Martin H. Voss, MD: You speak to the dosing very eloquently. It is notable to say now that we’ve reviewed the 3 most current TKI [tyrosine kinase inhibitor]-I/O [immunotherapy] combinations that each pursued a very different strategy when it comes to dosing. You rightfully pointed out that the lenvatinib dose in the lenvatinib-pembrolizumab combination is the highest we’ve seen. In axitinib-pembrolizumab, it was the standard dose of axitinib, 5 mg, as Tom taught us just a minute ago. In the nivolumab combination, on CheckMate 9ER, nivolumab plus cabozantinib, the cabozantinib was started at a reduced dose. I wonder if any of you can speak to how we might or might not see this reflected in the toxicity, particularly when it comes to hepatic dysfunction, GI [gastrointestinal] dysfunction, and so forth. Do you feel that we see a reflection of the different dosing strategies in what is reported of tolerance?Sandy, can you start by talking about that?

Sandy Srinivas, MBBS: Dosing is definitely something that, even if you go back to TKIs, I’m not sure we even know what the appropriate dose is for sunitinib. Even after a decade of having the drug, there have been a lot of trials looking at 50 mg and 37.5 mg. TKI dosing is a little tricky. Lenvatinib at 20 mg is the starting dose. If you look into the details of the study, close to 70% of patients required some level of dose adjustments. The dose adjustments happened really early in the study.

It’ll be interesting to look at future data as to whether dosing correlated with response or PFS [progression-free survival]. We don’t have that yet, but in clinical practice overall, I didn’t see too much data that were concerning in terms of grade. There were no deaths. There weren’t any big concerns about toxicity that couldn’t be managed. With the starting dose at 20 mg, one of the biggest questions in my mind, which I get asked a lot about, is would patients be able to sustain this dose? One thing about lenvatinib is that it does come as an easier dosing schedule. It allows itself to be easily adjusted. between the 10 mg and 4 mg, you can do 14 mg, you can go to 10 mg. We still have more to learn about lenvatinib’s dosing.

Martin H. Voss, MD: Bob, do you want to speak to the lower starting dose of cabozantinib used in the CheckMate 9ER study, combining it with nivolumab, and whether you feel that strategy panned out for the trial?

Robert S. Alter, MD: We’ve had experience using cabozantinib even back in our thyroid cancer days. The starting dose of Cometriq was a significantly high dose that most of the patients reduced from 140 mg to 80 mg within the first 2 months. When you look at the data from METEOR on patients who’d require dose reductions as a second-line therapy, 20% of the patients were at 20 mg, and 60% of the patients ended up being at 40 mg. Recognizing that was second-line data and they tried to push the envelope, as Sandy was just saying, this is a durable therapy. Not only do you want patients to achieve good quality of life, but this is potentially a curable disease. When you’re dealing with the durability of the therapy, I tell my patients, “It’s not about winning the first mile, it’s about winning the marathon.” I find that starting at a lower dose makes it more tolerable, first of all. Second of all, positive reinforcement with the patients, it gives the patients the ability to not have too much toxicity early on. It gives a little more ability to treat the patients with confidence. I believe that the longer the patients are on combination therapy, they do better.

On the CheckMate 9ER study, 5% of patients came off the combination. They were drug discontinued because of the combination. I believe 6% came off of the nivolumab and 7% came off the cabozantinib. Dose reductions were seen throughout both arms, including Sutent [sunitinib]. We’ve been playing with Sutent for close to 15 years, and we expect that. But if we can give our patients the benefit of being on a durable therapy for a prolonged period, physically and mentally getting through this therapy and this regimen, it gives a lot more credence to the fact that we’re not only taking care of the cancer, but we’re taking care of the patient who has the cancer.

Transcript Edited for Clarity