Metastatic colorectal cancer: Dr. Kasi (2020)

Manju George  0:00 
I want to welcome everyone to the DocTalk of our very first online Empowered Patient Leadership Workshop. We have with us Dr. Pashtoon. Kasi. Most of us in Colontown are very familiar with Dr. Kasi. But for those of you who don’t know him, he will introduce himself very briefly, Dr. Kasi.

Dr. Kasi  0:27 
Again, thank you for the opportunity. So I’m at the University of Iowa, I focus on GI cancers, and within GI cancers, I focus on colorectal cancer and circulating tumor DNA testing. Today, I was gonna focus on, at a high level within the time we have, on some of the updates and also some of the key aspects that would be important for anybody who is a patient who gets diagnosed with colorectal cancer in 2020. I think some of it blends well with the issue that many of us are already aware that more young patients are dying of colon cancer for a lot of the reasons that are still yet to be defined. Colon and rectal cancer is on the rise in young individuals. So individuals in their 20’s 30’s and 40’s are getting diagnosed with colon cancer and therefore obviously would not have met the screening guidelines. Some of you are aware that the age has been moved to 45 years. But even until now, a lot of the individuals who were in that age group weren’t getting screened. So by the time we diagnose them, the cancer is already advanced, and therefore, it’s important to kind of recognize some of the key advances, since a lot of these patients are alive for years, even with metastatic disease (1:42). We also have done some research on this topic as well and it seems like some of it is related to more left sided cancers and rectal cancers on the rise again, for reasons that are still yet to be defined. And I guess one of the key messages as we talk on this EPL, Empowered Patient Leaders Workshop is, I guess, the main theme, if there’s one takeaway that I would mention for everybody who’s a patient or a caregiver is the fact that colorectal cancer is a very heterogeneous disease. What do we mean by that?

Dr. Kasi  0:26 
Well, even it’s not just about the mutations, or aberrations that are different from each individual to the next, but even the sidedness, meaning if somebody’s colon cancer was arising on the right side of the patient’s body versus the left side, they can be markedly different in terms of how they’re going to respond, what kind of treatment options they have, what drugs besides chemotherapy can be used. So, for example, often the right-sided cancers tend to be seen more in females. And a lot of the Lynch Syndrome or the hereditary colon cancers, they tend to be more on the right side.

Dr. Kasi 2:46 
There’s a lot of talk about BRAF V600E mutant colorectal cancers, which are about 10% of all colorectal cancer. Again, while it can happen anywhere in the colon, they tend to be more on the right side as well, and this goes for  MSI high tumors as well. And then, in general, for whatever reason, despite the lack of mutations, they don’t respond to anti-EGFR therapies, at least in the first line setting, it is not recommended. So that’s just an actual kind of giving an example that it’s important to kind of know, at least for every patient to kind of know if their tumor is mismatch repair deficient or mismatch repair proficient and so that is relevant to 2020. Since just a few weeks ago, the FDA approved first line immunotherapy in the form of Pembrolizumab for patients with MSI high tumors. And again, if you don’t know your tumor, you wouldn’t be eligible because a lot of these drugs are more like lock and keys, the lock has to be present for the key to be prescribed. So testing is extremely important for mismatch repair deficiency, or microsatellite instability. And then, after that, the next step, knowing within the RAS/RAF highway, which you can see on the right here.

Dr. Kasi  4:14 
This is typically one of the highways that the cancer can take to grow with the red showing the BRAF V600E mutation or in other patients there could be presence of the RAS — NRAS or KRAS mutations. Again, they cause signaling and are extra powers that the cancers may have, which leads to the growth and all the problems that the cancer causes in terms of metastases. Knowing the presence or absence of them, again, would change options in terms of treatment for systemic therapy, especially with somebody with advanced cancer. So that’s going to be the key and some of these figures I refer, and we can probably share. We recently had compiled a review which is written as best as possible, not to the level of the oncologist. It was published in The Lancet and we’re happy to share that with the group where we’ve tried to summarize the key findings in every treatment option and added some figures and graphs to make it illustrative as best as possible as to what colorectal cancer is, what treatment options are, what kind of surgeries are indicated, what role does radiation play, and also, advances for colorectal cancer are coming in subsets. So it’s important to kind of know what particular subset of colon cancer one may have.

