Round 1—Targeted Therapy in Marrow-Compromised Patients

Watch Round 2 Next Here!

Jonathan Mizrahi, MD: We're going to start Round 1 of our debates here, talking about the role of these targeted therapies in patients with myelosuppression. So first we're going to have Dr Chakrabarti, who's going to talk about it being a routine addition, and then we'll have Dr Biachi explaining how it would be an addition of, I think, last resort is how we're wording it. So, Dr Chakrabarti. 

Sakti Chakrabarti, MBBS, MD: Good morning and welcome. So the hardest part is to make sure the slides work. Let's see. Okay. Alright. So I do use targeted therapy in the third-line setting, preferably frequently. I'll explain why I preferentially frequent it, but let me step back a little bit and explain the rationale for using an antiangiogenic agent in the third-line setting. So, we are familiar with this paradigm. First line, we generally do FOLFOX plus the biologic. I like that because with FOLFOX, people don't lose hair and all that. So most people like that. So I think 90% of US oncologists will use FOLFOX in the first-line setting, and then we move on to fall theory or something similar in the second-line setting with or without biologic, depending upon the circumstances and the biomarkers and all that. Now, why an antiangiogenic agent in the third line? Because these patients have received chemotherapy for years, some of them over 2 years. 
So bone marrow is tired, is beaten up with all that chemotherapy over and over and over. That's number one. Secondly, patients are tired of coming to the cancer center and trying to find a spot in the infusion center, and they have to carry this pump for 2 days. If you talk to the people, it's not always easy. So that's another advantage. You can get rid of the pump. You can get rid of coming to the cancer center, infusion center, and poking and prodding and all that. That's why I use one of the antiangiogenic agents, which has almost no bone marrow toxicities whatsoever. And why is that? Because, okay, so when you are giving frequent or something similar, you are buying some time. You are keeping the cancer under control for a few months—3 months, 6 months, or whatever it is—and then the bone marrow recovers. 

Then you can use another chemotherapy in the fourth line. I tell you, often I use oxaliplatin again because a lot of these patients did not actually progress on oxaliplatin. We stopped oxaliplatin because of neuropathy, and now, in 2 to 3 years, neuropathy has become better, and then we can put them back on oxaliplatin-based chemotherapy or other chemotherapies because, now, bone marrow has kind of recovered, and people are feeling somewhat better; their quality of life has improved. Basically, by giving a nonchemotherapy in the third-line setting, you are setting them up for an effective fourth-line treatment, whatever it is you choose. See, there is a principle I think we have been talking about over and over, that for metastatic colorectal cancer patients. You ought to expose them to all effective treatments and do it in such a sequence so that they can go through all these, because chemotherapy, back-to-back to back-to-back. I have seen particularly older people, their counts crash, they get neutropenia, get a neutropenic fever, get admitted to the hospital, and then start talking about hospice. These kinds of situations, I think, can be averted if we don't do chemotherapy in the third-line setting. So that's the rationale behind the sequence in which I prefer. Now. 

So let's talk a little bit about fruquintinib. Fruquintinib is a unique antiangiogenic agent because it is very targeted to VEGF 1, 2, and 3. It has very little, almost no, off-target activities. In a fun fact, there have been more than 20 antiangiogenic agents have been tested in more than 40 clinical trials, and most of them failed because those molecules have so off-target activities. So they're not only binding to the VEGF receptors, they're binding to other receptors and causing a lot of toxicities. So those agents never came to routine patient care. But fruquintinib being such a specific inhibitor of VEGF 1, 2, 3, that it has very little off-target activity, and that's why I think its tolerability profile is so good. 

So these are all theoretical considerations and biology and all that is good. But then, what is the clinical data? We're all clinicians, so we have to see clinical data before we believe it, right? So there were two studies. One is FRESCO, original. FRESCO was a Chinese study, but FRESCO-2 was a Western study. So I'll talk to you about the FRESCO-2 because FDA based their decision looking at the FRESCO-2 data. So FRESCO-2 is a very good and variety phase three study where patients who progress through multiple lines of therapy. And I remind you, FRESCO-2, most patients who are fourth-line patients have progressed through three lines of treatment. So these are highly refractory patients. A few years ago, we were talking about hospice for these kinds of patients. These patients were divided into two groups. One group got fruquintinib and best supportive care, and the other group got a placebo and best supportive care. 

Another thing I would want to point out is that these were not easy patients with good biology because a large, over 70% of these patients, had a KRAS mutation. Over 70% of these patients had liver metastasis. So these are all bad actors. All these patients were enrolled in the FRESCO-2 study. If we look at the result, the median survival actually improved remarkably with a very significant P value, as you can see in this curve. Then, if you quantify it as 7.4 versus 4.8 months, that doesn't sound like much. But then this is a fourth-line patient. These people have progressed through three lines of treatment. However, if you go to FRESCO, the original Chinese study was mostly a third-line study. The other thing is in the FRESCO study; most patients in the original FRESCO study did not get bevacizumab because, in China, bevacizumab is not commonly used for whatever reason. So now in FRESCO, they showed that in a fourth-line setting, it actually improves overall survival significantly. So I think the FDA has done something very smart. They have approved it in the third-line setting, which means that it'll probably give you a better bang for the buck in the third-line setting because now these patients are not as refractory. So I would applaud the FDA for that leveling in the third-line setting. 

