Tian Zhang, MD: In light of that, I’d love to hear from each of you on the pivotal trials that support the use of each of our approved therapies in the first-line space. Dr Bilen, I would love to start with you. And please give us the highlights, if you will, about the CLEAR Trial of lenvatinib [Lenvima] with pembrolizumab [Keytruda].

Mehmet A. Bilen, MD: Thank you so much Tian. As we know, this is another important trial for patients with advanced clear cell RCC [renal cell carcinoma]. If you just remember the study, this is a 3-arm study [that] tested 3 different combinations; Pembrolizumab plus lenvatinib, versus lenvatinib plus everolimus [Afinitor] versus sunitinib [Sutent]. Overall, the study showed improvement in all OS [overall survival], PFS [progression-free survival], and objective response rate favoring lenvatinib and pembro [pembrolizumab] and got FDA [Food and Drug Administration] approval in August 2021. And during the most recent ASCO [American Society of Clinical Oncology] 2021 [annual meeting], we had some additional data regarding subgroup analysis by risk and target kidney lesion, this data [was] presented by Dr Viktor Grünwald, MD, PhD, et al, and they showed PFS favored lenvi [lenvatinib] plus pembro [pembrolizumab], with a median of 22.1 months versus sunitinib, which is a median of 5.9 months in IMDC [International Metastatic RCC Database Consortium] intermediate and poor subgroup. What about in favorable subgroup? Again, the combination is like a barrage. Median PFS is 28.1 months in lenvi [Lenvatinib] plus pembro [pembrolizumab] versus 12.9 months in sunitinib. And as we know, IMDC risk groups are important for our patients as well as for us when we make a treatment decision with diagnosis RCC. And also, patients with kidney lesion, again the combination is positive, have a better PFS, OS, and objective response rate. And all of those are better than the control arm, which is sunitinib. I think after then, we are comfortable to use this combination. This is 1 of the IO [immuno-oncology]/VEGF [vascular endothelial growth factor] combination and we have at least 2 of those currently present in our toolbox. Overall management of adverse events are very important. I tell my patients this is like a marathon run. We need to keep our patients on those agents longer and safer. Because of this reason the measurements are important especially for diarrhea, hand-foot syndrome, mouth sores, and so on. Dose halt and dose reductions can be very helpful to manage toxicity because we know that we are treating the real-world population and that population can be different from the clinical trial population. [They] can be frail and have other medical issues. Because of this reason, toxicity management, I think is key for any drugs, any combinations, including the VEGF combinations.

Tian Zhang, MD: That’s great and a wonderful summary. Thank you so much, Dr Bilen. Speaking about the dose modifications, what starting dose then do you use for lenvatinib in your practice when you’re starting lenvatinib with pembrolizumab combination?

Mehmet A. Bilen, MD: If this is not a frail patient, I start with 20 mg, which is the dose that was used in [the] CLEAR trial. Based on the tolerance, again dose reductions and dose halts are helpful. This is about maybe the 60% to 70% of the patients I see in the clinic. And also, the lenvatinib doesn’t have a very long half-life. Because of this reason, if an AE [adverse event] occurs after dose halt, we see improvement relatively quicker. And hopefully the patient will maintain on a dose that they can handle. If this is a frail patient and does not pass the eyeball test, then I use reduced dose, which is 18 mg or even lower, and it depends on the tolerance we can titrate if we need to. Definitely this is a once-a-day pill which is more convenient for most of the patients because medication compliance is important for any oral drug including lenvatinib and hopefully they will take the medications every day rather than skipping doses without any reason. And sometimes, the course of toxicity can be challenging whether this is VEGF toxicity or IO-related toxicity. At that time, I think short half-life is also an advantage. At least we can stop 1 and see whether we see any improvement. After that, resume if we need to.

Tian Zhang, MD: Wonderful. What a great, practical way to approaching lenvatinib with pembrolizumab.

This transcript has been edited for clarity.