This is a pretty typical case of metastatic colon cancer. The patient is 53 years old, probably never had a colonoscopy at this point. He presents to primary care and, ultimately, to a gastroenterologist with some abdominal complaints and rectal bleeding. He gets a colonoscopy, and there&rsquo;s a finding of a descending mass, a mass in the descending colon. Biopsy is positive for adenocarcinoma and sent off for genetic testing.

In the meantime, he has a CT scan showing, unfortunately, metastatic disease. There&rsquo;s one big spot in the lung and a bunch of spots in the liver. And that&rsquo;s very important when we think about resectability and all of that. He&rsquo;s symptomatic with this abdominal distension. Biopsy comes back, as I said, positive for adenocarcinoma. And genetic testing for RAS shows that there&rsquo;s a

-mutated left-sided colon cancer with metastases in the liver and the lungs, and has a little hypertension.

Mom had breast cancer, but there&rsquo;s no other real family history of cancer. And the decision was made to go ahead and initiate therapy with chemotherapy. There are a bunch of choices here. I think the physician did what most physicians do in the United States, and that is oxaliplatin and a fluoropyrimidinein this case, FOLFOX&mdash;plus bevacizumab. Primary is still in place, no surgery has happened to remove that primary, but even with the rectal bleeding, that was done. And in this guy&rsquo;s case, it was a good decision. The cancer responds nicely. There&rsquo;s a nice regression of the primary and of the other metastatic lesions, and chemotherapy is continued.

So, typically, now with metastatic colon cancer, we say folks are going to live 2 to 3 years. We&rsquo;re learning more about being able to be more specific because we all know there are some patients who have a very short prognosis and others who have this forever prognosisthey do very, very well over a long period of time. And to date, we have just been treating them and seeing what happens.

A guy who has a really nice initial response like this would be one of those people that I&rsquo;m thinking is going to be around a while. We now know, for example,

-mutated tumors don&rsquo;t do so well, they don&rsquo;t respond as well. I&rsquo;m more anxious about that person&rsquo;s prognosis than a person like this. So, 2 to 3, or more, years is what we would tell the patient. At 53 years old, that&rsquo;s still way too short.

In this case, the patient&rsquo;s tumor was sent off for molecular testing, and this has been a really rapidly moving space as to what you need and when. And it wasn&rsquo;t a year ago that we said, &ldquo;Oh, if they&rsquo;re metastatic, if they don&rsquo;t have a high family history, you don&rsquo;t need MSI.&rdquo; But that&rsquo;s completely different now. You must have microsatellite instability testing on every patient with colon cancer, regardless of stage, regardless of age, for 2 reasons: 1, of course, is to screen for the genetics. Is the patient a lynch patient? Do they have HNPCC (hereditary nonpolyposis colorectal cancer)? But honestly, more importantly now, we know that those patients with MSI-high colon cancers respond really well to the immunotherapy drugs, to the checkpoint inhibitors. And already on guidelines, you see MSI-high metastatic colon cancers being recommended checkpoint inhibitors. So, we absolutely want to know, in this guy right from the get-go, the RAS status.

wild-type. Many doctors are stopping there and not doing any additional RAS testing. But there are another 20% or so of other

mutations that are seen. We also know that BRAF is a negative predictor for response to the EGFR therapies. So, what we&rsquo;re doing is these broad profiles now so that I know everything, so I don&rsquo;t have to keep up. I just test everything, and I&rsquo;ll have in the bank what I need for an individual patient. It&rsquo;s really important to have MSI, and it&rsquo;s really important to have broad RAS and BRAF testing for every patient with metastatic colon cancer.

