstand any type of treatment.

The Challenges in Determining Second-Line Therapy for mCRC

The decisions on overall survival [OS], the tyrosine kinase inhibitors [TKI] and how to dose them has been one of our biggest challenges in oncology. That doesn&rsquo;t only pertain to regorafenib. It&rsquo;s also sorafenib, sunitinib, lenvatinib. I mean, you name it, any &ldquo;-ib&rdquo;, cabozantinib, all these agents that we&rsquo;ve been working with for many years, we&rsquo;ve always had the same challenge. What is the correct dose to start with? And with regorafenib, at least in the refractory metastatic colorectal cancer, that patient population is already challenging as it is. And starting at 160mg for all patients had been even a bigger challenge. Because most patients at 2 to 3 weeks start having significant toxicitieshand and foot syndrome reaction, diarrhea, a little bit of diarrhea, and fatigue.

And so with that said, the challenge when you actually see your patient in clinic, first time you use it, you say, &ldquo;Wow, this is tough.&rdquo; Second patient is going to come to your clinic and you&rsquo;re going to think, can I start this patient on 160mg? They&rsquo;re tired of their chemotherapy, their disease burden is significant. Perhaps I should consider a lower dose. So dosing was all over the place. Some physicians start at 80mg, some physicians give the patient 120mg, 30% to 40% start at 160mg and de-escalate. So there was no standard.

So we brought this study called ReDOS: regorafenib dose optimization study, which essentially tried to ask the question in a rational way. Can we essentially create a strategy where patients start at the lowest dose, 80mg, and then escalate them to 120mg and then to 160mg on a weekly basis, so 40mg a day for a week, every week as tolerated versus starting the patients at 160mg and then de-escalate. And the rationale for that was that we hit a lot of toxicities in the first 2 or 3 weeks, so hopefully we will know very quickly what is the optimal dose for the patient.

The other theoretical benefit from all this is with all these TKIs [tyrosine kinase inhibitors], there is a theoretical benefit of continuous exposure versus chopped exposure. Meaning, if patients stop and go, stop the treatment because they have toxicities, they get very little exposure, we know that the first 2 months are very critical for the treatment, that a lesser exposure may actually get less patients to benefit from the drug. And that was the other reason why we did this.

So the primary endpoint of the study was a composite endpoint of efficacy and toxicity. There was a question about how many patient or what % of patients will be able to reach cycle 3, being able to continue on the drug because lack of toxicity or significant toxicities, because we figured out the right dose, and they haven&rsquo;t progressed on their disease. Our goal was to see 15% extra for the dose escalation strategy versus the 160. And the study was positive for its primary endpoint. Meaning more patients were able, 24% to 43% were able to actually make it on the dose escalation strategy, so 80mg, 120mg, 160mg, were able to make it to cycle 3 than the 160 mg.

Very intriguing. The survival of those patients on the dose escalation strategy was about 10 months, a little bit less than 10 months, whereby on the 160mg was 6 months which is very consistent with what we&rsquo;ve seen with the CORRECT study. And that was very intriguing. I can&rsquo;t really explain why this was not powered for survival, but that&rsquo;s an interesting observation. The other thing that we&rsquo;ve observed is the quality of life of the patients on the dose escalation strategy was preserved. So there was no dip, there was no loss of quality of life, and the toxicities were lesser. And the hand and foot syndrome reaction, fatigue, everything was lesser. So, overall, this study suggested that the best strategy for regorafenib is perhaps to start with 80mg, then 120mg, then 160mg for patients that has tolerated. The goal remains to get to 160mg as about 20% of the patients were able to get to 160mg and continue through beyond cycle 3.

This was a practice-changing study. ReDOS was a practice-changing study. The NCCN guidelines adopted the ReDOS schedule as one of the schedules, proposed schedules for regorafenib. The FDA actually did issue a little guidance on it as well, allowing exposure to it. So there was an uptake about the understanding that this will change the way we treat patients with metastatic colorectal cancer. In my clinic, of course, it&rsquo;s the only way I give regorafenib now. The PK [population pharmacokinetic] studies are underway, so we can learn a little bit more about the exposures on the short and long-term. We haven&rsquo;t completed those. We also are looking at the effects of preemptive steroid, clobetasol versus reactive. These results will hopefully be presented at ASCO [American Society of Clinical Oncology]. So there will be much more to come regarding these options.