Okay, so the other thing is that the survival benefit is consistent across the board. If you look at patients who got more than a few lines of treatment, they had significantly improved survival benefit—people with KRAS mutation, people with liver metastasis. So all these subgroups did benefit. It is just not the whole patient population. So even if you look at the bad actor subgroups, like patients with liver mets, patients with KRAS mutation, they also benefited. So that's another important aspect of fruquintinib. Okay, so I'll stop here, and then we'll talk more about it. Thank you. 

Jonathan Mizrahi, MD: Alright, Dr Biachi, it's your turn. And remember, please, if you have the QR code, participate in the poll. I think we'll show it again. 

Tiago Biachi, MD, PhD: Hey, morning, everyone. Thanks for having me here. Sometimes it's nice to serve as a devil's advocate. I don't think that I'm going to win this debate. But anyway, not here at least, right? Yeah, I just want to bring another point of view, why I believe that not only fruquintinib, but TAS-102, fruquintinib, and regorafenib, they all should be considered our last resort for this patient. So, I was taking some notes when my colleague was talking. I agree with the fact that usually patients hate the pump. That's true, but we have to keep the pump only for the first line. So, in a second-line setting, there is no data. Actually, there is one Chinese randomized data saying that FOLFIRI is not superior to irinotecan. Those patients can receive easily irinotecan chemotherapy only instead of FOLFIRI, buying some time. Well, we'll talk more about what kind of time we're buying with this therapy in later lines in colorectal cancer. And of course, mainly because of toxicities. So we're talking about toxicities. 

I'm not saying that other options don't have toxicity, but if you take a look at this table, I got this from the FRESCO-2 trial, so the Western population here. So you can see, in general, you have—I would say—very low incidence of a grade 3 or higher for those patients. So you have only 4% of patients with grade 3 with diarrhea, fatigue, like 8% grade 3 or higher, which sounds reasonable for later lines in colorectal cancer. However, sometimes we just forget to think about grades 1 and 2. This is not like a therapy that patients get every other week, like FOLFOX or FOLFIRI, et cetera. This is a daily treatment. I just want to have 1 second of your attention. Think about your life having grade two diarrhea every day, and what kind of life expectancy would be prolonged in a patient having eight episodes of diarrhea per day. If you think that it's reasonable to prolong 2 more months or 3 more months, what kind of social life will this person have with grade 2 fatigue and grade 2 diarrhea, for example? 

This is something to think about, mainly when we have these TKIs that we're treating daily. Possibly, something that we need to start reporting better when we have papers, et cetera. I'm not saying that those other options don't have toxicity, don't take me wrong. Actually, this is from the table, from the RECOURSE trial that is without bevacizumab. It's just TAS-102 versus placebo, and you still have a good number. Patients with lower-grade nausea, grade 1 and 2 diarrhea. The incidence of grade 3 or higher, again, is low, and it's usually reported separately because everybody wants to emphasize that this is low. But again, you have a high incidence of lower-grade diarrhea, fatigue, and other toxicities. What about my other toxicity? Well, it's not that I don't care about it, but this is a number. Usually, if the patient comes having neutropenia, well, you can just hold the treatment a little bit or reduce the dose, and this patient doesn't feel that neutropenia. 

I'm really more concerned with fatigue, diarrhea, nausea, and vomiting than a patient coming to see me with low platelets. This is just a number, and while you can always dose reduce, and then you're going to be fine. Well, yes and no. So there's a lot of data saying that you have to kind of keep the dose intensity in those trials to show the benefit that was demonstrated in the clinical trial. This, for example, was a paper that basically showed that, well, those patients with more grade 3 neutropenia receiving TAS-102 did better. Of course, they got more drugs, so they did better because they got more drugs. But again, the issue is not living longer. It's what kind of life expectancy we are really prolonging for those patients, would I say, well, this is for the TERRA trial. Again, the same population, that same intervention within a different population is for the Asian patients. 

So again, you have kind of the same description with low incidence of grade 3 or higher, but again, you have almost 40% of patients with nausea, vomiting, diarrhea, and 20% of patients probably with grade 1 or 2 diarrhea. When I say that all these therapies—A-102, regorafenib, fruquintinib—they all should be the last resort because we have to think about other options for those patients. So, probably if we split this group of this disease, like in KRAS wild type and KRAS mutant, all those other therapies like BRAF and et cetera, they're coming to the first line. So we're not going to use probably those therapies in later line settings. But for example, for patients with RAS wildtype, we have data that if you use anti-EGFR in the front line, you can probably rechallenge this patient in third line in response rate with 30% in a small phase two trial published from our colleagues from Italy. 

This is way higher than the numbers that we have, but this and usually better tolerated when we use irinotecan, for example, with anti-EGFR in patients without liver mets. Well, we have phase two, of course, phase three is still ongoing. But we have a phase two trial with a BOT/BAL combination showing like 20% of response rating those patients without liver metastases. We do have options. Clinical trials are the standard, of course, and this is a population that we receive more patients looking for clinical trials. Well, of course, after the community provider tried for FOLFOX/FOLFIRI, everybody agrees that those next options are not great. They're more toxic; the benefit is lower. Usually, this is the time that they refer patients for clinical trials. And, of course, we have to mention about KRAS inhibitors—they're everywhere. Many companies are now developing those kind of drugs. We might bring those therapies to the second line for patients with KRAS mutation, but we'll see what happens with the mechanism of resistance. We might use those drugs like in second- or third-line setting in the near future.