Dr. Kasi  5:37 
This is another simplistic schema of the available tools in our toolbox. In blue on the left hand side are drugs that are familiar to a lot of us in the form of chemotherapies. So the 5 Fluorouracil (5FU) is the pump that often patients go home with the Oxaliplatin or Ox is the chemotherapy that causes a cold sensitivity and Irinotecan is often combined with the 5 Fluorouracil  to make it Folfiri or Folfoxiri, often combined with the VEGF agents like Bevacizumab or anti-EGFR that causes the acneiform rash, in the form of Cetuximab or Panitumumab. They’re often combined in doublets or triplets, meaning two or three chemos at a time, in addition to a biologic, which is the Bevacizumab or the anti-EGFR agents, to give the best chance at shrinkage, or for somebody who is not a surgery candidate to be on the best palliative chemotherapy as possible to extend their life as much as possible. And then in shaded black are our salvage drugs, the TAS-102 or the Lonsurf. Those are anti-metabolite pills that are approved for patients as long as they have tried the other IV drugs first. In 2020, there’s more data regarding combining TAS-102 with Bevacizumab. So it’s not FDA approved yet. But definitely, there’s more discussion with the experts in terms of once somebody has seen all the IV options, the additional Bevacizumab to TAS-102 under compassionate use is something that would be considered unless there is obviously a clinical trial. And then Regorafnib is another pill, which is a dirty tyrosine kinase inhibitor. What do we mean by that? It affects many targets. And that’s why it’s called a “dirty” drug because it can affect VEGF and some of the other targets as well. And there’s been some recent enthusiasm in the usage of this drug for two reasons. One is, we’ve been better able to figure out what’s the tolerable dose of Regorafnib. So there are so called re-dose studies, something that a lot of our patients and caregivers need to be aware of since with some of these drugs, we are recognizing that less is more, meaning that the recommended dose was 160. But in the trial, we showed that even half the dose was good for most people. And it was only escalated as tolerated and common side effect that many of us are familiar with in terms of hand-foot syndrome, it can be alleviated by preemptive use of steroids as opposed to waiting for the hand-foot syndrome to happen.

Dr. Kasi 9:25 
And then in the era of targeted therapy, the first chemo-free regimen for our patients with BRAF V600E colorectal cancer, was the combination trial was with BRAF inhibitor,  with a MEK inhibitor, with an EGFR inhibitor. However, right now the FDA approval is for the BRAF and the EGFR combined. And then for the subset of patients who have the NTRK fusion, we have two pills, Larotrectinib and Entrectinib, which are approved. Again there is immunotherapy, like I mentioned earlier, is something that’s approved for MSI high tumors. So a lot of the recent advances as you can see is not necessarily in chemotherapy drugs or generic things that would work for everybody but combinations of various targeted therapies and chemotherapies combined. And then recently in 2000, Regorafnib with the addition of immunotherapy for the microsatellite stable or mismatch repair proficient tumors, immunotherapy alone doesn’t work, so the question is, what trials we should consider for these patients and often, for patients and caregivers, we recommend that some sort of a trial that adds immunotherapy with something else is a consideration. So immunotherapy with Regorafnib, REGO-NIVO or REGO-PEMBRO are agents that are being studied. A few weeks ago at ASCO, there was the data regarding Regorafnib with Avelumab, as well presented and at ESMO they had more data regarding some of the REGONIVO patients treated in the US. The phase III trial is still accruing so it will be important to kind of see what the readout is, but a lot of the other trials that are using Immunotherapy are combining immunotherapy, the Pembrolizumab or the anti-PD1 agents, Nivolumab,  with something else, whether it’s some form of radiation. So one trial that we have open here, in Iowa, led by us, is the combination of immunotherapy with Y90, which is the radioembolization for patients with liver predominant metastases. In this trial, we’re trying to combine Y90 with immunotherapy to see if it’s safe, and if it is safe, can that be something that could be considered for patients who have had IV chemotherapy in the past and still have liver predominant disease where immunotherapy would be combined with radiation, where there is enough rationale for each of them to help supplement each other. Again, it’s important to recognize that advances for patients with colorectal cancer has not been just one wonder drug or one treatment. And often sometimes when the discussion comes about using Regorafnib for that matter, or TAS-102, sometimes, this discussion regarding maybe not as much enthusiasm in using some of these pills, it’s important to recognize that it’s not just the fact that you want to look at the exact specific numbers, you have to be careful about how you interpret some of these trials, because often, they will just give you the median number, which is the middle number, not necessarily the average. So some patients derive more benefit from certain agents than others.

Dr. Kasi  11:06 
And like noticing this curve, which is almost 12 years ago, advances were not just in medications, but also better surgical modalities, better imaging, other loco-regional things that all can be used one after the other after the other. And also with now, this enthusiasm about using circulating tumor DNA testing liquid biopsies, exposure to any one of the these agents, unless there is a trial available, would be something that I wouldn’t necessarily ignore.

