Round 2—Quality of Life Considerations With Targeted Therapy

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Jonathan Mizrahi, MD: Now we're talking about the quality of life perspective: should it be a routine addition early on, or considered as a last resort? So turn it over again to Dr Chakrabarti.  

Sakti Chakrabarti, MBBS, MD: Okay, so looking at me, you can probably understand I've been doing that for a while, for over 20 years. One thing I always talk about the patient during the first visit, which is, what is my goal of treatment? What am I trying to accomplish here? Am I trying to cure you, or am I trying to preserve your lifespan as much as I can and preserve your quality of life? I think that is very important to discuss. So I'll always do that on the first or second visit. And to make it funnier, because these people are under stress, I tell them, well, if I'm trying to cure you, that approach would be different. I call it the Full Metal Jacket approach. A lot of people laugh about it. A lot of younger people probably don't know what Full Metal Jacket is. If that is not the case, if I'm trying to preserve quality of life, that would be a Sound of Music approach. Again, a lot of people probably don't know anyway, so you get the point.                                          

So I have seen when people come closer to the third line, a lot of people are already thinking about, should I give up or should I keep going, because life has not been easy, and other things. What we have experienced, every cancer center struggles with the infusion spot. Any cancer center you go to, they're having a challenge with finding chemotherapy, infusion nurses in infusion chairs, and such. So all these things actually interfered with the quality of life. People have to go to the scheduling desk and say, “Hey, where is my appointment?” “Can I get it tomorrow? I have something else coming up later this week. My grandson is graduating. I really have to get my chemo tomorrow or the day after.” So all these things add to that quality of life question.  

Another thing, I don't know where you work. Where I work, it's kind of, I call it the ivory tower, where people have a hard time getting in there, and it's downtown. Finding a parking spot is difficult, but they don’t want to come to this cancer center to see us. So often when I put these people on a pill, I can do a virtual visit. I can tell them, go to one of the nearby blood draw centers, which are in our network, get your blood drawn, and I'll talk to you through a virtual visit. I get to see their dogs and cats and their environments. It's actually a lot of fun, and people love it whenever I tell them in the third-line setting that you don't have to come to see me all the way to downtown Cleveland. I will see you virtually.  

You take the pill, no infusion center, no struggling with your infusion schedule, and then you don't have to carry the pump. So they actually are elated. They love that whole idea. Sometimes I can keep going with these oral agents for months. I have a few patients who are like 6, 7, 8 months out on fruquintinib. So, this quality of life issue, when they don't have to deal with the infusion and all that, is important. So I think those are all subjective. We all understand those challenges we face. But, then, how about the actual data? So there is some data here. As you can see, you don't have to necessarily start with 5 mg. Actually, with older people, I don't start with 5 mg; I start with 4 or sometimes even 3. Now, depending on how they're doing, I can go up or down. But in the clinical trial, though, the minimum dose used was 3 mg. So I never go below 3. So you can always, I think, the focus is on the quality of life. We need to preserve their quality of life so they don't get too much of side effects, but at the same time, we can control this disease.  

When you look at the grade three areas, and I actually appreciate the comments of my colleague, grade two and grade one, those are not negligible toxicities, and we have to be cognizant of that, too. I mean, if somebody has a grade two, the area, we need to intervene; we need to make it better. We need to do something: cut back the dose, give them a drug-free time, or whatever it is. If you look at the serious ones, grade three and higher, like grade three, the barrier is zero, fatigue is zero. Other hand, foot reaction, all that. So a lot of these grade three side effects are very minimal with this oral frequenting. So that's another advantage.  

Then, these are from FRESCO-2, again, highlighting the fatigue and the area that is the lower incidence of these side effects. So that's another consideration. You can just improve the quality of life. They feel better. It's just not the bone marrow that needs to recover the people; the patients themselves have to recover. You're just setting them up for an effective fourth-line treatment. If they crash and burn in the third-line setting with another chemotherapy, then there is no fourth line. They'll be talking about hospice and all that. I find that useful where I can control their disease and at the same time preserve their quality of life so they'll be there to receive the fourth-line treatment, whatever it is. That's the point I just wanted to make. Thank you again for your attention, and I will shut up at this time and listen to other people.  

Jonathan Mizrahi, MD: Alright, so, a round of applause. All right, so Round 2, arguing that targeted therapy should be a last resort given those quality of life considerations, is Dr Biachi.   

Tiago Biachi, MD, PhD: So I would say I totally agree with that. What we're looking for here is to preserve quality of life and try to keep the disease under control. Of course, it all depends on what kind of disease we're talking about and where this patient has metastasis. If the patient is progressing with tiny lung mats, it's probably better to do nothing, as it might be a good option for this patient, sometimes. Well, it was mentioned before here that fruquintinib is a real targeted therapy, which is partially true. So, it is a targeted therapy, but in 40% of those patients, the drug does nothing, right? So, 40% of those patients, as you can see in the curve, were completely on the same placebo, which means that we added only toxicity for those 40% of patients. This is important because we have to start thinking about how we can really recognize who is going to benefit from those patients.  

This is the way that precision medicine is moving forward. We have all these diagnostic technologies to identify targets, but then when we develop clinical trials, we're trying to include all those patients. Of course, there is a lot of discussion in the background, including economics, but it is something that we have to start thinking about because, mainly, in scenarios where we have more than one option. For example, for us as clinicians, it's important to try to recognize who gets the benefit of what. In 40% of patients, the drug does nothing. If we try to measure quality of life, this was published early this year. This is the quality of life measurement for FRESCO-2, and sorry for the side, but basically, you have two different sports. Red, you have red, you have a placebo, and that did not improve the quality of life. So, you might see a lower decrease in the quality of life of those patients. So you have a larger number of patients on placebo here, and you can see, for example, around cycle three, where 40% of those patients stopped taking fruquintinib, and the placebo starts. So we are definitely adding toxicity to those patients. When we use this, and this is just another image regarding the same study, actually. But you can see, for example, again a comparison with a placebo. Here you have, in blue, here you have patients with duration, stable spread.  

You can see that there's some variation with the blue, which is the patients with deterioration, and the purple. For example, you can see that in cycle four, you have like 8% of patients, 8% higher deterioration compared to like 5% improvement. So you can see a small variation improvement in the quality of life. If you take a look at the purple and at the same time with deterioration, and maybe at cycle four, which is the time when half of those patients have already stopped taking fruquintinib. You have more patients with deterioration in the quality of life compared to patients with real improvement in the quality of life. Again, I'm not saying that I don't use this medication; actually, I use a lot of this medication.  

But again, we have to think about fruquintinib. We have to put fruquintinib, TAS-102, and regorafenib. But as a lead resort for those patients, of course, this choice will depend on what kind of toxicity. You think about this need for infusions, usually with TAS-102; you do have data with TAS-102 monotherapy. We do know that bevacizumab ads and, of course, ongoing trials, including the trial combining TAS-102 with fruquintinib, are a good option for part of those patients without IV infusions. But of course, we have to think about toxicity for those.