Along the lines of thinking about treatment of metastatic colorectal cancer as more like a marathon, rather than a sprint; we’re thinking about 2, 3, 4, plus lines of therapy. We’ve touched upon the shared decision-making points, across moving from one line to the next.

What do we know about responses in beyond first line, and is response actually the goal, or is it stable disease, or a little bit of response? What exactly are the factors that come to mind, when you’re choosing your second-line therapy, and beyond?

 For second-line therapy, in general, we’re usually not seeing very much of a response. It ranges from the various second-line trials that we have, anywhere from 5% to 15%, sometimes upward of 20%. But that’s really optimistic. Usually, we’re seeing a very minimal response.

The one time we really need a response is if patients are symptomatic of their disease. In that situation, if they’re 

 wild type and they hadn’t used an EGFR inhibitor before, that might be a situation where I’d use an EGFR inhibitor to try to augment the response in the second line if they were really symptomatic.

For the most part, I’m continuing a VEGF inhibitor into the second line, mainly because response usually isn’t the goal. It is typically progression-free survival that we’re looking at, as well as trying to maintain some quality of life. I usually start FOLFOX [folinic acid, fluorouracil, oxaliplatin] or FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan], in the first-line setting.

In the second-line setting, usually people still have some residual peripheral neuropathy, so instead of reintroducing oxaliplatin, I typically will move to an irinotecan-based regimen. I’m most commonly using FOLFIRI [folinic acid, fluorouracil, irinotecan ] for that since I don’t have good luck mixing capecitabine and irinotecan together.

It’s weighing the risks and the benefits. If they have a nice response but are getting fatigued from chemotherapy, you can make some adjustments. You can go back to maintenance fluoropyrimidine, BEV [bevacizumab]. You can go to a single agent, to irinotecan. There are a lot of things you can do to make adjustments to help ensure the quality of treatment because you’re right, it is a marathon. We’re just trying to balance that quality and that quantity as long as we can.

Most physicians in the US prefer oxaliplatin, Dr Hubbard does. Dr Eng, you actually prefer for many patients to start with irinotecan if it’s not a triplet. Any differences? Why irinotecan first?

 Irinotecan, overall, is tolerated extremely well, except for the alopecia, which is not pleasing to many patients. They don’t want the alopecia; often our male patients ask me about the alopecia as well. Overall, they don’t have to worry about the cold toxicity, they can eat or drink whatever they want. A lot of what I do is asking the patient what their hobbies are. If they’re a surgeon, which can be problematic, a musician, if they like going hunting and they’re out there with a big gun, I would like them to feel their extremities. That would be my preference. I usually do ask them, and then they ask me, what’s the difference? I tell them the response rate’s the same, but obviously, the toxicities are different. That’s how I make the decision.

Videos

Drs Cathy Eng and Joleen M. Hubbard explain how patients with metastatic colon cancer typically respond to initial treatment and describe the factors that impact second-line treatment decisions.

Preferences for Second-Line Therapy for mCRC

Let’s discuss the whole concept of maintenance therapy. Throughout the years, a number of studies consistently show that giving chemotherapy until progression may not be the wisest decision, at least intensive chemotherapy. What do the data tell us? What do you do typically for your patients? How long do you treat them, and what type of maintenance therapy would you consider? Do you ever consider chemotherapy-free intervals, and what does that mean?

 This is something we grapple within the clinic, even today, despite having all of this evidence. The basic principle here that we follow is that we know patients will reach their point of maximum response with first-line chemotherapy, generally by about month 3 to month 4. After that, the responses tend to level off.

At the same time, as you go past month 4 on your frontline combination chemotherapy, the toxicity can build up, specifically for the oxaliplatin-based regimens. We can see worsening neuropathy, which in some cases can be disabling and cause quality-of-life issues. There’s no evidence that continuing a combination chemotherapy approach past that initial point of maximum response improves overall survival.

Right around month 4, we take a step back, and we say, “How are you doing? How are you feeling? What’s the scan showing?” If a patient has achieved some degree of benefit from that regimen, we oftentimes are thinking about peeling off that aspect of chemotherapy that’s causing the patient the greatest quality-of-life issues. If a patient is receiving oxaliplatin, that would be something that is routinely discontinued, right around month 4. Rarely do I continue it past that point, though in some rare cases I might consider it.

But additionally, there are some patients who just need a break period, from everything. Maybe it’s the travel to the cancer center, the emotional demands of coming in, they want to go on vacation, or be with family; it is also OK for that patient to take a chemotherapy holiday and take a break. It does mean that that patient is more likely to start second-line chemotherapy sooner. On the other hand, there would not be a major impact on overall survival for a person to take a break or a holiday, for a period of time.

Recommendations regarding the selection, initiation, and length of maintenance therapy to help manage cases of metastatic colon cancer.

Maintenance Therapy for Metastatic CRC

When you’re sitting with a patient, and we have moved more toward the shared decision-making, what things get discussed with the patient to help them make the right decision as you’re navigating them through the treatment options?

 It’s always a risk-vs-benefit discussion. With FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]–bevacizumab] for first line, it’s hard to argue with 2 randomized phase 3 trials showing a 4-month overall survival benefit. If it’s purely the palliative situation, we don’t need conversion, and we have a patient who says they’re concerned about adverse effects and would rather have fewer adverse effects and more interaction with family or at their job than having more adverse effects and potentially other outcomes. Those are things you always have to take into consideration. Each step of the way, we look at the risks and the benefits. When we get into second-line therapy, usually patients are still feeling good, and you can get a doublet cytotoxic and biologic in. When we start to get to third- and fourth-line therapy, that’s when we need to take a deep breath and ask, “Is this worth to continue going forward for minimal response and a small amount of survival benefit for some patients, but definitely with some toxicities?” In addition, asking what their goal is in the time they have. Each patient is different. Some patients want to try everything and push, and some opt for more comfort and quality of life. It’s all how they want to spend their time.