Dr. Kasi  11:42 
And that brings us to the discussion regarding the fact that even between patients while the tumor is different, within the same patient as well, the tumor can be different where there are many studies to show that even in the same patient where let’s say the cancer went to the lymph nodes or went to the lungs, and they’ve done studies to kind of see if these are different or the same. They tend to be, even within the same individual, different. And previously, it was not necessarily as relevant because A. We didn’t have many options and B. You see more of this as when somebody is exposed to targeted therapies. And now they’re increasingly becoming an option for the patients who are RAS/RAF Wild Type with anti-EGFR or the usage of some of these combination in patients with the BRAFV600E mutant colorectal cancer.

Dr. Kasi 12:32 
I often give the example of some of my patients who, when I’ve done liquid biopsies, they acquire different mechanisms of clones that can potentially disappear over time, and then one can potentially reuse the same medication that stopped working.

Dr. Kasi 12:47 
And again, we’ve seen and demonstrated and written about some of these patients and presented some of this data at ASCO, ESMO as well.

Dr. Kasi  12:57 
And there’s some neat work from our colleagues at MD Anderson, where some of the half-life of some of these clones as well arbitrarily is in the range of three to seven months. Again, these are not hard and fast numbers. But can illustrate a point that often in practice as well, we would often recycle treatments, if they hadn’t been used for a while and our enthusiasm by using some drugs is higher when the time from the last exposure or when the last time the patient’s tumor tasted a drug. The longer the duration, the better the odds that something may work. But why it would work in some and not in others, knowing that through some mechanism, invasively or noninvasively, and here it could be blood testing to look at the presence or absence of some of these clones, could be something that could be employed. And that’s another thing that this year and last year, we’ve had more data regarding the rechallenge of some of these medications, where we’ll be more enthused about the rechallenge if the clones had faded away, simplistically speaking.

Dr. Kasi  13:59 
Some of this is actually now in ESMO and some of the other guidelines where this phenomenon is increasingly being recognized. It’s not necessarily research where

Dr. Kasi 14:09 
Whether or not whether these clones were there to begin with, and then they prospered as the other sensitive clones faded away, or truly, if these clones learn to evolve and acquire new mechanism of  resistance. Probably, it’s a combination of both. But we’ve seen that in practice that with serial testing, if you gave the treatment a holiday that you could potentially resensitize the tumor to the same drug that stopped working and eventually rechallenge it again. So again, adding one more option to our patients with colorectal cancer. And again, these strategies are being talked about in terms of how to switch treatments and go back to something that stopped working.

Dr. Kasi  14:48 
And within colorectal cancer for the BRAF patients too, some, not all patients, are alike so you can use it to monitor response to treatment.

Dr. Kasi 14:58 
Again, that’s another thing, especially where somebody does not have a good marker.

Dr. Kasi 15:01 
Some of these assays are something that we have used in practice to study response.

Dr. Kasi  15:06 
Or for patients who don’t have enough tissue and knowledge of if they’re mismatch repair proficient or deficient, that is something that blood testing can act as a surrogate.

Dr. Kasi 15:17 
In patients as well, where they’ve had a response to immunotherapy, we’re using it to see if they have leftover cancer left behind to indicate some of the questions that are often brought up as to how long some treatment needs to be continued.

Dr. Kasi  15:29 
Because right now arbitrarily, we continue treatment for immunotherapy for a couple of years, with more trials being an option and open in this area as well.

Dr. Kasi 15:38 
Again, these are not my slides regarding liquid biopsies on Cell-Free DNA and ctDNA. Other discussions over the years at ASCO have shared the same.

Dr. Kasi  15:48 
I wanted to kind of switch gears and talk about this, which was now presented in the first line setting as well. The combination of a BRAF inhibitor, with a MEK inhibitor, with an EGFR inhibitor, with the so called BEACON regimen with Binimetinib and Encorafnib for the E and Cetixumab for the C for patients with BRAF V600E colon cancer where it was recognized that it was EGFR overregulation that was causing the lack of response to a BRAF or a MEK inhibitor alone, which often works really well in melanoma but did not work well for patients with colorectal cancer.

Dr. Kasi 16:24 
This is what led to the approval of the triplet combination as well as a doublet that was studied in comparison to Folfiri with an antiEGFR. We now know that immunotherapy is not only approved for the MSI High, but also just a few weeks ago got approved for first-line as well.

Dr. Kasi 16:43 
We also know that double immunotherapy is an option as well. While they haven’t been studied yet head-to-head, in somebody where you are worried about response or they have a lot of burden of disease, a combination is also available. And in case reports, it seems like if a single immunotherapy didn’t work, a combination may be considered but this is something that we are studying in clinical trials.

