Sorafenib and Lenvatinib Side Effect Profile and Dosing

Lori J. Wirth, MD: Frank, I have a question. In your experience, do you see much difference in the adverse effect profile between sorafenib and lenvatinib?

Frank Worden, MD: I see similar things, such as the fatigue and the hypertension. We do not see as much hand-foot syndrome with lenvatinib as we would see with sorafenib in the SELECT and DECISION trials, which is the same in clinical practice. Occasionally we do see mouth sores with lenvatinib, but patients tolerate it better in that regard. The hand-foot syndrome was dose-limiting for sorafenib, prompting most of us to stop the medication, treat with nonsteroidals, and then reduce the dose. Similar to the sorafenib study, fatigue was an adverse effect in the lenvatinib study. Fatigue may be worse with lenvatinib than with sorafenib and is primarily what prompts patients to stop and causes dose reductions. 

Lori J. Wirth, MD: There has also been a lot of discussion in the field about what the right starting dose is of lenvatinib. We now have data. After the FDA approval, there was a mandated study to look at the best starting dose of lenvatinib in patients with RAI-refractory DTC [radioactive iodine-refractory differentiated thyroid cancer]. Patients were randomized to 24 vs 18 mg. Before we talk about those data recently presented at ESMO [the European Society for Medical Oncology annual meeting], before those data were available, Frank, what did you do? What did you do for your starting dose of lenvatinib?

Frank Worden, MD: In order to attain the best response, start with the 24-mg dose. Sometimes I will prescribe a 20-mg dose, and then once patients can’t tolerate it, I’ll drop the dose. To get the best benefit we had to start early and then drop the medication. I know some will start at lower doses like 10 and 14 mg, and if the patient can tolerate that, the dose can be increased. Personally, I don’t think that’s the right way to approach it. I think we need to get a response, and then if we need to hold because of toxicity, hold, and then lower the dose based on that. 

Lori J. Wirth, MD: What do you do for dose holds? 

Frank Worden, MD: Usually I see the patients back more frequently. Now we have televisits because of the COVID-19 [coronavirus disease 2019] pandemic, which has made this a little easier. I will start with a 24-mg dose and check back with the patients within a week and see how they’re doing. Oftentimes, we have them purchase blood pressure cuffs, if they don’t already have them at home, to take blood pressure. If they’re not tolerating lenvatinib, the fatigue is so bad, we would hold the medication until the toxicity level came down to a grade 1 or grade 2. If the patient is doing relatively OK, I may continue treatment and check back with them the next week. I treat patients to a point where they feel that the toxicity is too much or their blood pressures can’t be controlled, despite us trying to adjust them, and then I’ll hold. But I will hold until a point where I feel the toxicity level has dropped enough, so that when we restart, the patients aren’t so fearful, and we can move forward with the treatment.

Lori J. Wirth, MD: I do a similar thing. Data recently presented by Makoto Tahara, MD, PhD, look at the SELECT trial and outcomes in terms of dose intensity. The analyses showed that patients who have a longer period off of lenvatinib do worse. The analysis might be confounded a bit, but if dose holds are kept to less than 10% of the overall period, patients seem to derive more benefit, which certainly makes sense. The half-life of lenvatinib is short, so patients usually begin to feel better quickly.

Frank Worden, MD: Correct. 

Lori J. Wirth, MD: Let’s talk about the study that was presented at ESMO. 

Frank Worden, MD: Marcia S. Brose, MD, PhD, presented results of the SELECT study at ESMO, focusing on the starting dose of lenvatinib. We participated at the University of Michigan in that study. We enrolled a few patients. Initially the starting dose, or the lower dose, was 14 mg compared to 24 mg. But when there was a small, short interim analysis, they found that there wasn’t a response with the 14-mg dose. To garner that response, you had to start with a dose of 18 mg. Patients were treated. They were blinded to the dose, and then the data show that it’s not noninferior. It tells us that the starting dose for lenvatinib is 24 mg. With that, just like we’ve been talking about with toxicities, we need to adjust accordingly. And I do agree with you, the shorter the hold, the better. Reducing by about 10% or so makes the most sense rather than doing a complete drop and leaving the patients at a lower level, which may cost them overall efficacy in the long run. 

Lori J. Wirth, MD: Frank, you were right from the get-go, huh? 

Frank Worden, MD: I guess. 

Lori J. Wirth, MD: It’s always that way. 

Frank Worden, MD: Right, exactly. It made sense. If you’re going to get a response—especially since these patients are oftentimes symptomatic—you want to get a response, and then you can play around with the dosing more. 

Lori J. Wirth, MD: I completely agree with you. I also find that just from a clinical point of view, it’s easier if a patient is feeling poorly on a drug to say, “You know what, let’s do a break, and then we’ll get you feeling better really quickly and resume at a slightly lower dose” than it is to say, “I don’t think you’re feeling quite sick enough on this drug. I think we can increase it. I think you can tolerate a more in the way of adverse effects.” 

Frank Worden, MD: Right.

Lori J. Wirth, MD: I find the latter conversation more challenging. 

Frank Worden, MD: Lori, I totally agree. I think that’s why we’re friends. 

Transcript edited for clarity.