So, in October 2015, the patient, a 64-year-old woman, presented with obstructing symptoms. She was found to have an obstructing mass at the rectosigmoid junction and then eventually underwent hemicolectomy. At the time when she was seen, labs were drawn, including CA level, which was elevated. After the left hemicolectomy, the pathology suggested a poorly differentiated adenocarcinoma that invaded through the muscularis mucosae up to the pericolic fat. Fourteen lymph nodes were taken out along with the tumor, and about 10 of them were actually positive for cancer.

Staging with CT scans and PET/CT showed multiple lung lesions; 3 of them actually measured up to 3 cm in size. The patient had a mutational analysis on her tumor, which was essentially

wild-type. So, mutational testing was performed on the tumor. It revealed to be a

wild-type tumor, so no mutations. There was also

. MSI testing revealed a microsatellite-stable tumor. Essentially, this was a metastatic stage 4 cancer because of the liver lesions.

When looking at the past medical history with this patient, she had a history of hypertension, which seems to be well controlled. The patient also had a prior history of coronary artery disease. She had an angioplasty for 4 years, but she continued to be asymptomatic. Her coronary artery disease was under control. She met with the oncologist, and the decision was made to proceed with FOLFIRI and cetuximab, which is an EGFR inhibitor. The patient tolerated the treatment well. She had grade 1 rash, which was manageable, and grade 2 thrombocytopenia, and this was manageable with dose adjustments to the FOLFIRI. Follow-up imagings at 2 months and at 4 months revealed significant response and shrinkage of these tumors in the lungs. The patient was doing well. So, the decision now was to move to maintenance therapy, and the oncologist decided to put the patient on maintenance cetuximab.

So, this patient is stage 4. Of course, her prognosis is guarded since the presence of multiple lesions in the lungs will make those unlikely to be ever resectable. Ultimately, she will succumb to her cancer. Right now, in patients with the

wild-type tumors, the average survival is about 3+years, up from 6 months with no therapy. It&rsquo;s much better from that standpoint, but unfortunately, her life is ultimately going to be limited by the cancer. For some patients, this may translate into many years. For other patients, it may translate to less. But nonetheless, the median is close to 3 years. So, her disease is ultimately going to take over her life.

In terms of what are the best frontline options for this patient, this patient has a left-sided tumor and this patient has no mutations,

. Now, her disease is microsatellite-stable so that only tells us that immune therapy may not be an option, other than onset in clinical trials, but it&rsquo;s not an actual option in clinical practice. So, that&rsquo;s death, and it also tells us that it&rsquo;s unlikely to be related to Lynch syndrome. In term of RAS wild-type and

wild-type tumors, we have 2 options proceeding with a biologic. The 2 biologic options are either a VEGF inhibitor or an EGFR inhibitor. A VEGF inhibitor would be bevacizumab. The EGFR inhibitor would be either panitumumab or cetuximab.

Because the tumor is on the left side, the data does suggestboth from CALGB 80405 and FIRE-3&mdash;that there may be a slight advantage for an EGFR inhibitor, specifically cetuximab over bevacizumab. And so, I think it&rsquo;s very appropriate to start the patient on FOLFIRI/cetuximab. I think that&rsquo;s a choice that&rsquo;s acceptable with those tumors. My personal preference would still be to start those patients on bevacizumab, understanding that I can use those EGFR inhibitors at any point of therapy. It gets a bit complicated because those patients will have the longest exposure to their therapy in the first line. And EGFR inhibitors have a number of toxicities that can be quite significant, such as rash. It doesn&rsquo;t get any worse with time, but it may be persistent for some patients and the rash would never improve significantly.

Hypomagnesemia, those patients almost universally will have issues with retaining magnesium. They shed magnesium out. Some will require infusions of magnesium more than others. Then, the other question would be, how do you maintain those patients and do we have data? We don&rsquo;t really have strong maintenance data with the EGFR inhibitors. Unlike capecitabine and bevacizumab, we don&rsquo;t have it with the EGFR inhibitors. So, that is relatively limiting. But if you look at the data overall, they look very similar between the EGFR and the VEGF inhibitors, maybe a slight edge for the EGFR inhibitors. After a discussion with the patient, typically I think you have to expose the patients to the benefits, the pros and cons of the 2 biologics, and have the patient be part of that decision with you.