Dr. Kasi  17:04 
And I guess one of the biggest updates in 2020, ASCO, was regarding HER-2 as a target, which is also not just relevant to colorectal cancer, but gastric cancer and breast cancer is where all this story began. There are many drugs in treatments that are now options for patients who are HER-2 positive for colorectal cancer. And it seems like a lot of the patients with HER-2 positive, it’s less than 2% when you look at it at a baseline and it tends to be more in the rectal cancer or the distal colon, but if these patients get exposed to anti- EGFR, HER-2 is also a mechanism of resistance. It’s important to retest the tumor after somebody has had anti-EGFR based therapy, the same therapy that gives you the rash.

Dr. Kasi 17:49 
Because right now in the NCCN guidelines you have Lapatinib and Trastuzumab as well as Trastuzumab, Pertuzumab, which are drugs that are specifically for the HER-2 positive colon cancer.

Dr. Kasi 18:02 
And then for the rare patients who have NTRK or ROS of FGFR or ALK or the other fusions, there are drugs either on trial or FDA approved for patients who would benefit from that. And for some of these patients, we know that if they do get a response, it tends to be durable and curative in some of these situations with patients with colorectal cancer.

Dr. Kasi 18:24 
Where are we headed? Well, it’s important to kind of know that for patients with BRAF, there are more targeted therapy options.

Dr. Kasi 18:31 
It was the initial study of Dr. Kopetz with VIC or the VIP regimen and the BEACON and now at ESMO a few weeks ago the first line Array study with ANCHOR with the same combination that was studied in second line was presented. For MSI high, we know that we have combination as well as single agent and also now single agent approved first line as well. It’s important to recognize who don’t respond to treatment because even in the data presented a few weeks ago, a third of the patients don’t respond to treatment.

Dr. Kasi 19:01 
And then for the left-sided RAS/RAF Wild Type patients, a lot of the onset colorectal cancer patients tend to be this particular type of colon cancer where with the addition of Panitumumab or Folfoxiri, these are regimens that can be used if really conversion therapy where you need massive shrinkage, those are considerations. HIPEC is something that under select centers are considerations for patients who have peritoneal only disease and was something that was being offered. There is some concerns regarding that whether or not HIPEC adds anything more than just removal of metastases. So since a year ago when this randomized trial was presented more and more surgeons will be open to removing everything but not necessarily doing HIPEC since it seems like even that alone offers patients an advantage. And then within the bucket of RAS mutations, there are several new pills that are specifically targeting the KRAS-G12C mutation. It seems like over the years, anything that we had for strategies, in terms of KRAS has not worked well. They had to be specific to one specific type of KRAS, and within KRAS one specific type of “spelling mistake”, the KRAS G12C. And not that for others, they wouldn’t be options. This is just the first proof of principle that this was possible. But I would imagine it wouldn’t be long before other inhibitors of other targets come along. They probably just chose this because of how common it is in lung cancer, and also colon cancer and pancreas cancer, and some of the other cancers as well. It is something that, again, just like the story with the BRAF imhibitor, it seems like the pill alone may not be sufficient, but the addition with the anti-EGFR or with some form of immunotherapy would be considerations.

Dr. Kasi  19:53 
And in terms of, you know, what I’ve been doing or focusing on is, again, for trials for patients with colorectal cancer, some of the trials, specifically that are involving or under the bucket of liquid biopsies or ctDNA testing,

Dr. Kasi 21:10 
We have a basket trial called the COLOMATE trial, which is looking at liquid biopsies and then assigning a particular treatment. And right now we have several that are open. One of the studies called the MOUNTAINEER study is already open at many centers, and Iowa will be another one that’s about to open the study as well.

Dr. Kasi 21:32 
But it’s kind of unique, where it’s using liquid biopsies to offer treatment options for patients with colorectal cancer. That in a nutshell, is kind of like things that we’re excited about and things that are options for our patients with colorectal cancer and what trials are present.