Diagnosis of mCRC

This is a really interesting case where most of his cancer is actually in his liver. He&rsquo;s got this lung lesion; he&rsquo;s got a primary there as well. And we do have new techniques around liver-directed therapies that are increasingly used, increasingly popular. We know we have a PFS advantage, but we&rsquo;re still waiting on the overall survival advantage. So, the question is, who&rsquo;s a good candidate for that? Well, this guy&rsquo;s on the border. He had a fairly large lung lesion, his primary is still in place, but if he has a really good responsethis is one of those patients that 4 to 6 months into treatment, I&rsquo;m thinking about sending him to surgery&mdash;remove the primary. Nowadays, that&rsquo;s laparoscopically done; you have to hold the chemotherapy around it. There&rsquo;s evidence that says maybe removing primaries is a good idea, and you get it out of the way. It&rsquo;s done. And then you&rsquo;re dealing with this isolated lung lesion in the liver metastases. It wouldn&rsquo;t be crazy to do liver-directed therapy at that point, although that might be a card I would hold until later. So, we are increasingly aggressive with surgical and local therapies when patients have oligometastatic disease and these kinds of patterns.

Whenever I see a brand new patient with metastatic colon cancer, I ask a question that actually is a question that throws them off, but I ask them anyway. I ask, &ldquo;What do you do for fun?&rdquo; and they, like, freak out. They don&rsquo;t have any fun, but they think about it a minute and then I get a really interesting look into their lives with that answer. It tells me about their hobbies, it tells me about how they really enjoy their time, what they do with it. And what I&rsquo;m really doing there is trying to get a sense of what side effects to avoid. Because if I&rsquo;ve got oxaliplatin, then I&rsquo;ve got this cumulative neuropathy.

So, I&rsquo;ve got a guy right now who really likes to play guitar. He&rsquo;s a 70-year-old guy. He plays in this band, and you wouldn&rsquo;t think it when you see the guy, but he likes his guitar. And so, I&rsquo;m going to avoid oxaliplatin in this guy for a long as I can. Others, particularly in these younger folks, are raising kids. They are driving all over the place, they are busy at work, and they don&rsquo;t have time for a 2-day infusion. So, these are people that I&rsquo;m already steering over to capecitabine as their form of 5-FU. When you find out more about your patients, you can decide between oxaliplatin/irinotecan and pump 5-FU/capecitabine.

We have been ignoring data for 15 years. Trial after trial has shown that left-sided colon cancers behave better than right-sided colon cancers, but we ignored it because we really didn&rsquo;t know what to do with that. It didn&rsquo;t influence our treatments, it didn&rsquo;t change anything. It really wasn&rsquo;t until Alan Venook went back to 80405this big randomized clinical trial&mdash;reviewed every single chart himself and determined whether the patient had a left-sided or right-sided colon cancer. And then, he not only confirmed that left-sided colon cancers did much better than right-sided colon cancers, but he transformed our practice in showing that right-sided colon cancers, even those that have

wild-typeso the ones that are molecularly profiled appropriately&mdash;failed to benefit from EGFR therapy, and this made no sense to us. It still makes no sense to us. We thought we had the enriching molecular profile, but it turns out just being over here means that it won&rsquo;t work as well.

So, this is further narrowing the patient in frontline who should get EGFR therapy. It really is that

wild-type, left-sided colon cancer where you would use EGFR frontline. Other studies have reconfirmed this, so this is not just the 80405 trial. It has not made it to the NCCN guidelines with a little asterisk that says &ldquo;Right versus left.&rdquo; I&rsquo;m always nagging our doctors in our practice to make sure you put in the right

codeand there&rsquo;s a right one and a left one. Everybody says it doesn&rsquo;t matter. And I&rsquo;m like, &ldquo;Now it matters. I want you to know, we have to know which side it is.&rdquo; And so, when you characterize a colon cancer patient now, you need to know

status, you need to know MSI, and you need to know sidedness.

Whenever we set out on patients, we decide which regimens they should get. And as I said before, it&rsquo;s either oxaliplatin-based, irinotecan-based, or both. There&rsquo;s FOLFIRINOX with bevacizumab in the frontline. That&rsquo;s generally reserved for the higher tumor burden, the

-mutated tumor. So, in this case, I would say you&rsquo;re between an irinotecan-based regimen and an oxaliplatin-based regimen.