We recently presented a meta-analysis and a systemic review on a systematic meta-analysis at ASCO GI [Gastrointestinal] which looked essentially at all the studies with regorafenib and TAS-102 [trifluridine/ tipiracil]. And that study was interesting, at least the results of the study is interesting. And we&rsquo;re writing this up now as a manuscript. It suggests that in the comparisons of regorafenib with 80 mg going to 120mg, 160mg would be superior to best supportive care or placebo in an historical fashion. But, interestingly, again, it confirmed that regorafenib dose escalation strategy would likely be a superior strategy. Although, again, we didn&rsquo;t reach quite the statistical significance. But at least numerically it seems to be superior to both regorafenib at 160mg and TAS-102.

Now, both regorafenib and TAS-102, regorafenib at 160mg and TAS-102 seemed to perform equally well in that meta-analysis. But REGO [regorafenib] 80mg is going to 160mg seemed to actually have a better trend than either. So more to come. We&rsquo;re learning more and more about how to optimize the strategies. But, at this point of time, at least from the clinical standpoint, I think it would be preferable if you choose to treat your patients with regorafenib to go with the dose escalation strategy based on the results of ReDOS trial and what followed in terms of the meta-analysis we presented at ASCO GI.

When we look at the real-world data from the CORRELATE study and others that tell us about how physicians practically use regorafenib in their own clinics, certainly aligns with our concern with a lack of adherence to the standard dosing and also wide array of different dosing patterns and dosing strategies. I think now that we have ReDOS and soon we&rsquo;ll have the results of RE-ARRANGE study that are asking these questions of how to dose optimize regorafenib in the setting of a prospective randomized clinical trial, that we go back and start standardizing a little bit better how we treat our patients without just randomly assigned dosing strategies.

The Optimal Dosing Strategy for Regorafenib in mCRC

Overall, the patient population in the refractory setting does not do well. There are few patients who do extremely well. There are a number of patients who do somewhat well, and the overwhelming majority actually does not do well because of the setting where patients are treated. In my experience, at least half of the patients will be treated for at least 2 to 3 months with regorafenib. And then beyond that, about 20% of the patients will go beyond 6 months of treatment. In fact, interestingly enough, when we looked at ReDOS, when we looked at the median overall survival [MS], for those patients who actually were able to get through 3 cycles of treatment, so started cycle 3, their median overall survival was a year or more. And that&rsquo;s the median which means for some patients it was a little bit less, but for some patients we&rsquo;ve seen the survival benefit extend beyond 1 year, actually some to 2 years.

So, even though this is not every patient, and, in fact, most patients will not achieve a meaningful outcome, but there are few patients who essentially end up achieving a significant outcome. We&rsquo;ve had patients on our study, for example, going a year plus, and there is, in my clinic, a number of patients who have been on regorafenib for more than 6 months, few more than 1 year. And I&rsquo;ve had very few patients who actually made it 2 plus years. So they are there. They&rsquo;re not, unfortunately, the majority or even a large minority, but there are there. And, for those patients, it&rsquo;s an incredibly meaningful response.

When looking at the totality of the data, what transpires is that perhaps bringing regorafenib to less pre-exposed patients or less heavily pretreated patients, but specifically less pre-exposed patients, may confer, historically at least, may confer a larger benefit. That&rsquo;s where we learned from CONCUR study versus CORRECT study. CONCUR was a smaller study, it was an Asian study. Less patients received prior. In fact, in CORRECT, everyone had to fail all the biologics. In CONCUR, about 20% to 30% of the patients did not receive prior biologics, either an EGFR or a VEGF inhibitor.

And the deltas around the median survival, the median PFS [progression-free survival] were historically much, much higher with CONCUR versus CORRECT. I think another study that added to this was the REVERCE study which essentially tried to place regorafenib ahead of cetuximab versus the reverse. And that study was powered for survival. It was 100-patient Japanese study, which suggested that there is a significant survival advantage if you start regorafenib ahead of cetuximab versus the reverse. And that survival was a few months higher with that strategy.

Interestingly, in that study, what they&rsquo;ve shown is that regorafenib seems to perform better if you move it ahead of cetuximab. Cetuximab itself continued to do well, whether you put it ahead or after regorafenib. So, meaning, cetuximab continues to preserve its benefit. All through lines of therapy, regorafenib seems to do better if you move it upwards. And so I think when you look at all these combined and it certainly gives us a moment to pause as the findings are quite intriguing in terms of perhaps trying to think about regorafenib for our patients, for those who may be candidates for it, of course, a little bit earlier before thinking of it as a last ditch effort.