Dr. Kasi 21:51 
But, I think, you know, one of the key messages or things that I tell patients with colorectal cancer is the fact that I think before you know about any options for you or for your tumor in terms of treatment, I think it’s important to kind of know your tumor in terms of genetics, know what exactly makes your cancer tick in terms of whether or not you have the presence or absence of mismatch repair deficiency or microsatellite instability, versus what specific mutations are present because there’s a lot of trials, where, as opposed to trials that are for everybody, a lot of the trials are becoming options for subsets of patients with colorectal cancer, whether it’s HER-2, which is one of the exciting new targets for which we have more options in terms of antibody drug conjugates, and new pills, which have shown tremendous activity in breast cancer and gastric cancer. Now, early signals in colorectal cancer are showing similar efficacy, which again would be options. And then immunotherapy based trials, again, would look at if you have the presence or absence of MSI. So knowing that is critical. And then for the other patients as well who may benefit from immunotherapy, some of these rare patients who may have mutations that would make their tumor, hypermutated so your immune system is able to recognize them, the so called POLE mutations and stuff. Again, comprehensive testing to know as much as possible. Again, it’s doesn’t have to be any specific platform as long as it’s a comprehensive platform to test the patient for the known relevant mutations. But also, knowing about tumor mutation burden or TMB. All those things are relevant in 2020, as opposed to maybe a few years ago, it didn’t make a difference, because what were you going to do differently? But now, it’s imperative to know all of this because treatments on trial as well as off trial will be dictated by the presence or absence of these aberrations. So with that, I will stop here and focus on other questions that would be relevant to you and your group, Manju.

Manju George  24:13 
Thank you Dr. Kasi. That was wonderful. So at your place, you mainly have the COLOMATE trial, is that the main one?

Dr. Kasi 24:25 
Yeah. Also so, you know, it depends on the stage and diagnosis. So for patients with early stage colon cancer, stage II or III, we have several trials that are looking at minimal residual disease or circulating tumor DNA to see if there is the presence or absence of any cancer left behind that will guide their care. So the so called COBRA study for stage II colon cancer through the NRG platform is something that is open here. For stage II and III, we also have the BESPOKE study which is using the tumor informed assay, which is a Signatera assay for patients with colorectal cancer. In the NRG, it’s a different assay called the LUNAR assay from Guardant Health. So, different studies that are using different assays to guide care for stage II/III patients are open. For stage IV specifically, in terms of first line, we have the NRG COMMIT study which is studying MSI high tumors, whether or not they have colon with an MSI high tumor, whether it’s immunotherapy versus chemotherapy combined with immunotherapy, which would be an option alongside Bevacizumab for these patients. Right now, with the new data, it’s being revised in terms of options and arms that would be open. Again, for stage III MSI high, we have the so called ATOMIC study open, which is looking at chemotherapy in the form of FOLFOX versus FOLOFOX with Atezolizumab. Again, that’s for MSI-high tumors. And then for stage IV, specifically for BRAF V600E, we’re looking at other phase I studies that are looking at different combinations of BRAF or immunotherapy or MEK inhibitors in different iterations. The same for patients with RAS mutant tumors, specifically the KRAS-G12C, we should be opening this week. The Amgen study with KRAS-G12C, the AMG-510 that’s in conjunction with the MEK inhibitor, as well as it will have an arm for immunotherapy with the same feel as well. So starting two different combinations for the same patients who have KRAS-G12C. We’re also in the process of opening the Mirati’s KRAS G12C inhibitor as well. And that’s with the IRB at present. And then for anybody with RAS mutations or NRAS or KRAS, we have a novel drug with a CDK4/6 inhibitor with a glutaminase inhibitor. A lot of the KRAS mutant trials have something to do with CDK4/6 in some combination with another pill, like there’s a study right now through ACCRU’s platform that Dr. Kopetz is leading that is combining a CDK4/6 inhibitor with a MEK inhibitor. This one is combining a CDK4/6 inhibitor with a glutaminase inhibitor. It seems like there is more activity, at least in the preclinical setting seen in patients with KRAS mutant colorectal cancers. So that’s actually specifically looking for patients with KRAS mutant. The other trial that we have open, which is open for colorectal cancer, but it’s also open for anybody and everybody and that’s actually looking at more the mutations, not necessarily the specific cancer. So the breast cancer gene or the BRCA gene, that’s a usually a DNA repair protein. So a lot of individuals, we talked about Lynch Syndrome, which is a hereditary colon cancer syndrome, but there are also other genes that can be present, especially in anybody with young onset colorectal cancer. Actually, that trial will also take not just germline, which is if you were born with the gene, but also any tumor or even liquid biopsy results, as long as we have the gene they will provide the pill which is Rucaperib, and it is a PARP inhibitor which binds to BRCA2 and PALB2. It also has some other Fanconi Anemia or the FANCA  genes and the RAD genes. Again, these are all family of breast cancer genes. And we can share the links separately as we upload the talk, for some of these trials. Because some of these trials come and go, but this one is open right now, for anybody with any kind of cancer, including colorectal cancer, as long as they have the gene, they will get the pill on it.

