Hepatocellular Carcinoma Update, Issue 1, 2017 (Video Program)Efficacy and toxicity profile of regorafenib as second-line therapy in the RESORCE trial; dose modifications and adjustments
7:35 minutes.
TRANSCRIPTION:
DR LLOVET: Here are some examples that I will explain about potent drugs in advanced — next slide. This is the regorafenib concept. If you look at the structure of sorafenib and regorafenib, it’s pretty similar, only you have a floor difference. And this provides regorafenib with a more potent antitumoral effect. In the Phase II data that I’m showing below, the median survival was up to 14-month median survival for patients with advanced disease. Next slide. So this prompted this randomized study comparing regorafenib versus placebo only in those patients progressing to sorafenib. This means that the patients should tolerate sorafenib. We know that in the front-line population 15% of the patients do not tolerate sorafenib and, therefore, these patients were out. And then among those that tolerate sorafenib, if they present progression to the disease and ECOG 0-1, they were included in the study. Next slide. This is the most important result, as you can see. Regorafenib provides survival differences, 10.6 months versus 7.8 months. And this was outstanding because we were not actually expecting such a noteworthy effect, I would say: hazard ratio 0.62. This is a very important effect in the second line, leading to 3-month differences in survival. DR LOVE: Could I just ask before you go forward, what about the issue of toxicity with regorafenib? You’re using full dose. In colorectal cancer, when that dose has been used, at least in the United States, there have been a lot of toxicities. Most people now are using a lower dose. But these patients have already had sorafenib. So how did they tolerate the 160? DR LLOVET: Well, surprisingly enough — there was more toxicity than with sorafenib, I have to say, particularly in terms of hypertension, hand-foot skin reaction and fatigue. These are the 3 adverse events that are more prominent. At Grade 3 or 4, for hand-foot, you can have 15%-20%. And hypertension also you can have 15% to 20%, and fatigue. But certainly it was surprising for us to learn that we were able to maintain regorafenib in 85% of the patients. Only 15% of the patients we had to withdraw the treatment as a result of toxicity, which is a very acceptable figure. Of course we have a bias here. The bias is that all the patients included in the trial tolerate sorafenib. If you tolerate sorafenib, probably you are more prone to tolerate regorafenib because the adverse events mechanism of action is very similar since the targets are very similar. So we were able to give full dose to 50% of the patients, reduce the dose in 35% and 15% withdraw completely the treatment. This is the spectrum of the management of adverse events, which is very acceptable and different from, I would say, third-line colorectal cancer. I would say that these patients eventually are in a better physical condition because, despite that they progress to sorafenib, still they have to be ECOG performance status 0 or 1 and have good liver function. And if you check the median survival in the second line, it’s very similar to the one we reported in the front line. It’s around 10.6 months. This represents that we are super-selecting the good candidates. That may represent, let’s say, 40%. The calculations are 40% — 40% to 50% of the patients in the second line are suitable for this therapy. DR LOVE: Just for practical purposes, for example, if you think back to the patient you’ve been presenting here, how did he tolerate sorafenib? Did you have to do any dose adjustments, or he tolerated it fine? DR LLOVET: Well, he tolerated fine. We had to adjust the dose, but he tolerated fine. And this patient is a good candidate for this trial. DR LOVE: So if this patient then were to receive regorafenib, what dose would you start? Would you start on the full dose or would you — DR LLOVET: Full dose. And deescalate depending on the adverse events. DR LOVE: Any situations — maybe somebody who had problems with sorafenib — where you would start at a reduced dose of regorafenib? DR LLOVET: No. Of course one thing is what we’re doing in a trial for regulatory purposes and what we think will be more effective for a patient. Then we’re publishing that and we are reporting that, and we’re giving this information to the physicians. But the physicians, at the end, they handle the patient the best way that they can. In some instances they may start at half dose, then stepping up, as opposed to what we recommend, start with full dose and stepping down in case you have adverse events. So this depends a lot on the physician, as well. But the physician needs to know the information. The information is that, if you start with full dose, at the end, according to the inclusion criteria of the trial, you will have 15% of the patients that will be removed from the study — in this case will not receive regorafenib — as a result of adverse events. And then you have 35% to 40% of the patients decrease the dose. And only 50% of the patients will receive full dose. This is more or less the spectrum. Then of course the real practice is different than a trial. You may have patients even with ECOG 2 that you want to treat the patient, or with Child-Pugh B, 7 point without ascites, that you want to put it in. And then this depends a lot on the physician. DR LOVE: Another thing that’s been observed with colorectal cancer with regorafenib is that when people do have toxicity issues, they happen very, very quickly, within a week or two. And people like Axel Grothey talk about at least contacting the patient in a week, seeing them fairly frequently in that first month. Is that the same thing with HCC? DR LLOVET: The same pattern. Sorafenib and regorafenib have a very similar pattern of adverse events. Certainly adverse events are slightly more severe with rego, but the pattern is the same. Most of the adverse events occur very early — the first month, most of the cases. Then you have a few percentage of patients in which the adverse events emerge beyond the first month, but mostly it’s the first month. DR LOVE: And is regorafenib being studied up front? DR LLOVET: Not at this point. Certainly the company is planning a trial in the front line at this point, but the design is not completely established. |