Every line of treatment, with every visit, you’re having that discussion with the patient.

John, do you want to add anything to that?

 It’s important to sit down with your patient on day 1 and then continue to have discussions about what’s important to that person, what they value, and what they want to be doing with their time. You must understand that, unfortunately, in most cases, we can’t cure patients with metastatic disease. We are looking to give people as great a quality of life as possible. In some cases, length of life is the primary consideration. In other cases, the primary consideration is minimizing the risk of needing to come in more frequently for IV [intravenous] fluids and minimizing toxicity related to treatments. Most preferences can change over time. We’re incorporating those discussions into our treatment decision-making. By doing that, we’re giving our patients the best care possible.

An overview of topics that oncologists should counsel patients on when working with them to select therapy to treat metastatic colon cancer.

Optimizing mCRC Treatment: Decision-Making With Patients

® titled “Personalized Approaches to Treatment of Metastatic Colorectal Cancer.” The past 12 months have been transformative in gastrointestinal oncology. Practice-changing data continue to emerge, particularly surrounding more personalized management of metastatic colorectal cancer. These are exciting times in the treatment of metastatic colorectal cancer. My name is Tony Bekaii-Saab. I’m from the Mayo Clinic in Phoenix, Arizona. Joining me in this discussion are John Strickler from the Duke Cancer Institute in Durham, North Carolina; Kanwal Raghav from The University of Texas MD Anderson Cancer Center in Houston, Texas; Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee; and Joleen Hubbard from the Mayo Clinic in freezing Rochester, Minnesota.

In today’s discussion, my colleagues and I will discuss recent data from the key clinical trials and implications for how metastatic colorectal cancer should be treated in 2021. Let’s start by discussing your approach to the initial assessment of a patient with newly diagnosed metastatic colorectal cancer. How do you decide on choices of frontline therapy? What factors or characteristics help you decide on treatment?

 The first-line chemotherapy for colorectal cancer has evolved over the past few years. Overall new patient tumor characteristics need to be balanced before I make those decisions at least for current management. In totality, molecular profiling and tumor characteristics trump most everything. We try to do next-generation sequencing and molecular profiling up front for our patients with colorectal cancer. Then there are these buckets that you recognize, and that’s how treatment follows. The most important thing is…testing where immunotherapy becomes a good first-line option. Beyond that group, if you have a…population, then your treatments are restricted to cytotoxics and anti-VEGF agents: Bevacizumab–FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], bevacizumab–FOLFIRI [5-fluorouracil, leucovorin, irinotecan hydrochloride], and bevacizumab–FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] are 3 good options. That depends on other patient characteristics. I have become a big fan of using triplet cytotoxics after the positive data from TRIBE and TRIBE2 studies, but only for patients who are robust enough...

The choice between FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] and FOLFIRI [5-fluorouracil, leucovorin, irinotecan hydrochloride] is mostly based on discussions with patients about hair loss, toxicities such as neuropathy, and certain comorbidities that could restrict the use of 1 agent over the other. Then comes the question of anti-EGFR drugs, which are the 

 wild-type group. In this group, we like to identify 2 separate groups, the BRAF and the…separately because those preferably should move toward clinical trials as early as possible. But for the remaining ones, if you’re left-sided, we try to make anti-EGFR up front if possible. These things are also dependent on how quickly we need to start treatment and how quickly we’re going to get results. If you’re a right-sided tumor, then we go more along the lines of…patients.

 You said you’re moving more toward 3-drug regimens. How do you decide on a left-sided patient who has all the good molecular genetic markers for a triplet vs an EGFR inhibitor?

 On the question of a triplet cytotoxic regimen like FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan], the favorable factor is usually bevacizumab. FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan], even though there are some data out for its feasibility, becomes extremely toxic. If you have appropriately selected your population for an anti-EGFR, if they are distal left-sided, 

 negative, then the response rates, with Cytoxan in combination with a double agent should be big enough not to warrant the extra toxicity of FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan].

FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] is best in really young individuals, possibly 

-mutant patients, or those who have an aggressive disease like peritoneal carcinomatosis. That’s where I generally use it in combination with an anti-VEGF like bevacizumab.

 Regarding the FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] combination with anti-EGFR therapy, the VOLFI trial was a small, phase 2 study, less than 100 patients. Some individuals like to consider utilizing it, but they did have 25% grade 3 or 4 diarrhea. That’s important to keep in mind. I agree with Kanwal on this. There’s a very select population that we can potentially use that for. I also tend to use bevacizumab in that setting much more with anti-EGFR in a triplet.

 Would you ever use FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] and an EGFR inhibitor? Is there any setting where you think this is a reasonable option?

 Given the high response rates, if you have a young patient with good performance status, and you need a Hail Mary to try to convert them from unresectable to resectable, that might be 1 situation for someone with a left-sided tumor where I’d consider using that. Otherwise, based on the toxicities and the lack of phase 3 data, I’m not using it routinely in a first-line setting.

 A triplet FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] is appropriate in some cases of robust, fit patients who are wanting to be aggressive. The preferred partner of TRIBE and TRIBE2 studies is bevacizumab, but in most cases, that regimen is a bit much for the average person coming in, so we need to be thoughtful about who we’re giving that to and just make sure that we’re matching the right treatments to the right person.