Dr. Kasi 29:16 
We also have an agnostic FGFR inhibitor, which is the pemigatinib, which is approved for cholangiocarcinoma for FGFR fusion, but also it potentially may have activity for FGFR mutations. That it is also accepting anybody with colorectal cancer as long as they have an FGFR mutation or fusion. And there’s a whole laundry list of things that they would accept but again, that’s another trial which is just a pill for our patients with colorectal cancer. And then more so in the preventative space, not necessarily treatments space, the so called PACES study is combining two pills to prevent second colon cancers from happening. Again, it has a randomization to placebo because as of right now, the current standard is not doing anything except for just watch. So it’s ethically okay to have an arm. Otherwise, you wouldn’t know how much benefit these drugs provide.

Dr. Kasi  30:13 
So again, you know, as I see a patient with colorectal cancer, obviously there are colorectal cancer specific trials. But then often for somebody who’s had a lot of treatment, we look at trials that are then more in the bucket of the early phase or phase I trials. And there’s also a lot of misconception about phase I trials. And I would try to clarify that getting on a phase I trial, that main goal is safety does not necessarily mean that you’re not getting enough of a drug. And often patients are looking for phase II and phase III studies. And I would say that, right now, with all these novel drugs and precision medicine based therapies or biomarker driven therapies, often, a great drug may be sitting in a good phase I trial, and often because FDA increasingly is recognizing the value of some of these highly efficacious drugs, no longer would you have, or the need for large phase III studies and single arm phase II’s or early phase I’s that often go into a phase II are studies that would provide access to a lot of patients. So I would definitely encourage patients and caregivers as they’re looking for trials, not necessarily to discount the early phase study, because unless you talk to the oncologist or the PI who is running the study, you may or may not know how much of value it could be for that particular patient. We also now recently opened another study, which, again, for the rare patients who may have brain metastases, this one in particular, will be looking at different treatment strategies, again, in the form of targeted therapies that would be dependent on whatever was excised. So you do need the tissue from the brain to be excised. Again, fortunately, patients with colorectal cancer don’t have brain metastases, but it’s not uncommon, as they get years of treatment for them to develop metastases later. So, again, those trials are not necessarily meant for colorectal cancer, but they will take anybody with brain metastases. So it depends on the situation.

Dr. Kasi  32:27 
And with all the different options, as you can see, you know, any given patient at any given point in time may get exposed to, you know, the three different chemotherapy agents, the Bevacizumab. if they’re RAS/RAF Wild Type they’ll get the anti-EGFR in green, and then you have the TAS-102, Regorafenib, you know, that’s already, depending on the subset of patients with cancer, they already have five or six treatments that can be used one after the other after the other and potentially recycle in select patients, which means that at any given step of the way, trials would be a consideration.

Manju George 33:08 
Okay, thank you so much. I think this is a lot of information. So I would like to end with asking you one question. What is your message or advice for a newly diagnosed stage IV patient. What would it be?