One of the biggest challenges in oncology, as we move more and more to these oral agents, is how do we ensure that our patients adhere to the prescribed medications. There are a lot of elements that confuse the patients. One, many of them are depressed. They may have cognitive impairment. They may not have support at home. We give them all these complicated regimens with TAS-102 [trifluridine/tipiracil], with regorafenib, with others, as well with capecitabine. And more of them coming makes it relatively complex to patients.

So what&rsquo;s been happening more and more is that we have to rely a lot on close follow-up. Whether you have a nurse or a pharmacist, in our practice it&rsquo;s a pharmacist that follows up with the patient on a weekly basis to make sure they&rsquo;re taking the appropriate dosage. Oftentimes, one of the reasons why patients are not compliant with their regimen is that they start having toxicities earlier on and they decide to stop on their own, or they cut down the dose on their own without talking to the physician, or just because of cognitive impairment they just are not taking the right medicine. So the discussion is always very important with the patient, with the family about the importance of adherence.

But I think one of the other important elements is close follow-up, especially in the first month of treatment. If possible, you want to see your patients every week to make sure they&rsquo;re adhering to the regimen and then you&rsquo;re watching out for the early toxicities, every week for the first month. If you cannot because patient lives far or they have no means to travel, then make sure that they&rsquo;re called by a nurse, by a nurse practitioner, by you, or by a pharmacist. And have them seen at least twice in the first month if at all possible. This would optimize adherence. This also would help us pay closer attention to the toxicities if they emerge early. Because it makes a much bigger difference to patients if we can intervene sooner rather than later, especially as we get to the later lines of therapy where time is of the essence, and exposure in the first month or 2 makes a big difference for patients who are able to continue versus not on treatment.

Achieving a Durable Response with Regorafenib in mCRC

There are certain subgroups of colorectal cancer that we know may benefit from either targeted agents or immune therapeutics. We know the NTRK fusion&rsquo;s a good story across all solid tumors. If you have that NTRK fusion, you have a great response. And we have agents, 1 agent that&rsquo;s approved, larotrectinib which is approved essentially in all solid tumors that express NTRK fusion. In colorectal cancer, a rate of .3% to .7% may have that fusion.

Immune therapy, which, as we know, has made strides in a lot of different cancers, is also available to our patients in colon cancer for those with MSI [microsatellite instable]-high phenotype. Those are the patients, that&rsquo;s about 4% of all your metastatic colorectal cancer that have a significant and meaningful response to agents like pembrolizumab, nivolumab. And 1 study suggests perhaps adding ipilimumab to nivolumab may also have benefit. That&rsquo;s CheckMate-142. So we know that there is a subgroup of patients with MSI-high and about two-thirds of them will have very good response, and about half of them will have not just a very good response but a very durable response. So it&rsquo;s very important to understand that.

Now, other cancers have immune therapy options like melanoma, lung cancer, and others that apply to a number of patients beyond just a specific biomarker, typically PD-L1 [programmed death-ligand 1] would help you to select in those patients but there may be others as well. So, in colorectal cancer, for the last few years, we&rsquo;ve been hoping to find an entry point for these immune therapeutic agents and to the microsatellite stable. So those patients where we know a single-agent PD-1 does not seem to help.

Now, it&rsquo;s important to understand why PD-1 inhibitors or CTLA4 [cytotoxic T-lymphocyteassociated antigen 4] inhibitors, on their own or even combined, don&rsquo;t show much activity in the microsatellite stable. It&rsquo;s because those tumors are not very inflamed. They&rsquo;re not very hot. They have very few mutations. They&rsquo;re not very apparent to the immune system. And so the whole work that at least preclinically has been done about how can we make those tumors more inflamed and more visible to the immune system.

So one of those strategies was with applying a MEK [mitogen-activated protein kinase kinase enzymes] inhibitor to the milieu which seems to essentially invite some of these tumor infiltrating lymphocytes into the tumor and then allow PD-1, PD-L1 inhibitors to amplify their effect, and thus you see more activity. An early phase IB study suggested that the combination of a MEK inhibitor called cobimetinib and atezolizumab which is essentially a PD-L1 inhibitor, when you combine the 2, that you do see a certain level of response in disease where you see almost no responses from immune therapy.