Experts in gastrointestinal oncology highlight their approaches to assessing patients with newly diagnosed metastatic colorectal cancer and explain the variables that factor into first-line treatment decisions.

Initial Strategies for Assessing and Treating mCRC

 Luis, let me give you a chance to opine on this as well. You’ve reflected a lot on the testing and the new medicines that are coming. What are your thoughts about the future with these agents, either alone or in combination?

 This is very important. I don’t get discouraged because there are low percentages. We have more than 225,000 new lung cancer patients this year. If you calculate that in America, we should be able to treat around 8000 patients with all the cancers together with 

The other thing I don’t understand is why our payers do not encourage testing, not only for 

 fusions but for everything, because a lot of people say these are expensive drugs. You see how much we bill for 1 cycle of chemoimmunotherapy. It’s 2 or 3 or 4 times of the cost of targeted therapy.

If I were the medical director of an insurance company, I would require that every cancer patient gets NGS [next-generation sequencing] done, because I can show that it’s going to save money. Maybe they are not interested in doing that. But that would be a cost-effective way to save money to put people on targeted therapy.

Also, the quality of life is most important, because if you’re going to be with an 

 fusion for 28 or 30 months before you progress, you save a lot of money on hospitalizations and all the other issues. That’s why we should advocate the cost-effective benefit for our patient, on top of the amazing quality of life they get with targeted therapy.

 Yeah. Mark, I’ve left you in the most difficult position. After all these smart comments, set the stage for our marching orders as we go forward. You’ve been in the lead on much of this throughout your career, driving things in lung cancer, really helping to transform the business there and educating so many of us about this. Are you excited about what’s going on here? What’s some advice you’d like to share with our audience?

Yeah. I thank my colleagues. All 4 of you gave great insight and great answers. John, the older I get, the more I take cancer very personally. For anyone on this panel, or any oncologist, if a family member—their dad, their brother—or their best friend came down with cancer, or in my case with lung cancer, the first question we would all ask is, “Did you test for 

I treat cancer as if it were a family member, and the greatest thing we can do is diagnose from oncogenic driver, because we have these highly effective therapies that work very well and work for a very long time in these patients. They’re associated with low toxicity, for the most part. It has rung true in multiple molecular alterations in lung cancer. 

Hopefully we’ll discover more of them. We’re beginning to understand that, yes, when resistance occurs, we have a second plan. We learned that early in lung cancer with the T790M story of 

, and we’re going to learn it in other cancers too. My message to community oncologists is not to let testing exhaustion get the best of you, because if all you’re going to do is find 1 patient, you’re going to make such a huge difference in the survival outcome.

Remember, every patient is connected to a family and a social situation that’s important to them, and it’s a little self-serving. These people get better, and you’re responsible for doing that. Don’t let any patient go without understanding the DNA and the RNA of that patient.

What a great close. Don’t miss a chance to change somebody’s life—that is so apt. Listen, all of you—you’ve been just fabulous, and I want to thank you all for joining us today and sharing all your good insights. For the audience out there, on behalf of all of the panel, I really hope you feel that this 

® has been useful and informative and will influence your practice. 

Future of NTRK Fusions

 Let’s wrap up our whole discussion. What a great discussion, and everything that you all have brought to this will be valuable to all who listen in. Tony, give me a sense of what you think are the challenges going forward for 

 The biggest challenge is the obvious. These are rare, incredibly rare, and the rarity becomes even more problematic when you’re not consistent in looking for them. This means for something that’s 1 in 100 or 1 in 1000, if you just randomly pick every other patient that comes to your clinic and send for testing, then you are 1 in 100,000 just by randomness alone.

One thing we have to keep in mind is that if you a have a fusion, you’re going to have a great response, for a patient who may not do as well on chemotherapy. For some patients, this is 1 of the longest reported responses so far. There are many that are ongoing. It is now almost 4 years. We know that if patients respond, they can respond pretty well. So we want to find them.

This is the same thing with MSI [microsatellite instability] high and the same thing, frankly, with a lot of these alterations that are at the level of 1% or 2%. We have to be consistent. We have to look for them consistently—that’s the biggest challenge.

Luis was talking about how these next-generation agents that are looking, essentially, at patients who fail because of the development of the mutation. Now we’re looking at even a smaller subgroup of patients and how to salvage them and make a difference in those patients. That also brings the question of those who are intrinsically resistant because they have the core mutation, and how do we actually put all these together? Frankly, it’s not just multidisciplinary collaboration, it’s also multispecialty collaboration.

We can’t do it in the GI [gastrointestinal] space or in just the lung or saliva. So how do we bring everyone together to essentially work on this? That’s 1 of the challenges. The other challenge is, of course, testing.

We heard a little about IHC [immunohistochemistry], FISH [fluorescence in situ hybridization], RNA for fusions. DNA-based testing is problematic because it may miss 25% or 30%, and we know that the most commonly used 1 in clinic is actually DNA-based genomic testing. You’re missing on some of these patients—30% of a very small percentage is problematic, so the DNA-RNA hybrid assay is probably the best, but at the same time it’s the most costly and takes a long time.

IHC and FISH are useful, but again, how many patients are you going to test for IHC and FISH to find 1 patient? They’re not costly. IHC is highly sensitive and specific and requires 1 unstained slide, but you’re wasting a slide, and you may be wasting time when you need to find a lot of other alterations.

If we can find a better way to do this DNA-RNA, have sequencing more efficient or faster so we can give the answer to our patients, and rely more on these liquid-based biopsies to find them better, that would actually be the best bet to continue to move these things forward and eliminate some of these barriers that are prohibiting us from finding these patients, because they do better.