Dr. Kasi 33:26 
One key consideration is & I think, Steve, and you and the group also has done at least a good job in terms of coming up with, you know, what are the basic questions that you would want to know about your tumor. So knowing your tumor in terms of whether or not you are MSI high or not, whether or not I have a BRAF mutation or not, whether or not I have a KRAS mutation or not. At least knowing the basics of what you have. And, you know, again, you don’t have to have an oncological or medical background. As you go along, understand, you know, how your tumor is the same or different compared to others. And also what treatment you’re getting. You know, at the end of the day, it’s a handful of treatments, so at least having some knowledge of what treatment you’re getting is going to be important as you understand your options now and also in the future. But, importantly, I do think it is one thing, especially with stage IV patients with metastatic colorectal cancer, and that’s something that we also highlighted in our review as well, it’s of value to at least have one consultation or opinion at a tertiary care center or an academic center because it is not infrequent that we come across situations where somebody with, we won’t go too much into it, but you know, even with metastatic stage IV cancer, like you mentioned, there are two kinds of situations. One is you could have metastatic stage IV cancer where you have metastases everywhere in your body. So obviously in that kind of situation, you’re looking at some sort of systemic therapy indefinitely. However, the other intriguing aspect or a unique situation is the so called oligo, the word oligo means few. So somebody could be oligometastatic and meaning that they have few metastases and there’s no question about the fact that they have stage IV cancer or their cancer has metastasized, whether it’s the liver or the lung, but within reason they are few in number where often we’ve partnered with our, depending on the location of the metastases, with our liver surgeons or with our thoracic surgeons, because often the rectal cancer tends to go in the lung, or our colleagues in interventional radiology who may ablate something and/or with radiation oncology, who may radiate when it comes to rectal tumors or even radiate spots that surgeons can get to, so a combination of some sort of multidisciplinary effort can potentially offer the chance at cure for these oligometastatic cancer patients. A decade ago, somebody said metastatic cancer always meant some form of chemotherapy or systemic therapy indefinitely and something locoregional, or surgery, was frowned upon. Now we know that we really need to differentiate the extent of disease at baseline and its important to kind of seek an opinion early on, because the other issue is, all these drugs that we give for colorectal cancer, they all, for example, the 5FU with the pump chemotherapy, the Irinotecan chemotherapy, the Oxaliplatin chemotherapy, they all affect the liver. So if there is any discussion or chance at getting some sort of surgery, you got to do just enough of the chemo, but not too much of it. Because at the end of the day, they need to leave some portion of healthy viable liver behind as an example. So seeking an opinion at a tertiary care facility, whichever is closest to you, I would say many, if not most, if not all of our colleagues are open to a second opinion. There’s no egos involved here. But also I think the other aspect is trials,  the opening of trials is like often each center may have trials or have access to trials that are unique to that center. So by seeking another opinion to the nearby or whatever is within reason, an academic center that is in reach to you would pretty much,I would say, double up your chances of the number of trial options like you were asking me about trials in Iowa. You know, even across the street, you know, the trials may be different. You know, even within a few hours of distance, trials that are at academic institutions may not be the same. So I would say while it’s important to help navigate trials yourself, you always need somebody from a physician side of things to be your advocate or champion to help you find trials and some of the trials, that may be opening next week or in two weeks from now or a month from now, which will be very relevant to the patient I see tomorrow in clinic, but that information may or may not be on the website or the typical platform. So nothing really replaces a physical face to face visit or right now with a COVID situation, a video visit or tele visit to help establish care. Because I do think some of this journey, simplistically speaking, is more of a marathon, not a sprint race. So as you look at your options now or seek opinions now, it may be relevant for treatment or trial that may become an option for you a year down the line. So I do think it’s imperative, especially with all the young-onset colorectal cancer or even with anybody of any age with stage IV colon cancer at the time diagnosis, it’s reasonable to potentially start. But even right now, it used to be that first-line trials were not available, but now there are several. So I would say before you even start any treatment as long as it’s not, you know, a life-threatening emergency, getting some sort of an opinion from an academic center would be of value and most centers are pretty good about getting their patients in as swiftly as possible. So that would be something that I would talk to my doctor and see. And they may have a relationship or some physicians or some way of better access to an academic center or may know of a name. So if there’s any trouble getting an appointment, somebody else may step in. So I would bring that up to my doc in terms of would they be open to a second opinion and if yes, what center do they already work with as a liaison or whatever preference for so they can work as a team in taking care of the patient.

Manju George 39:51 
So okay, so I would just like to summarize quickly. So one is like, if you’re a CRC patient, it’s important to know your biomarkers, right, first?

Dr. Kasi  40:01 
Yep.

Manju George  40:01 
And then to find out when you’re stage IV whether you’re oligometastatic and what is your metastatic spread. And if you’re oligometastatic, early on consider some other options, non-chemo options. And then when you’re on chemo, find out if you can recycle. First go through what all things that you can do, add biologics on top and then see if you can recycle and reuse some of them. And then while you’re doing all of this, keep an eye on trials, consult with your doctor, make sure to get an early second opinion in the beginning, and then keep an eye on trials, right? And then the last, and maybe the most important thing of all is like, find out some way to keep track of your tumor do genomic testing, or use liquid biopsy,  so you know, what the response to treatment is as you go through the different steps, right?

Dr. Kasi  40:50 
I would say for trials, I would say that it used to be taught that, okay, trials are meant when you use your options. That’s not necessarily the case since there are first-line trials meant for patients who have not had any treatment. There are secondline trials as well, meaning that you’ve had one treatment that did not work. There are trials that are third line, for example, our imunotherapy, with the Y-90 studies, looking for patients who have had at least two chemos, but no more than three. So again, as you look at all these trials, I would say at any step of the way, if the previous treatment is not working, or if it’s too toxic, and the discussion is, let’s switch treatments, before you switch treatments, as a patient or caregiver, my question would be before we do whatever run of the mill option that is by the books, is there a trial that is suitable for me, both here or whatever is within reach at an academic center? Because you’ll be surprised that, you know, there are trials in all these spaces now more than ever, so unless you ask you will not know.