In this particular patient, the decision was to proceed with FOLFIRI/cetuximab, which, as I said, is very appropriate. And obviously, the patient benefited from the treatment. Then, the question is, what type of maintenance therapy would we perceive? Given the absence of data, the question is, do we continue with the fluoropyrimidine or the EGFR inhibitor or with the 2? Again, we don&rsquo;t have data. We know that ultimately, the toxicity of the EGFR inhibitors is amplified when you combine them with chemotherapy, and EGFR inhibitors, unlike VEGF inhibitors, have activity on their own. They can&rsquo;t induce responses on their own without the assistance of chemotherapy.

So, logically just putting all these things together, I think it would make more sense to just proceed with the EGFR inhibitor on its owncetuximab or panitumumab&mdash;as a maintenance strategy. The next question is, of course, how long do you continue with this? Given the cumulative toxicities and the issues you start having, I tend to limit this to a year or so if you have a persistent response. And then, the decision after that will depend on toxicities, patient preferences, etc. So, the key would be to have that discussion continuously with the patient to see if maintenance would make sense to continue.

Upfront Therapy for Metastatic Colorectal Cancer

The patient did fairly well on cetuximab maintenance and, in fact, continued on it until August 2016. The patient started to complain of more symptomsweight loss, fatigue, nausea. And then, a CT scan of the chest, abdomen, and pelvis done at the time showed progressive disease both in the lungs, and now there were some new spots in the liver. So, the question is, what do you do?

There are 2 options, frankly. You have the option of reinstituting the FOLFIRI or switching to CapeOx/bevacizumab. The decision was to proceed with CapeOx/bevacizumab. That came through a discussion with her physician. At that time, her blood pressure seemed to be well controlled and continued to be well controlled on CapeOx/bevacizumab. And after 2 months, the patient had stable disease. After 4 months, it was the same, and so she continued with CapeOx/bevacizumab for another 4 months. At 4 months, the decision was made to drop oxaliplatin and continue with capecitabine and bevacizumab. So, this patient progressed on FOLFIRI plus cetuximab. The first question that comes to mind is, do you reinstate FOLFIRI? Because technically, it has taken many months before she actually progressed, and so she could still be sensitive to FOLFIRI. So, that&rsquo;s one option. The other option, which I think is a very logical option, is to switch both the chemotherapy backbone and the biologic. My own preference would probably be to institute FOLFIRI first and continue with cetuximab. And then, after the progression on FOLFIRI/cetuximab, then I would go CapeOx/bevacizumab. But as I said, both options are very reasonable.

CapeOx, or FOLFOX, would be the next option after failure of FOLFIRI, and then the switch of the biologic as well. The most important question, given the best medical history of this patient, is, should we give bevacizumab? We know bevacizumab increases the risk of arterial thrombolic events, like strokes, heart attacks, even increases the risk of uncontrolled hypertension. This patient has controlled hypertension, and it&rsquo;s being controlled on just 1 drug and for quite a while. She also had coronary artery disease that had angioplasty 4 to 5 years prior, so the decision was made whether to institute bevacizumab or not. And typically, 6 to 12 months is a comfort zone. And since that patient had years of symptom-free coronary artery disease, seems to be well controlled, I think it would make sense to place her on an anti-VEGF agent, specifically, bevacizumab.

Now, of course, we have 3 agents available on the market: ramucirumab, ziv-aflibercept, and bevacizumab. And all 3 agents seem to induce a very similar benefit when given in the second-line setting. There doesn&rsquo;t seem to be one that stands out versus the other, except one is more expensive: ramucirumab. Ziv-aflibercept seems to be a little bit more toxic. And in fact, for most patients, we&rsquo;re very used to bevacizumab and that would end up being the default.