Most of us in the United States use oxaliplatin-based frontline therapy. I think that&rsquo;s tradition. We&rsquo;re used to it. One of the things we&rsquo;ve learned early on is that you can only give so much of it because of the cumulative neuropathy. So, most of us are pretty good at backing it off at a certain point. The one really strong note is if you start with oxaliplatin-based therapy frontline, you cannot get to 12 cycles. Don&rsquo;t do it. There&rsquo;s nothing magic about 12 cycles of the drug. Six to 8 is plenty and then back off to your maintenance approach.

I know a lot of doctors who favor irinotecan frontline because they don&rsquo;t have to worry about that; they can just keep giving it as long as they want. I think that&rsquo;s a perfectly legitimate choice. My bias toward an oxaliplatin-frontline regimen, quote honestly, is that almost all clinical trials in the second-line use irinotecan. And so, as soon as I give irinotecan frontline, those patients are now ineligible for second-line clinical trials. Maybe not the best rationale for that, but that&rsquo;s why I do it. The second is that with oxaliplatin, you don&rsquo;t really lose your hair. These are newly diagnosed patients, and the last thing they wantthey&rsquo;re getting a Mediport, they&rsquo;re going through all of this&mdash;is to be losing their hair. I know how miserable that is. So, we try to put that off until later and use the irinotecan second-line.

Deciding on Upfront Treatment for mCRC

For our case, if you remember, the patient had metastatic diseaselung, liver, primary is still in place, treated initially with FOLFOX-BEV. He probably then went to some maintenance therapy, had a nice initial response, and then 10 to 12 months later, starts to show signs of progression&mdash;some increasing shortness of breath, marker rising, new CT scan shows some progression. And so, now you&rsquo;ve got to move into second-line therapy. I think all of us with oxaliplatin-based therapy frontline would move to irinotecan-based second-line, remembering that this patient has a

mutation. So, the question is, does one carry a biologic through to second-line? We have a mountain of evidence that VEGF inhibition through lines of therapy is positive. And so, in this case, the patient got irinotecan-based therapy with bevacizumab, continued through the frontline.

When we go from frontline to second-line, we have a lot of choices. One is we usually change from oxaliplatin to irinotecan, for example. Many people debate, &ldquo;Do we keep the 5-FU going?&rdquo; Most of us do. We would use FOLFIRI or even capecitabine. Irinotecan is doable. Where we differ around the world is the use of biologics in second-line. In the United States, we have 3 VEGF inhibitors approved in the second-line. Most of us continue on with bevacizumab through lines of therapy. You have the randomized clinical trial that supports that: the TML study, which supports a survival advantage by continuing bevacizumab through second-line. You already have a patient who&rsquo;s tolerating the regimen. I never thought I would say this, but it&rsquo;s actually the least expensive of the 3. Bevacizumab is a bargain relative to the other 2. So, I think most of us do bevacizumab beyond progression, in through the second-line, using that rationale. Europeans, other folks, feel like the impact of biologics in that setting is less strong based on the randomized trials, and so they choose to stop it. But if you look at our overall survivals, I believe it is that continuation that&rsquo;s getting us to those 2 to 3 years&rsquo; overall survival.

So, our patient now has been getting FOLFIRI/bevacizumababout 6-months of therapy&mdash;had an initial response, and then progressed again. There are new scans based on some symptoms. The patient has a little bit more abdominal distension, not feeling all that well, but still going to work. Now, they&rsquo;re still slogging along doing what they&rsquo;re doing. But on your imaging, you see some new early peritoneal carcinomatosis, which is never a good sign, and some progression of his disease. His performance status is about &ldquo;1&rdquo; now. Like I said, still going to work, still doing okay. And the question is, what do you do in third-line?

