Adverse Events with IO-TKI Combination Regimens for Advanced RCC and Their Management

Arnab Basu, MD: Dr Anakwah, can you please talk about the dosing for lenvatinib and pembrolizumab in your practice? What is a typical starting dose, and how does it compare to the CLEAR trial?

Shawnta Anakwah, MD: I haven’t had a lot of experience, but the patients I’ve tried it on, typically my patients are more frail, have a lot more comorbid conditions. One particular patient I had was on dialysis but she had a very high disease burden, so I started her lenvatinib dose at 10 mg instead of 20 mg as per the CLEAR trial. She tolerated it very well. I tend to start lower and then try to titrate up in my patient population.

Arnab Basu, MD: That’s a great strategy.

Shawnta Anakwah, MD: Exactly.What are the commonly observed adverse effects with IO/TKI [immunotherapy/tyrosine kinase inhibitor] combinations, and how do you manage them in your clinical practice?

Arnab Basu, MD: Good question. The adverse effects of combination therapy would be from the VEGF inhibitor or from the systemic immunotherapy. Speaking of VEGF adverse effects, hypertension is very common, and I try to see if the patient can tolerate a calcium channel blocker. This appears to be the mechanism of choice for VEGF-mediated hypertension. We do a nitric oxide release. I use that as a first-line agent. As a second line, I try to use an ACE [angiotensin-converting enzyme] inhibitor based on patient comorbidities, if possible. Other than hypertension, fatigue is unfortunately a difficult problem, and there’s no good way to address that other than through dose reductions or sometimes through some regimens that are friendlier to the patient, like taking a few days off of therapy, for example.

For stomatitis, which our patient here had, I typically use a dexamethasone mouthwash, 0.5 mg twice a day. The data for this come from some of the mTOR inhibitor trials, although there are some data in VEGF inhibitors as well. It is important not to swallow, as this can impair the TKI absorption. And you must be careful in prescribing, especially in patients with a likelihood of future fungal infections or viral infections. If you don’t want to use dexamethasone, you could certainly use magic mouthwash, or viscous lidocaine in these patients for mild symptoms. Another VEGF adverse effect is hand-foot syndrome. I suggest using moisturizers for mild symptoms. For moderate symptoms, I do some dose reductions or interruptions as necessary. And for GI [gastrointestinal] effects like diarrhea, Imodium is usually the first one, then Lomotil.

In regard to immunotherapy adverse effects, as you know, these are varied and unpredictable, but recognizing these early and intervening with steroids is associated with the best outcomes, in my experience. Dr Anakwah, when do you dose reduce some of these TKIs such as lenvatinib?

Shawnta Anakwah, MD: I try to reserve it for patients who have severe adverse effects, to the point where it’s affecting their quality of life. I agree with the management of the stomatitis. With patients, typically I’ll interrupt the dose, treat them with the supportive care, and then once their symptoms resolve or improve, I typically would try to start them at a lower dose.

Arnab Basu, MD: Do you ever revert their dose to their starting dose?

Shawnta Anakwah, MD: Typically, I don’t. From my understanding, in clinical trials, when patients have adverse effects and must be dosed reduced, typically they don’t dose escalate back up in the trials. It’s not allowed.

Arnab Basu, MD: Absolutely, this is why there’s no grade 1 evidence in this field. This is always an important question because we do think that the dose density of the TKI would be important in clinical outcomes. But once someone has demonstrated they’re not tolerating that dose, perhaps keeping going on that would essentially lead to the same problem down the line again. That’s a great point.

Transcript edited for clarity.