If you look at the NCCN guidelines, all 3 are listed. However, bevacizumab is preferred for the specific reason that it doesn&rsquo;t make sense to have 3 of the same that may be more expensive, more toxic, and we&rsquo;re less familiar with. So, for that purpose, we&rsquo;d go with bevacizumab. This is a patient who has isolated disease both in the lung and the liver, or that&rsquo;s isolated to the lung and isolated to the liver, that&rsquo;s actually pretty extensive because of 2 organs being involved. Nonetheless, there&rsquo;s always this, and should always be, discussion: could we address the local disease first? And the answer is, in the patient that has metastatic disease, localized approaches do not make sense. Thus, this patient, at this point, would not be eligible for any localized approaches, just systemic approaches with chemotherapy plus bevacizumab.

Treatment of Relapsed Metastatic Colorectal Cancer

So, in January 2017, the patient presents to her oncologist with, again, more symptoms of weight loss, nausea, and fatigue. And so, she gets referred back for another CT scan, which showed even further progression in the lungs, a little progression in the liver, and now the patient has a couple of boney lesions that are nonthreatening. The patient essentially shows evidence of progressive disease, and her CA levels are rising significantly. The patient, after discussion with her oncologist, expresses motivation to continue with therapy. Her performance status is 1. She&rsquo;s doing great, she&rsquo;s still doing her house chores. She&rsquo;s a little bit more fatigued, limited, but overall, she&rsquo;s still very functional and she wants to continue on further therapy. There are no clinical trials that she would be eligible for. There was a discussion between herself and her medical oncologist regarding the 2 oral agents that are available for refractory disease: regorafenib and TAS102. The decision was to proceed with regorafenib.

So, now the patient progressed through FOLFIRI/cetuximab, CapeOx/bevacizumab2 lines of therapy&mdash;and the question is, what do you next? What would be done next is essentially a couple of options that are now made available to us. Again, as a reminder, this patient is microsatellite stable, so immune therapy outside clinical trials is not an option for this patient. Our 2 options are TAS102 and regorafenib. There are differences between the two. TAS102 is your traditional cytotoxic agent, and that essentially is fluoropyrimidine or part of that fluoropyrimidine super family. It&rsquo;s not 5-FU, it&rsquo;s not capecitabine. It actually has functions within it that will allow it to work when 5-FU and capecitabine fail. And so, in that sense, it&rsquo;s a little different although it belongs to that super family. But it&rsquo;s a cytotoxic agent.

Regorafenib, on the other hand, is what we call a multi-kinase inhibitor. It has multiple targets. It&rsquo;s not your traditional cytotoxic agent; it&rsquo;s a targeted agent. It has a lot of targets on the cancer cells and in the environment, including VEGF. This agent essentially is what we call a dirty drug; promiscuous, essentially, with all these targets. So, they&rsquo;re different. And these agents have never been compared head-to-head. Actually, each one of these agents had 2 large phase III studies, and regorafenib, in addition, had an observational study called CONSIGN. We have CONCUR and we have CORRECT, and CORRECT is the larger study that essentially led to the approval of the agent, regorafenib. CONCUR is an Asia-only study, and CONSIGN is essentially an observational study, which I think collected more than 2000 patients.

On the other hand, we have TAS102 in the RECOURSE study, which was the large study that led to its approval versus placebo; so, similar design to the CORRECT trial. Then, TERRA is very similar to CONCUR. Again, it was the drug versus placebo and was in Asia only, similar to CONCUR. We have these studies on hand that are similar, but like I said, we don&rsquo;t have any comparative data looking at TAS102 versus regorafenib to help us with a decision. So, we really have to rely on historical controls, personal experience, and other factors as well.

When we look at regorafenib, and between CORRECT and CONCUR, CONCUR had patients who were less pre-exposed to treatment. In other words, in Asia and certain Asian countries where there is less availability of VEGF and EGFR inhibitors, those patients will get regorafenib a little earlier on. Historically, when we looked at CORRECT and CONCUR, it does seem that regorafenib may have a further benefit if moved up the line. When we look at TAS102, we have, as I said, RECOURSE and TERRA, and when we look at very similar populations again, RECOURSE patients had to fail all standard therapies similar to CORRECT. And in fact, with the TAS102 study, the RECOURSE, about 20% of the patients had prior regorafenib. Prior regorafenib did not seem to affect the benefit that you see with TAS102. So, whether you had regorafenib or not, you still derived benefit, which is good news. At least we have that little hint there.

