Metastatic Renal Cell Carcinoma: Safety and Efficacy of Available Treatment Options and Considerations for Patient Management – Episode 18
Mehmet Asim Bilen, MD, provides an overview of commonly observed adverse events in patients with metastatic RCC receiving single-agent or combination therapy.
In an interview with Targeted OncologyTM, Thomas Hutson, MD, PharmD, director of the urologic oncology program for Texas Oncology Baylor University Medical Center, discusses the challenges that naturally come when adding therapies to treatment, such as the use of lenvatinib (Lenvima) and pembrolizumab (Keytruda) in patients with renal cell carcinoma (RCC).
According to Hutson, with combination therapies, there will naturally be more adverse events (AEs) to manage than with monotherapy, but efficacy from the combination treatment will increase. Therefore, Hutson describes strategies, such as dose reduction, to manage additional AEs and make sure patients continue to see a superior benefit on a combination than they would with monotherapy.
The phase 3 CLEAR study (NCT02811861) demonstrated that the combinations of lenvatinib and pembrolizumab or lenvatinib and everolimus (Afinitor) were superior to sunitinib (Sutent) in patients with advanced RCC for progression-free survival, objective response rate, and overall survival.
However, nearly all patients in the study and combination therapy experienced treatment-related AEs with 67.3% of patients treated with lenvatinib plus pembrolizumab compared with 49.7% in the sunitinib arm that led to dose reductions. Hutson says being proactive about dose reductions in this patient population allows patients to still experience the superior benefits without having to lose those benefits as clinicians manage AEs. He discusses empowering the patient to be a part of these decisions to help find the best dose for them and how the health-related quality of life is also still favorable with combination therapies.
TRANSCRIPTION:
0:08 | As we start adding on therapies, there is going to be an addition of [AEs] and that’s just the way it is. Again, I think the surprise has been that if you can work through the AEs with the patient and optimize the dose. There is a dose response effect for people that as the higher the dose, the more chance of benefit, but also the more toxicity, so they go hand in hand.
0:34 | So, it’s trying to optimize and individualize the dose for the patients sitting in front of you, using the standard for how we dose people, which is starting off at full dose, allowing AEs to declare themselves, then lowering the dose and optimizing it to try to keep that highest dose intensity. Sometimes that is just taking breaks periodically and allowing them to stay at the same dose, but saying, “Hey, when that AE gets to that point, that it’s really impacting your quality of life, take a break for a couple days, when it gets better go back on it.” Patients like that they have power, they’re in control of that, and if that doesn’t happen then go into the lower dose. So that kind of strategy is important.
1:18 | As we combine therapies, we’re going to have added to have additive toxicity. Where we can feel comfortable and point your patients too and say, “Hey, if we can get this to work out and if we can find this right dose for you, then the data we have so far from the trials to health-related quality-of-life data, you’re actually going to start feeling better as your tumor gets smaller.” The health-related quality of life data shows us that, that even though there’s more overall AEs with the combinations, the health-related quality of life is improving over the comparator drug that had less AEs.
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.
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