 Jyoti, maybe you could comment for me. I hear so many comments from community oncologists and the like who are frustrated by the concept of raw molecular profiling, and they’re like, “I never find anything.” They get tired of looking because they don’t see much value in it. What’s your counsel to somebody who’s having that feeling?

 Sure. These drugs and these targets certainly feel like unicorns, but if you don’t look, you’ll never find them. They radically change the outcome for these patients, their ability to get back to life, the improvements in performance status, and the rapid diminution of symptoms. It’s really remarkable.

Certainly just at the beginning of this COVID-19 [coronavirus disease 2019] crisis, we believe we just had a patient with what looked like horrific disease, and we found out she had an 

 fusion before we all went in to hunker down. The entire team was ecstatic and so happy for her. She’s already feeling a lot better.

The point is, even if it’s 1% in common cancers, that adds up to a lot of people every year. These uncommon cancers in which the fusions are pathognomonic, certainly that’s easy, that’s knee-jerk. But taking the time to individualize for each patient, developing the right plan, takes discipline, as you mentioned, but it also takes moving away from what we think a patient with an 

 fusion should look like. It can occur sporadically in anyone with colon cancer, pancreatic cancer, or lung cancer. You just need to look.

As the cost of testing goes down, that barrier is changing. The ability for us to look across multiple fusions and multiple mutations is now backed by better and better evidence. Again, that barrier should be less, and we should really push our systems to make that cleaner, to rely on less tissue, and to get answers faster for our patients.

 Yeah, and I know this whole wave of precision medicine has got it to where most insurance is covering these tests with CMS [Centers for Medicare & Medicaid Services] support. I think about how many Chem-20 tests and how many screening CT [computed tomography] scans I’ve done over my career where I got nothing back. It’s normal, or it’s negative, yet that hasn’t slowed me down from ordering those Chem-20s and the CT scans. I wonder if that’s the way we should be thinking about this.

Shubham, why don’t you give us your thoughts on this issue of testing and impact on patients?

 As Tony and Jyoti said, if we don’t test them, we won’t find them. So testing is important, especially where you can really find it. Right now, at least for these fusions, you really want to find these fusions, otherwise you might miss them. You might get false negatives. So RNA-Seq is a very important factor in this. As Tony was saying, we don’t catch all these on DNA or RNA-Seq.

It’s still the missing part that can really make it robust. This is because the sensitivity and specificity of RNA-Seq is far better, and we can really find that. When you’re looking at a needle in the haystack, you want to find that needle; you don’t want to miss it.

The second thing is, once you pick out in these patients, especially with these rare tumors—as I said, the responses and everything are very gratifying, obviously for patients but also for the treating physicians when you see these patients do better for a long period of time.

 Yeah, and to add to what you just said, RNA-Seq is important. It’s important for you to understand where your test is going, where your sample is going, and that your shop is doing the appropriate testing in support of that. Is that fair enough?

Challenges for TRK Fusion–Targeting Agents

 Luis, just to let you have the last word on this, as with many of these agents, resistance is emerging in 

 fusion-positive cancers. Could you talk a little about what’s going on in that space to deal with those people who are progressing on these drugs?

 This is a really fascinating story, because as Mark mentioned before, we have broken several paradigms in drug development.

Normally we develop 1 drug, then we wait 3 or 4 years, and then we develop the next 1. This was amazing, and that’s why in 2016 it was not a surprise that they already published the first 2 resistant mutations. For me, it’s very easy to remember, because there’s a road 595 nearby. There is G595, and G667 looked very similar arrangement to a lot of the drugs in development.

But the thing is, the reason we have to give a lot of credit to Alexander Drilon and all these people involved, is that in 2016 we already knew the resistance. To go back a little, when you develop resistance to a drug, the resistance can be on target and it can be off target. In the case of 

, the resistance is so far on target, meaning that it is a mutation in the 

 tyrosine kinase that is caused by amino acid substitution. That originated in the binding of larotrectinib and entrectinib. This mutation essentially it doesn’t happen anymore.

In 2016 they discovered the first 2 resistance mutations in vitro. In 2017 Alex Drilon had a chance to put the first 2 patients who had failed larotrectinib in treatment with the drug LOXO-195, which is now called selitrectinib.

We already have 2 patients treated, 1 with colon cancer who responded for many months and a patient with a salivary gland who was unfortunately a baby. She responded for, I think, 6 to 8 months, and finally developed resistance again. But since that time, LOXO-195, or selitrectinib, is accruing patients who have resistant mutations, and there are several other resistant mutations that have developed.

This is a very similar story with what we have seen through 

 fusions in developing resistant mutations. We are also really lucky that we have other the drugs. We have 3 compounds more that are in vitro. They have shown that they can rescue patients who have failed. The second is repotrectinib. Repotrectinib is the 1 that was called TPX-0005.

Repotrectinib is effective against ROS2—that’s what we are accruing now nationwide for ROS or NTRK failures. But repotrectinib already has a preliminary report of patients who have responded after they have failed larotrectinib. The other drug is called DS-6051b, from Japan. That’s a drug that in vitro shows benefit, but in vivo there is at least 1 report already—it was a year ago—that a patient with thyroid cancer already has responded.

The last drug is a drug from Ono Pharmaceutical Co, Ltd, that in vitro seems to have some efficacy, but in the clinical arena we haven’t seen any publications yet.