TERRA, on the other hand, is a study that is like CONCUR. It had less pre-exposed patients. Interestingly, TAS102, as it moves up the line, didn&rsquo;t seem to have a larger delta, meaning the benefit is maintained regardless of where you place it in the line of therapy. And maybe one of our hints that, perhaps, in terms of sequencing regorafenib, there are some patients whose performance status is borderline PS 2 or the liver is quite dysfunctionalnot too dysfunctional, of course, because you can&rsquo;t give either drug, but dysfunctional enough to worry about regorafenib, and we would give TAS102 first. On the other hand, in patients who clearly had issues with their bone marrow, you want to avoid TAS102. Their toxicity profiles are different. CONSIGN just confirms a lot of the observations with CONCUR and CORRECT.

Options for Third-line Therapy in Metastatic CRC

The 2 drugs, because of their natureone is a multi-kinase inhibitor, one is a cytotoxic&mdash;have different toxicity profiles. TAS102&rsquo;s toxicities are primarily bone marrow toxicities&mdash;neutropenia and thrombocytopenia. Neutropenia is pretty pronounced. In fact, 4% of the patients will have febrile neutropenia, which is pretty significant. We think about an oral drug as easy, but you do have some toxicities and they happen actually earlier on. There are also some GI toxicities and fatigue that can happen in patients who have been exposed to it in the longer term. Regorafenib, on the other hand, has toxicities like hand-foot syndrome, diarrhea, hypertension, some VEGF toxicities, and the kinase inhibitor toxicities that also happened earlier on.

Now, in terms of this patient, the patient was placed on regorafenib after discussion with her oncologist, which I think makes a lot of sense. This would be the natural positioning for regorafenibpatient has good performance status, failed 2 prior lines of therapy, and now gets to this level.

My personal experience with regorafenib has been pretty much placing it at the third- or fourth-line of therapy. When I look at my own experience and patients I&rsquo;ve treated over the last couple of years, we&rsquo;ve had a few patients who had CA responses, stable disease, and we&rsquo;ve had many patients who did not respond to treatment. So, it&rsquo;s what you would expect at this line of therapy. Most patients actually do not respond or respond well to treatment. For those patients who actually had a responseand when I say response, we almost never see significant shrinkage&mdash;you do see some shrinkage that wouldn&rsquo;t qualify a patient for what you call a partial response. You do see what we call minimal responses. And we see, in some patients, steep drops in the CA. In fact, I have patients who went for 6 months. My longest patient has gone for close to a year, or a little bit more continuously, on regorafenib.

One of the things about regorafenib is its toxicity. Its toxicity has been a deterrent for some. And I think the concern is real because patients are pretty beat up when they get to this point. They have had a lot of therapies, they&rsquo;re tired, and these toxicities can get amplified. But regorafenib&rsquo;s toxicities happen very early, in the first 2 to 3 weeks. And in fact, the worst toxicities, so not just the toxicity itself, happened in the first 2 to 4 weeks of the treatment. So, I think it is essential to educate the patients really well about the toxicities, like when to call. But also in our practice, we bring the patients every week to the clinic. They don&rsquo;t have to see the physician, they can see the nurse practitioners. Occasionally, they can have a quick check by the nurse. But the first 4 weeks are very critical and the patient has to be seen once a week for their follow-up. And that is one way to actually cut down on the risk of significant toxicities.

In the second month of treatment, every 2 weeks after the second month of treatment, patients will be seen on a monthly basis because most of these toxicities would have been figured out with dose adjustments. And the next question is, what dose do we start with? The dose at this point of time, that was defined by the CORRECT Study, is 160 mg orally every day for 3 weeks in a row, then 1 week off. Most physicians and most oncologists in the United States use a different dosage. Some start with escalation 160 mg, others start at 120 mg and stick to 120 mg. Others, like myself, right now in the absence of data, start with 160 mg knowing that 20% of the patients need that dose and will never actually require a dose reduction. We have a short amount of time for most patients with a PFS to 2 months. I don&rsquo;t want to play around with the dose without data and then deescalate.