I think this is a really good candidate for regorafenib. I think the drug itself stabilizes cancers in about half of everybody who takes it, and about one-quarter of everybody who takes it is stable at 6 months or beyond. I think, because there&rsquo;s not this traditional response seen with the drug, we feel like it has less value. But we don&rsquo;t want to wait too long to use this drug. Many would be tempted to recycle the oxaliplatin in this patient. If he had it all the way at the beginningit has been a year or so and now is coming back there&mdash;there&rsquo;s not really any evidence that that brings a response rate to this patient either. So, I like the choice in this case of using regorafenib as a third-line choice in this patient.

When patients get to third-line with metastatic colon cancer, it&rsquo;s a great place to do a hard stop and talk to our patients again. Remembering a couple of years ago, when we first started with this patient, we were all hope. We were all like, &ldquo;Lots of drugs. We&rsquo;re going to get a few years of survival out of this,&rdquo; and now they&rsquo;ve done that. They&rsquo;ve gotten a couple of years of survival, and they&rsquo;re at a different place. They understand where they are better. They understand that they&rsquo;ve got a bad disease that&rsquo;s probably not going to get better. They still want it to get better, but it&rsquo;s probably not going to be cured. And so, they are valuing quality of life more. This is, to me, a really good hard stop with patients to say, &ldquo;Alright, here&rsquo;s where we&rsquo;ve been, here&rsquo;s where we are, here&rsquo;s where our choices are going forward. What are your priorities? What&rsquo;s important to you?&rdquo;, and then setting out with a strategy.

This patient&rsquo;s prognosis, untreated, is probably 6 months. So, fairly short from this point on. And what our overall goal here is to try and kick this down the road. Can we slow the progression? Can we add chunks of time to the overall survival that are meaningful with a good quality of life?

Therapeutic Options at Progression of mCRC

When one gets to third-line therapyyou&rsquo;ve had oxaliplatin-based therapy, you&rsquo;ve had irinotecan-based therapy&mdash;you have a menu of things, and we spell this out for patients, &ldquo;Here&rsquo;s what you can do from here on.&rdquo; You&rsquo;ve got 2 approved drugs: regorafenib and TAS-102. You&rsquo;ve got clinical trials that are out there, and these patients often go on to clinical trials because they&rsquo;re still in pretty good shape. Their performance status is pretty good. And then you&rsquo;ve got recycling of chemotherapy&mdash;drugs that you stopped, usually this is oxaliplatin, not because it wasn&rsquo;t working, but because you were trying to avoid neurotoxicity. You have a pretty good menu of choices. And doctors and patients all bring to the table expectations, values, and discussions about what they should do at that point.

Where I have evolved over the last several years is to value the oral therapies, the TAS-102 and the regorafenib, and their survival advantage that they bring to patients. I&rsquo;m a big clinical trials guy, don&rsquo;t get me wrong. We&rsquo;re always looking for new things. But I also don&rsquo;t want to ignore the fact that these 2 medicines have survival advantage. I also want to emphasize that if you wait too long, then these drugs don&rsquo;t really work as well. So, to me, this good performance statuspatient in the third-line setting is really an ideal patient to start on the approved drug approaches and then push off the clinical trial piece until the next one.

For third-line metastatic cancer, patients were randomized in this clinical trial between placebo and regorafenibat a full dose, 160 mg daily&mdash;in a 2:1 randomization. And the clinical trial was positive, thus the approval. So, it improved overall survival and progression-free survival. The toxicity was acceptable, so it was brought forward. And it&rsquo;s really fascinating that this drug works because we don&rsquo;t really know how it works. It has a bunch of different targets&mdash;maybe as many as 19&mdash;one of which is a VEGF angiogenesis target, but there are others as well. And we&rsquo;ve been looking very hard for a biomarker to figure out who benefits and who doesn&rsquo;t. But despite lots of investment time and effort, we haven&rsquo;t figured that out yet. And so, all-comers&mdash;RAS, MSI&mdash;they&rsquo;re eligible for this kind of treatment. Based on the randomized clinical trial, there is a survival advantage and a progression-free advantage.