 It is great to know that these things are on the way and being developed. I was just thinking as you were describing all that, that it requires us to collaborate. No one center can do these centers because of the frequency or the rareness of this mutation and these fusions. It really is encouraging to see everybody working together to get that.

Acquired Resistance in TRK Fusion-Positive Cancers

: Jyoti, I couldn’t believe it when it happened, but there’s a second drug approved, entrectinib, and it’s basically the same space. Maybe you could give us that big picture about if it is a different mechanism, or why would you decide one versus the other?

:Sure. Larotrectinib is so well tolerated that we see patients getting back to function, and we’ve seen long duration of responses. When entrectinib was approved, it added another option for our patients. Entrectinib is a little bit different in that it has activity against a number of kinases. We know that there is also 

 activity, and so it’s been actually approved for both kinases.

For entrectinib, the earlier trials were based on a number of basket trials as well as a pediatric study, and the number of patients with CNS [central nervous system] metastases was a little bit higher. Perhaps there are more data there, particularly for those of us that deal with lung cancer, in which we see patients with 

 disease and translocations who have a proclivity for brain metastases. That figures into our rubric of putting these drugs together.

I would say that the clinical activity profile, to me, is functionally pretty similar. The total number of patients that we see who have been treated across these trials is very small and limited. Suffice to say, there are more patients with CNS metastases treated with entrectinib, so perhaps a little greater experience there.

The toxicity might be a little bit of a different story, a little bit more fatigue with entrectinib, and some weight gain, at least in my experience. Patients have had a little bit harder time with some of these low-grade toxicities. But again, for someone with known CNS metastases, that may be a way to tease these out. But again, these are small-number studies looking at different pockets of patients, 1 larger basket as opposed to subgroup analysis of some smaller ones.

:Yeah, that’s very insightful. Shubham, have you used this drug at all, entrectinib, and is it equally active across all of the 3 subtypes?

:Yes. So I think it does the same thing, just as Jyoti said, so it does the 

 for rearrangements. I think it’s fairly similar. Most of my experience has been more with larotrectinib than entrectinib, but I think…the data seem to be fairly similar. Just as Jyoti pointed out, brain metastases and everything, they looked at that, so we have larotrectinib data with brain metastases also.

Approaching Treatment for TRK Fusion–Positive Cancers 

:Tony, our friend Jordan Berlin published some work at ASCO GI [American Society of Clinical Oncology/The Gastrointestinal Cancers Symposium] or has an abstract for this ASCO about 

 fusions in GI [gastrointestinal] cancers. Have you had a chance to take a peek at that, or have any sense of what that’s going to show?

:I think it was presented at ASCO GI. There may be an update coming at ASCO [American Society for Clinical Oncology Annual Meeting] 2020 as well. There were very few patients with GI cancers, primarily colorectal cancer. There were a couple of cholangiocarcinoma, pancreas, and appendix cases. I think there was 1 liver, as well. Overall, what was seen in the general population both in terms of efficacy as well as toxicity data were some remarkable responses.

You see some durable responses, again, very similar. The median overall survival was around 2.5 years or so. But with a small sample size it’s very difficult to have a very heterogenous group and a very small subgroup of patients. It’s very difficult to say whether it’s standard, individually, for the different tumors. Those patients respond, and they respond deep. The responses tend to be durable.

I think that’s the main message. So when you separate the gastrointestinal cancers from the overall group, you still see about the same. It is possible that there is a differential response, if you have salivary gland or maybe a lung cancer, or perhaps a less pretreated tumor, that you may actually see a deeper and more prolonged response. Of course, I think for the experience, as Luis put it, it’s too early to tell at this point of time whether there may be variations dependent on the site of origin.

But overall, I think for the GI cancers, we’re seeing very similar trends in terms of the responses, the durability, and their depth.

:Mark, maybe let’s drill down on the all-important toxicity. We really haven’t focused on that at all. I think you mentioned earlier in the program about some of the specific toxicities. Can you give us a high-level look? Then I’ll ask others to chime in about toxicity.

With these very targeted agents, we’re all getting used to looking at the grade 3 or 4 columns with the 0s or 1s, which is great. When you look at this particular agent, actually the most common toxicity—all of which was grade 3 or less—was an alteration in either ALT [alanine aminotransferase] or AST [aspartate aminotransferase], with most of them being grade 1, to be honest. Fatigue, some GI toxicities, as well as dizziness, are common. But surprisingly there can also be some anemia, so some myelosuppression there.

Other GI toxicities include diarrhea, which we can see with many of the TKIs [tyrosine kinase inhibitors]. There can also be a low rate of fever, or some arthralgias. Weight gain was another one that stood out to me, as well as headache. But again, if you start to look at the grade 3 or 4 columns, it’s very uncommon to be either severe or life-threatening. Most of these end up in the grade 1 column and are manageable.

:The one I come back to all the time is neurotoxicity, and I think you mentioned that as well. When you think about chronic therapy, cumulative toxicities, have others experienced patients with the neurotoxicity or have any issues that you think should be brought out during this discussion?

: Normally, just as Mark said, these patients tolerate this drug well, even with chronic therapy. They’re not like some of the other drugs that, when you go to chronic therapy, grade 2 diarrhea is not grade 2 diarrhea. If you’re getting consistent grade 2 diarrhea, that’s not good—that’s impeding the quality of life. Grade 2 fatigue is impeding of quality of life. It’s pretty bad.

So what I’m saying is we’re trying to really look at these chronic toxicities, but as far as it comes to these drugs, in my experience they have been mostly fairly mild. So for toxicity, just as Mark said, there can be some fatigue. But normally for even the chronic therapy patients, they have done fairly well.

