Round 3—The Role of Patient-Specific Factors in Selecting Targeted Therapy

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Jonathan Mizrahi, MD: We are going to be talking about other patient-specific factors and clinical factors that would weigh into that decision of whether these would be routine additions, target therapies in this line, or last resort. So again, starting with Dr Chakrabarti. 

Sakti Chakrabarti, MBBS, MD: Well, it's me again. I hope you're not getting tired of listening to my voice,  but I actually want to make an important point here, which is the overall survival benefit. We've talked about that a little bit. We know that both in FRESCO and FRESCO-2, fruquintinib has increased the median overall survival. Small—it is not years—it's in terms of months. This improvement is significant. Another thing I want to remind you of is the fourth line. FRESCO-2 is the fourth-line study, but we can use fruquintinib in the third line, according to the FDA labeling. Okay, now I was talking about the subgroups. There are some bad actors. You all know that most colorectal cancers like to go to the liver, 80% of them. When that happens, that's a bad prognostic factor. Those people don't do well. 

Now what happened to FRESCO-2? The people who got liver metastasis, and 74% of those patients were enrolled, and that group also benefited. And that is also true for people. Like 73% people got more than three lines of treatment. Fruquintinib benefited them too. Basically, the choices come down to three. In the third-line setting, we have three different agents approved, right? Regorafenib, fruquintinib, as well as TAS-102 with or without bevacizumab. I put all this data side by side to make a point. Now, I often hear in the SUNLIGHT data that the median OS with TAS-102 and bevacizumab is so much better. If you look at the numbers in isolation, yes. If you look at the median OS in the SUNLIGHT study, with TAS-102 and bevacizumab, that's about 11 months. That's commendable. As opposed to if it is TAS-102 alone, it's only 7 months in that SUNLIGHT study in RECOURSE, it's even more than that, right? 

So why is that? I want to draw your attention to something. Any clinical data, any scientific data has to be interpreted in the background of its context. So once upon a time, many years ago, a journalist asked Einstein: does 2 + 2 always make 4? And Einstein said no. If they're in motion, they may not make 4. So the point is, if you take the context out, your interpretation of the data would be wrong. So, let's say your weight is 120 pounds, and you go to the moon tomorrow. Your weight will be 20 pounds, right? So if you take the context out, your data would not really give you the right information. So let's look at this data one more time. So let's look at the SUNLIGHT data, which is in the third column. See, these patients actually received two lines of….So most patients were actually second-line patients, 93.1% of them. 

In the SUNLIGHT study, they did not include all the refractory patients, as opposed to the study with regorafenib, as opposed to the study with fruquintinib, and as opposed to the study with TAS-102. We know that when chemotherapy is added to bevacizumab in the first-line setting, it does not improve overall survival. That does not improve the response rate. That was already published in a phase three study in 2008. Dr Leonard Saltz was the primary investigator in that study. So, how come in the second-line study, we're adding bevacizumab to TAS-102, and that's improving survival? It looks that way because these patients are less refractory. Most of these patients have received two lines of treatment only. In the other studies, there are three lines or more. So that's why I was trying to draw your attention to the context. Without the right context, our data would not give us the right information. And I think that is the point I wanted to make. And again, thank you for your attention. 

Jonathan Mizrahi, MD: Alright, and last but not least, his last try to salvage this debate—target therapy. Just kidding. Targeted therapy should be a last resort, given patient-specific factors, Dr Biachi. 

Tiago Biachi, MD, PhD: So, yeah. I agree with the point that, of course, the previous number of lines matters. And of course, if we do a study with fruquintinib in the second line, those patients will live longer. We might be talking only about the lead time bias. The side of metastasis matters. I mean, most patients with colorectal cancer die from the liver and then die from the peritoneum. I've been treating colorectal cancer for about 15 years. I remember that. I have seen maybe 4 or 5 patients who die from lung mats, for example. This is something to think about when we are discussing how aggressive we want to be with therapies for our patients. If we're talking about patients with lung mats only, sometimes this is the time to consider a break or look for clinical trials with experimental approaches, et cetera. Response rate is something that matters, sometimes for the patient after 2 years of therapy, and after 2 or 3 years, looking at CT scans every 3 months, trying to see those lesions shrinking a little bit. 

We keep talking about responses with those patients for 2 years and discussing CT scans. Then, we get all those options that we have to kind of change our speech. Hey, do not expect those lesions to shrink anymore. Why I'll take this then because it's toxic for me. Well, because you're going to live longer. Sometimes, the patient in front of us, they want to see those lesions shrinking. Taking medications that are really toxic and we don't expect any response, or very close to zero, sometimes is kind of frustrating for our patients. I have just one slide here to talk about a different type of toxicity that I haven't mentioned today, which is financial toxicity, which matters for our patients. Quite often, actually, we have messages in the port. Hey, I got this medication approved, but there is an out-of-pocket cost of $5,000 or $6,000 for me. 

Should I start it? Well, no. They probably have better options to invest this money instead of in this, but this is something really important for our patients. Remember that we have about 20% of our patients with colorectal cancer who are younger than 50 now, and they're usually the person supporting their families, et cetera. This was published earlier this year, too, in the PharmacoEconomic journal. You can see, basically, this is a comparison of fruquintinib vs placebo. They did an analysis for the incremental cost per QALY in the US. Of course, this varies according to disease, et cetera, but the benchmark is about 100,000. The incremental cost per QALY should be around 100,000 to call this intervention cost-effective. You can see that compared to placebo, the incremental cost per QALY for fruquintinib was 1.5 million. So, are we really helping those patients? I mean, this is something that we had to think about. 
Of course, the drug is effective; it's approved. It's something that we use every day. But is this something that we need absolutely? We need to balance. Mainly, when we have other options, those other options are expensive too. So I think as a pharma company, we have to work together and try to help these patients have access to those therapies because it's something that matters a lot. I mean, 1.5 million incremental cost per QALY is brutal for a good number of our patients. Remember that those patients have been sick for 2 to 3 years; most of them have not been working for months or sometimes for years. This is a brutal cost to our patients.