Manju George  42:03 
Yes, yes. And I think what you spoke like, you know, when he started speaking about the trials that are available at your place, I mean, it went through the whole range, right? From people who were NED and to prevent, you know, further polyp formation to stage II to stage III to stage IV, to using, you know, already existing chemo plus something else, to using all the targeted therapies. I mean, I thought that that was like a very good representation of just in one place, what are all the options available. So it’s so important for people to go and find out what is the nearest, NCI Cancer Center or to consult with somebody, right, like early on…

Dr. Kasi  42:40 
Yeah, and also not necessarily just academic centers, you know, there are some trials, for example, from Industry and some cooperative groups that  actually are open more at community sites than academic sites, you’ll be pleasantly surprised where there are some trials that are open at community centers that some of the academic centers don’t have access to. So as I’m looking for trials for my patients, it doesn’t matter if it’s here, or if it’s at a community site, or an academic site closer to home. Bottom line is, you know, any trial can only open shop at so many places, you know, if it was simplistically speaking, a business, they can only open their business in so many shops and vendors. So by going to another place, whether it’s, you know, obviously, if you’re at a community site, or if you’re going to make the effort of going to a place it would make sense to go to an academic center, but even if you’re at the community site, don’t discount the trials that are available to you at your site, because, like I said, there are some trials that, you know, don’t necessarily need complex mechanisms that are placed at academic centers to provide that trial. And sometimes it’s sometimes faster to open a trial in a community setting. So, you know, there is going to be an overlap of trials that are available in both but more often than not, every institution will offer trials that are unique to the institution, unique to the state, unique to the cooperative groups that they’re part of, unique to the investigators who are there. Because there are some trials that I have opened here that are open everywhere in the country as part of the bigger alliance, there are some that are only open at Iowa, there are some that are only open in the Midwest, there are some that are only open under a certain company. So again, if you do go to another center, you’re pretty much at least doubling your chances of getting into a trial.

Manju George  44:47 
Okay. That makes sense. And I also wanted you to say something about, me personally, I’m sending so many people you know when there is discussion about you know how to go to for a second opinion consult, we are sending many people to you, Do you want to say something about a telehealth consult and your style of functioning. I thought that’d be useful to the people of Colontown.

Dr. Kasi 45:07 
I think the key is, you know, it is always of value as you’re seeking an opinion in terms of, you know, going back to the basics in terms of knowing what you have, in terms of your tumor, knowing your biomarkers, because then it will be a more meaningful discussion. Also, in terms of what treatments have you had. So I think that’s not just relevant for patients coming to us specifically. But I would say for anybody seeking a second opinion anywhere, I would imagine that if you have that information about what you know of your tumor and what treatments you have had, I think the time and the discussion would be more meaningful. Also, with video visits in telehealth, where is it? One thing, which is a limitation is not all states may be legally open to offering that as an option. So the opinions in those scenarios, unfortunately, would have to be face to face. But I would say increasingly, week by week, some of these things that are being updated, where some states are open to second opinions towards tele or video visit, but also remember, at the end of the day, it’s not just about the trials or a video visit, or a second opinion. The other thing is the trials, if they are going to be something that you’re going to consider would be trials that you will be able to physically go back and forth from. Now one of the trials that you mentioned, like the MOUNTAINEER study, that is one thing that actually would pay for travel as well. So again, some trials within reason are doable, even if it’s somebody who’s not close by, but for others, it is a big commitment. And, you know, no matter how you see this.

Manju George 46:24 
Yeah, yeah, and I’m kind of wondering, you know, with the COVID situation, maybe some trials, which use drugs, like pills, may become more delivered to the patient, and, you know, like, having some visits for certain screenings, etc, right?

Dr. Kasi 47:06 
But you know, the interesting thing is, till you actually go and explore the trial physically, you will never know the intricate details because sometimes they may have pills, but they may have many visits that are tied into toxicity or other blood draws, but there could be a trial that could be IV or subcutaneous injection, and may have as few visits as once every six weeks. So it is very variable based on each trial. And some of this information, unfortunately, nowadays is not out there and it also is changing as well at any phase of the study the patient signs up for. So, seeing somebody face to face, I think your nearest academic center, I don’t think there’s any replacement to that.

Manju George 47:52 
Thank you, Dr. Kasi. This has been very, very informative.

Dr. Kasi 47:55 
No, the pleasure is all mine.

Manju George  47:57 
Yeah, thank you so much for your time. And, you know, you know that we all appreciate your comments and you know,

Dr. Kasi 48:03 
I learn from you more than you learn from me.

Manju George 48:06 
Oh, I don’t think so but thank you very much. Okay, take care and bye.

Dr. Kasi  48:12 
Thank you.

Manju George  48:12 
Thank you.