Some diarrhea has been easily controlled. The neurotoxicities are very interesting. It’s actually dizziness. In most of the studies we’ve done a neuro exam and everything, but that’s what we see. It’s more a loss of balance than the classic neuropathy. Some patients do experience dizziness, and it could be sometimes bad enough that they might need to use something to walk, such as a cane or something, especially if they’re older.

TRK Inhibitor in GI Cancers: Adverse Effect Profile

 Luis, let me shift to you a second and drill down more about the tumor types. You mentioned them earlier, but let’s go through them again. Were there certain tumors that were more prevalent? Were there certain tumor types where there was more benefit seen?

 Yes. In 2018, when Alexander Drilon published in the 

—Mark just mentioned the paper—there were only 55 patients and 17 tumors. At that time, I remember, I was lucky to be part of that publication. We didn’t have a specific list of the response rate of the tumor, but it probably didn’t matter because there were very few tumors. But now that David Hong has published in 

 this year, we have expanded the number of patients. Now we have 155 patients, so we can at least start to see what the response is for certain tumors. For example, these are tumors that are very enriched with 

I’d never seen a fibrous sarcoma—these are tumors in kids. For soft-tissue sarcomas, thyroid cancers, we have responses that average out to 80% to 100%. What is interesting to me in our business is that the responses for lung cancer and breast cancer are a little lower, maybe 75%, but also the number of patients are very old. There are only 10 to 15 patients with lung and breast cancer, and for pancreatic cancer it’s the lowest response, around 43%. But there are only 2 or 3 patients. I’m not sure we are ready to say the real response based on tumor type. It probably doesn’t matter because we are very lucky that the average response is high among the tumors.

But with time, as more patients are accruing and we have more of this information, we are going to be certain of what is the real chance of response for all these tumors.

 Yeah. I always think these tumors that are messy or that have multiple drivers respond less than the ones that are more driven by, perhaps, 1 gene. Shub, why don’t you take us through quickly? I want to go through a few studies with everybody, including the pooled analysis that was published in 

 Great. That’s what Luis was talking about. This is 1 of my colleagues, David Hong. We enrolled a number of patients on the trial as a group. Essentially the pooled analysis was for the phase 1 trial, which was an adult population. Then there was a phase 1/2, which was a pediatric population. And a phase 2 trial, which was an adolescent and adult trial. There were 3 trials that were pooled together, as Luis said—about 156 patients.

The interesting thing was that criteria, if you really look at it as you’re pooling, was 1 month or older. The cutoff was 1 month, so you had to be greater than 1 month old for enrollment on the pediatric trial. These patients had received some type of standard therapy that was previously available, so they were treated as if it was previously available. The response rate was 79%, the CR [complete response] rate was about 16%, and 63% of patients had a partial response.

Interestingly, as we said, the median duration of response was about 35.2 months, so that’s almost 3 years, and the progression-free survival was about 28 months. The amazing thing was the median overall for these tumors, which were advanced, was about 44 months. It’s amazing—that’s almost 4 years for these patients.

As I said, I’ve treated a number of these patients, and it’s very gratifying when they get the response. First, it improves their performance status. Quality of life is improved, and obviously their improvement of overall survival. They are very interesting pooled data.

 Yeah. Jyoti, Dr Patel, please give us a little review of what’s going on in brain metastases. Do these drugs work in that setting?

 Sure. In the larotrectinib trials, a smaller number of patients were enrolled. If we look across the gamut, I think most patients who were enrolled were those with CNS [central nervous system] primary tumors. There were a minority of other cancers, such as lung cancer, which have a proclivity for the CNS metastases. But in those patients, 14 patients total, the response rate was good. It was about 55% and varied a little between histologic type.

This is 1 of the situations where CNS response is a little more difficult to quantitate. It’s probably similar to pancreatic cancer response, for example, where we don’t see those really robust response rates primarily because of prior treatment there or lesions that can be target lesions but had received prior treatment. So it’s a multitude of factors.

In this trial, what we see is that patients do respond. But more important, there was freedom from CNS progression and long duration of response. You’re preventing other disease, and this is really where you see the benefit. Certainly larotrectinib has an active CNS profile.

Efficacy of TRK Inhibitors

 We’re going to shift gears to a very specific set of data around the clinical experience with the TRK inhibitors. Tony, we’ve tagged you to start with a fairly obscure abstract that just came out around biliary cancer. I know it’s a disease you like discussing. Talk about the recent ASCO GI [American Society for Clinical Oncology Gastrointestinal Cancers Symposium] meeting, and what that showed in biliary tract cancers.

 To focus on the gist of it, this was primarily focused on IHC [immunohistochemistry], but it also had NGS [next-generation sequencing] confirmation of the IFC [integrated fluidic circuit]. It just shows that there is a relative concordance between the 2, the IHC and the NGS. Although, as we’ve heard, we all favor an expanded genomic sequencing because we’re looking for a lot more than just the 1, at least in specific tumors such as biliary cancer, where 

 is relevant. We just had an FGFR agent approved for 

 fusions. We have IDH alterations, we have 

 [human epidermal growth factor receptor 2] amplifications.

We want to have the full gamut, not just 

 fusions. What this study mostly shows is that these 

 fusions in biliary cancer are present in about 0.7% of all patients, and that aligns with the rarity of these fusions, which is pretty consistent for most cancers. We know some cancers have these fusions at a much higher rate, but in GI [gastrointestinal] malignancies, and others as well, the 0.7% seems to be consistent, and that’s pretty much the gist of this. This confirms the rarity of these fusions in a rare tumor like this.