So this went to the IMblaze370 study comparing cobimetinib to atezolizumab versus atezolizumab versus regorafenib in patients with microsatellite stable metastatic colorectal cancer. What that study suggested essentially is that there&rsquo;s lack of benefit, which is very unfortunate, for combining cobimetinib to ATEZO [atezolizumab]. And ATEZO itself didn&rsquo;t have much activity. Interestingly, regorafenib actually seemed to have a superior median progression-free survival to the immunotherapeutic options but very consistent with historical controls. So, unfortunately, that first entry point for immune therapy into microsatellite stable tumors did not pan out, at least did not seem to be superior to regorafenib.

IMblaze370 Trial in MSS mCRC

When we look at the mutational landscape of colon cancer, there are certain things that are important for us. RAS is one that decides or helps us understand the role of EGFR inhibitors versus not, same for sidedness.

mutations are very important because when they&rsquo;re present, they drive an incredibly bad prognosis. Those tend to be different tumors. In fact, in our clinic, those are the patients we&rsquo;re treating first-line with Folfoxiri/bevacizumab. But, in second-line, there are rising standards. One is actually on the NCCN [The National Comprehensive Cancer Network] guidelines with irinotecan plus vemurafenib plus cetuximab.

But there is another one that I think is most promising and that&rsquo;s with encorafenib, binimetinib, and cetuximab, essentially a RAF inhibitor, a MEK inhibitor, and an EGFR inhibitor. But at least in the phase IB study with 30 plus patients, suggested a response rate to close to 50% in patients who are refractory, including those with colorectal cancer. But I think 10% complete responders which in this disease in the refractory setting is amazing by itself. So that&rsquo;s an emerging standard. The BEACON trial which essentially randomized patients to the triplet versus a doublet versus Folfiri plus cetuximab has completed and should report out hopefully by the end of the year. And we may actually see a new standard for our patients with

mutations. Very important to make sure that these are 600Es because the non-V600E behave completely different. They actually have a very good prognosis, and they respond really well to chemotherapy unlike the V600E.

, when amplified, suggests that EGFR inhibitors may not have much of a role. But also we have trials ongoing, one from SWOG study, one from the ACCRU [Academic and Community Cancer Research United] Research Network. The ACCRU Network has a study with tucatinib and trastuzumab. Tucatinib is an oral tyrosine kinase inhibitor [TKI] targeting HER2, very potent, with very low HER2 activity. And the study is about to complete its first stage and hopefully reported on. And then the SWOG study includes trastuzumab and pertuzumab versus standard chemotherapy. It&rsquo;s also ongoing.

There are also other studies that are looking at the HER2 question, but it all relates back to a study that was done in Europe called HERACLES trial that looked at lapatinib and trastuzumab in the setting of HER2-amplified tumors with a significant amount of responses seen, including some complete responders and very durable responses. Then we&rsquo;ve talked about NTRK fusions and MSI [microsatellite instable]-high, and hopefully still looking for reintroducing these immune therapy strategies in different shapes or forms into the microsatellite stables.

So there&rsquo;s a lot of activity in colon cancer. MSI,

, and then a slew of other lower yield alterations that are being looked at in smaller studies from the FGFR to those who are non-V600E BRAFs, et cetera. So it&rsquo;s actually becoming a disease that is more than one disease that&rsquo;s closing down that puzzle. We always thought of colon cancer as one or 2 diseases. Now we think it&rsquo;s 4 to 6, probably 10 or 15 or more diseases, and hopefully we&rsquo;ll have a target for each one of these subsets.

Optimal Treatment of Chemoresistant mCRC | Case Based Peer Perspectives

EP 1: A 60-Year-Old Male with Relapsed mCRC

EP 2: Treatment Overview of a Patient with Relapsed mCRC

EP 3: Determining First-Line Therapy for mCRC

EP 4: The Challenges in Determining Second-Line Therapy for mCRC

EP 5: The Optimal Dosing Strategy for Regorafenib in mCRC

EP 6: Achieving a Durable Response with Regorafenib in mCRC

EP 7: IMblaze370 Trial in MSS mCRC

EP 8: Treatment for Chemoresistant mCRC