Dosing regorafenib is a hot-debated topic out there. The standard dose is 160 mg, 4 pills once a day. A lot of people are dose modifying right from the beginning. I think the most common pattern is to start at 120 mg, 3 pills a day, and then watch them weekly. Some will start at 80 mg and escalate, some will start at 160 mg and come down. So, I don&rsquo;t really care how you do it. I just think you need to recognize the need for monitoring.

When regorafenib, oral chemotherapy, first came out, we thought you could sort them, see them a month later, and that was the right thing to do. And that turns out not to be really the best way to go. You need to monitor these people, maybe more closely than you&rsquo;re used to even with chemotherapy. So, most of us pick a dose80 mg, 120 mg, 160 mg&mdash;and watch them a week later; go ahead, make sure you see them, do some labs on them, and look at their liver functions. See them 1 week after that because often it&rsquo;s in that window that hand-foot syndrome will all of a sudden arise and come on fairly suddenly. And just the process of seeing them is reassuring to the patient. It also emphasizes the need for them to be good stewards of their own toxicities, compliance, all of those things that you need to monitor with patients. Once you get to a dosing schedule, you can then opt out and see them once a month or so. So, you can get there, but the first cycle, the first month, you want to really see them 3 weeks in a row&mdash;draw labs, look at their hands, modify any doses, hold for 1 or 2 days, etc.

In terms of managing the toxicities, there&rsquo;s not a lot here, other than the dose, that we figured out. You can use good hand creams. Urea-based hand creams help. It&rsquo;s a good time for a manicure/pedicure, even for a podiatrist to remove calluses. Some people argue that that&rsquo;s a good idea. And you have to remember, the majority of your patients will tolerate 160 mg pretty well. But there are ones who really don&rsquo;t, who come in their house slippers 2 weeks later and say that you need to modify these doses. Liver function abnormalities are rare, but we watch and monitor for them in all patients. So, get them through that initial time. Figure out if they&rsquo;re in the half that benefits from initial therapy, and get them on a dose that you can continue long term.

I think a drug like regorafenib, to clinicians, has taken us a while to figure out its value. We want responses and CEAs dropping. And stable disease is okay, but we want more than that. I think our patients want more than that, too. Over time, as my experience has increased with the medicine, there are clearly patients who have long-term benefit. There&rsquo;s clearly a tail on the curve for some patients who have 6 to 12 months of stabilization, and it&rsquo;s very hard to predict who that patient is going to be. So, I&rsquo;ve seen it with big tumor burden and small tumor burden, young and old. What we need is that biomarker to figure out who that&rsquo;s going to be. But until such time, we really, I think, are obligated to ask, for our patients, &ldquo;Are you one of these people on the curve where you&rsquo;re going to have long-term benefit? Find those patients and treat them.

This patient has had oxaliplatin-based therapy and irinotecan-based therapy now, has had regorafenib therapy and progressed on that. Many, many of these patients will still have good performance status, still be eligible for more treatments. It&rsquo;s, in essence, the same menu we talked about before of, now you&rsquo;ve got TAS-102 as an approved drug, you&rsquo;ve got clinical trialswhich are out there&mdash;and you&rsquo;ve got recycling of oxaliplatin. And I think you make your decision at this point based on the overall needs of the patient, how the disease is doing, eligibility for clinical trials, and the like. Don&rsquo;t forget that TAS-102 is out there. Survival advantage is well with that. It&rsquo;s more of a myelosuppressive kind of drug, but one that can help patients as well.

We do have, in the refractory setting, 2 drugs approved: regorafenib and TAS-102. And because TAS-102 came second, we actually have, in the clinical trial, patients who&rsquo;d had regorafenib first. And so, if you look at the subgroup analysis of the patients who&rsquo;d had regorafenib first, there was still benefit from TAS-102 as a fourth-line, if you will, therapy. So, we at least have that experience that one after the other is still a positive for patients.

A Continuum of Care for Metastatic CRC

Diagnosis of mCRC

Deciding on Upfront Treatment for mCRC

Therapeutic Options at Progression of mCRC

Therapy in the Salvage Setting of mCRC