Biliary tract for us is a target-rich place, but it’s about the same as we’re seeing in other cancers as well.

 Yes. If you find it, you’re going to go after it, because these tend to be driver mutations, and the responses from the study look pretty interesting.

 Mark, we’ve tagged you with setting the stage for larotrectinib, along with its pathway and eventual approval. Set the stage for us about the trials, the inclusion criteria, and how that went.

 Yeah. The original trial that led to the FDA approval was a trial that selected prospectively patients that were 

-fusion positive. It was actually a combination of 3 different studies, a phase 1 study in the pediatric population, a phase 1/2 in the adult population, and then a phase 2 study that involved both adolescents and adults with 

There were 17 different cancers that were included in this. There were only 4 patients with lung cancer. Talking about the bile tract, I think there were a couple of patients with biliary cancer in this. It was fascinating that patients ranged in age from 4 months to 76 years. The interesting thing is that the response rate objective by independent radiological review was 75%, so the vast majority of patients responded. They had a couple of patients who were early progressors, and it’s not clear they were true positives. There were some issues about the testing that was done.

They also had a patient that progressed early that had received a prior 

 drug and had a resistance mutation, so that patient would not have been expected to respond in this particular setting. It was remarkable in the sense that no patient had the drug discontinued because of toxicity, so it was very well tolerated. There were very few grade 3 or 4 adverse events. Mostly they were grade 1 or 2, so it was the best of both situations. In the most recent update of this—correct me if I’m wrong, but I’m not quite sure the median duration of response has been reached at this point.

It’s the second drug after the pembrolizumab MSI [microsatellite instability]–high indication that was tumor agnostic but linked to a molecular alteration regardless of pathology. It’s an important step in how we think about cancer and get drugs approved.

 As another member of the panel who graduated from fellowship in a year beginning in 

, I remember being scolded for suggesting that we wouldn’t need phase 3 randomized trials if the benefit was obvious and that it would transform drug development. Even though I got beat up pretty bad for saying, “No, you’re wrong,” back then, I’m so pleased this is the way it’s going. Comment a little about how this has changed our whole perspectives of cancer and drug design.

 It’s been fascinating. John, you may be the only 1 on the call who remembers a gentleman named Joel Tepper, a radiation oncologist at the University of North Carolina. He would say, “I’d like to do a phase 3 trial that required only 50 patients.”

It was so big that he didn’t need 1000 patients to get the benefit. But again, the larotrectinib indication is a growing list of drugs that should be approved for these molecular subsets of patients that can be clearly defined. In lung cancer, we have the EGFR and ALK experience, where we actually went through a number of randomized trials to show that when you have a target that’s targetable with a targeted therapy, either an EGFR or an ALK drug, it’s better than chemotherapy.

 mutation? Do we have to do it for every single molecular category that we have to prove that it’s better than platinum? Why are we in love with platinum-based therapy in this setting if you have a target where it’s driving the cancer? With the targeted therapy, all the response rates are north of 50%, and the durability is 3 to 4 times longer than we see with chemotherapy.

 This wouldn’t be feasible with something so rare to randomize it against something.

 To me, the wisdom and the flexibility of the FDA has been terrific in this space.

Early Development of TRK Inhibitors

Let me say in closing for this session, I hear a lot of people complain about their molecular reports that come back, they don't understand how to incorporate that and interpret it. A favorite study we ran at Medstar Georgetown University Hospital was an eye-tracking experiment, because academic oncologists kept saying, “Don't tell me what drugs are related.” They wanted to see the genes or the fusions, and they'll do the reporting. Whereas community oncologists traditionally have said, “I don't want to know the genes. Just tell me what drug to give.”

When we did eye-tracking experiments we showed academic and community oncologists the report. Guess where everyone's eyes went as soon as they showed it? It was right to the drugs, and only then people would go back and reconfirm with that. I think that put our partner companies that do molecular profiling on the hot seat for some of the recommendations they were making with therapies. It was interesting to watch that tighten up over time. Tony, give me a sense of what your favorite type of report is. Do you want the genes, do you want to know the drugs, or you want both?

I primarily want to know the genes. I frankly find the drug listing a bit random sometimes for most of the drugs. We're looking for the drug genes that are relevant to the disease. If they're relevant, then we know we have to target them. I don't care what's on the listing.

On the other hand, a lot of the other background noise can actually end up detrimental in some ways. This is because I've seen patients with a random mutation, there was a case report that links it to everolimus, and then the physician wrote everolimus before even sending the patient to consider a clinical trial that may or may not be relevant for that tissue.

I find that very problematic. Linking it to clinical trials is very useful, and that does help. It helps especially when we have driver mutations or driver alterations that are targetable. By the way, I look at the variant of nonsignificance, as well, and what time they graduate to normal significance, and they do. Essentially, some of the 

 alterations of unknown significance have, in my clinic, initiated with some dramatic responses to FOLFIRI [leucovorin calcium, 5-fluorouracil, and irinotecan] or FOLFOX [leucovorin calcium, 5-fluorouracil and oxaliplatin].

 Yes, sometimes that little tiny pulmonary nodule is actually a met [metastasis]. Mark, any thoughts?

 I struggle a lot with some of the reports that we see. I agree with Tony, I'd rather see which genes are altered and how they're altered because I know what to do once you tell me what's going on with the DNA or the RNA. We had a recent case at our center where a patient was sent for a second opinion on a Guardant Health assay. He had a 

 mutation, and not a fusion. But he got started on entrectinib because the report said 

entrectinib, not making the distinction between the point mutation and the fusion.