I don&rsquo;t think there&rsquo;s a right or wrong strategy, and we are addressing this question. There&rsquo;s a study called ReDOS, which is a large phase II randomized study that&rsquo;s looking at the question of starting with the standard dose versus a dose-escalation strategy. The good news is this study is about complete. We&rsquo;re hoping to present the data at ASCO GI 2018 and help with the understanding of, can we safely and effectively start patients at the lowest dose and escalate rather than start at the highest dose when we know 80% of the patients will have to settle down at a lower dose?

Toxicity Management for Third-line Therapy for mCRC 

Now the patient goes on regorafenib and does well with it and then eventually progresses, as all patients unfortunately do. So, what next? I think at every point of the discussion with the patient, even frankly from the first-line, the question of palliative care and no therapy should always be part of the discussion. I think it&rsquo;s important to understand the patient preferences and where they stand. Most patients, the overall majority, want to be treated. There are some patients who actually prefer not to be treated at all. They may be older, they may be satisfied with their life and just accept their fate.

Most want some form of treatment, but at every line of therapy, I think it&rsquo;s important to have that discussion. And with a first-line, second-line, and third-line, now the patient progressed on regorafenib, and we&rsquo;ll have that discussion with the patientpalliative care versus another option. Another option outside of clinical trials would be TAS102; that is available. And we have data, as I mentioned, that suggest that patients who fail regorafenib and go on TAS102 still derive benefit from TAS102. So, I would have that discussion, and I think it&rsquo;s very reasonable to consider TAS102 in this patient in this particular setting.

I think these are all examples of how far we&rsquo;ve gone in terms of improvement over the last decade-and-a-half in treating patients with metastatic colorectal cancer. Our armamentarium has grown so much. Not as much as I would hope for our patients, but enough to bring the survival from a little bit less than 1 year to more than 3 years in the stage 4 setting. And for some patients, let&rsquo;s say those with MSI-high tumors or with specific targets we&rsquo;re able to develop, that survival is actually years and years and years. Those patients with liver-only metastatic disease or lung or oligometastatic disease that are amenable to resection, their survival is sometimes 10+ years.

So, overall, I think it&rsquo;s very, very important, from day 1 when you see that patient, to individualize and strategize how many lines of therapy you are going to expose those patients to. What kind of strategies are we going to use? Are we going to use surgery, radiation, or SIR-spheres as part of our global strategy? Are we going to use EGFR or VEGF inhibitors? Who is eligible, who is notleft side, right side, those on immune therapy? And then, we have all these clinical trials that are looking at immune therapy in those patients who are microsatellite stable. How can we manipulate the microenvironment, bring those T cells, those lymphocytes, and essentially make those PD-1 inhibitors effective in disease that typically doesn&rsquo;t respond to them?

Then, we start talking about HER2, an emerging target. And we talk about other targets that also are emergingEGFR rechallenge, MET, others&mdash;and we globally are testing all these questions. So, in many patients who may have a multitude of targets, either emergent or present from the get-go, you may think about patients being exposed anywhere between 3 to 4 lines of therapy to 7 to 8 lines of therapy and all done rationally. And then, when you start complicating matters with including surgical resection, intervention radiology, radiation, etc, you can see how we can amplify the outcome of our patients even further by providing them with more of all these various options. Then comes innovation in clinical trials, which add even more options to our patients. It&rsquo;s not unusual anymore to see a patient exposed to an average 4 to 5 lines of therapy, if not more, for most patients. All patients, except 5%, will respond very well to first-line therapy. So, chances are almost every patient you&rsquo;re going to see in clinic is going to be exposed to 3 to 4 lines of therapy, as long as you strategize well and you&rsquo;ve identified targets from day 1 in the patient&rsquo;s tumor.

Metastatic CRC Progressing on Multiple Therapies

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