The payer from Blue Cross Blue Shield missed it.

Yes, or wherever he was from, but I agree with Tony. Sometimes the reports are very damaging, so I think we have to be aware of that and educate our community doctors about these types of things. I get several calls a month about, “How do you interpret this report, or that report, what should I do?” It's good that they should be calling us to get the information.

You have to remember, though, that we are very focused, and it would be difficult if we had to know everything for every disease.

The nice thing about our center, too, is we do have a twice-a-month molecular tumor board. I'm sure others have it, too. We discuss a lot of these things in the tumor board, so that's very helpful as well.

I think the main point I want to leave us with is it's OK not to know. We're all learning. If you're looking at something that you're not sure of, you should check on it. There are ways to do that. Any other comments?

 One last comment. Looking at the drugs, a lot of the time there are 2 things out there. Let's say we’re talking about a 

 G13 mutation for pancreatic cancer. For the longest time, 1 of the NGS [next-generation sequencing] companies that we use all over has listed a MEK inhibitor for it. You've seen it, I've seen it, and we've seen it. We know what the response is. From our side it's an educational perspective, exactly as Mark said.

Then the second thing is the co-mutation when it comes up, not with 

 mutation and a KRAS, or something that is a co-mutation in which you could give a more of an antibody-targeted therapy, not a small molecule antibody target, it's not going to work in that. So I think they also list out, these are the 5 mutations, these are the 5 drugs you can give them. Sometimes that leads to the thought of what if I combine A, B, C, and D? We've seen that, too.

There's a lot of education needed on that. I really think the focus should be on the genes, and especially what Tony is saying because it doesn't mean that therapies don't exist, it just means that they really haven't looked at it. It's just not been that well described in the database.

There are a lot of little points in the report, and the reports are around 30 pages. Sometimes that can lead to things getting lost. That's the other thing with some of these NGS reports—they just go pages and pages. How many people look at more than the first 2 pages? Because some of the other things, nuances maybe hidden deep inside; that's the other issue.

 I want to say that there is no perfect report, because for us, we only practice 1 tumor, so it's very easy to know. Actually, I'm very excited with the genes because we have been discovering new genes, things like that. But I will mention I passed my boards, and in CML [chronic myeloid leukemia], I just discovered it's 4 or 5 lines now of TKIs [tyrosine kinase inhibitors], with a lot of names and resistant mutations.

I guess it's very hard for our community oncologists or general oncologists to know all of this. There is 1 platform where they mention the drug, but when you click there, you go to a link that includes the original study. You can not only educate yourself, but there is also corroboration that this is not a fluke. So if it's something very important or more serious that you can evaluate and take a more important suggestion in that case.

That's one of the complexities of the simple gene predicting for a response that ends up being the gist of the report. For example, as Shubham just mentioned, in colorectal cancer and I'm assuming in all cancers, if you have a 

 amplification, 2 things happen. One, you're not going to respond to the EGFR inhibitor. Two, you're not going to respond as well to the 

-targeted strategy that's essentially in the checkbox. That's unfortunate, because then at the end of the day it's contraindicated, meaning it's not going to work for the patient. You may have to go through a million hoops to get the patient on the study. I also mentioned the rare alterations that have a case report here and there. I'm not disagreeing with the fact that it's OK to have some recommendations that are there.

The problem is that many of those are very random, and they're probably generated by a computer listing that instructs, “If you have this, you go to this drug,” without looking at the global picture. That picture gets much more complicated now that we find a lot of these co-occurrences, some driver mutations, some mutations that actually drive resistance when you have a fusion or an amplification present.

I think the story is so complex now, it's much more complex, that I really want to have access to the gene. If I want to have access to understanding what all these co-alterations are doing together, I want a much more comprehensive type of report that tells me, “Wait a second, you shouldn't use this. Although the amplification is there, watch out for the mutation that's telling you that this will not work.”

We're all very used to if we get a funny radiology report, CT scan report, we'll either call up or go down to talk to the radiologist and say, “What do you mean with this?” I think we should treat these types of reports the same way and go to the source. We should apply good clinical judgment to the decision-making on the therapeutics.

John, I have one last point. Also these reports don’t make a distinction between tumor types. So as we know, if you target the 

 G12C mutation in lung cancer, you will see that it is very different than for colorectal cancer.

We know these differences, so it's really more of a push toward comprehensive NGS reports to get better on their algorithms they use to report this out. This is because it's very tumor-specific as well. So it's more of a challenge toward them. Obviously, it's very hard in the community to make sense of all this.

I think if they get their act together it might also help out a little bit more with the community oncologists getting the right therapeutics to the right patient. That's what it's about.

OK, we'll let that be the last word for that discussion.

Advice for Interpreting NGS Reports

Dr Pant, I want you to take us through this issue of when more than 1 target is found. As we talked about this, this is more common in the GI [gastrointestinal] cancer space. But how do you prioritize this? I'll be very interested to get some feedback from our lung cancer colleagues after your comments. How do you decide when you hit the gold mine, and you have a bunch of different targets to play with?

First, I wanted to add onto Tony's comment about when we are looking at somatic mutations. My patients say, “Of all these mutations, why can't you target it? I've got this thing called 

Some of them are drivers, but then you get on these NGS [next-generation sequencing] reports, and you get a whole host of passenger mutations, which are not the driver mutations. That's exactly how I explain it to my patients. You have the driver and you have the passengers. If you take out the passengers, that's not going to stop the bus. That's one of the ways to look at how to interpret these NGS reports because we get a lot of referrals about 

Tanios S. Bekaii-Saab, MD, Mayo Clinic

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