The Phase 3 CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced RCC - Episode 4

Implications of the CLEAR study in mRCC to Clinical Practice

Implications for treating patients with metastatic renal cell carcinoma with frontline lenvatinib plus pembrolizumab based on the regimen’s performance in the CLEAR study compared with other treatment options.


Moshe Ornstein, MD, MA: We’re fortunate to now have an embarrassment of riches in treatment-naïve metastatic RCC [renal cell carcinoma], where we have so many different combinations approved and trying to figure out which one is appropriate for which patient can be really challenging. In my practice, prior to the approval of lenvatinib [Lenvima] and pembrolizumab [Keytruda], I was primarily using axitinib [Inlyta] and pembrolizumab and some cabozantinib [Cabometyx] and nivolumab [Opdivo]. In my current practice, I have used lenvatinib and pembrolizumab as my go-to combination. However, I do find that there are some patients who are a little bit older and frailer, and the toxicity management might be easier with the short half-life of axitinib, and for those patients, I often choose axitinib and pembrolizumab. Although we’re not supposed to compare across trials, at the end of the day, all these trials did use sunitinib [Sutent] as the comparator arm. I think we have to do some comparisons to get a sense of the efficacy when we’re trying to pick a regimen that we think is most likely to benefit a patient. I’ll present my approach to the patient with treatment-naïve metastatic RCC.

For the average patient that comes through the door, my first question is, should I be giving this patient immunotherapy and immunotherapy, ipilimumab [Yervoy] and nivolumab, or should I give this patient an immunotherapy and a TKI [tyrosine kinase inhibitor]? The benefit of giving IO/IO [immuno-oncology] with ipi/nivo [ipilimumab/nivolumab] is that it has the longest duration of data. We have data 5 years and beyond. After 4 doses of ipilimumab and nivolumab, we moved just to nivolumab monotherapy. However, the downside of using that combination is that the response rates in the PFS [progression-free survival] are definitely lower than the IO/TKI regimens. I find in my clinical practice that many patients are symptomatic, many of them want a response right now to treatment, and they’re all still getting an IO therapy so there’s likely to be some durable effect. We do see that in some of the clinical trials already. Although the first question is whether to treat with IO/IO or IO/TKI, most of my patients are getting one of the IO/TKIs. Although I was previously using axitinib and pembrolizumab and cabozantinib and nivolumab, when you see the kind of complete response rates of 16%, a PFS close to 2 years, an objective response rate of over 70%, an OS [overall survival] hazard ratio of 0.66, really, especially with PFS response rate and CR [complete response], the data cross-trial, comparisons notwithstanding, appears superior with the combination of lenvatinib and pembrolizumab. And that’s become my go-to IO/TKI choice for those reasons.

I have found transitioning from 1 combination to the other to not really be a challenge. The same general management strategies in one can be used for another. In other words, identifying an IO toxicity versus a TKI toxicity is similar in axitinib and pembrolizumab as it is in lenvatinib and pembrolizumab. Teasing out the overlapping toxicities is also similar. The general TKI strategies of dose interruptions, dose reductions, etc., can be used in both. I do think that if someone has a general framework and had to manage the toxicities of 1 regimen, that really can be translated to another regimen. To summarize, the first thing I do when a patient comes into my practice is think about an IO/IO regimen versus IO/TKI. Within the IO/TKI field, my general preference for the average patient who is otherwise well is to use lenvatinib and pembrolizumab. However, I do think there’s a role for the other combinations as well, especially in patients where there is a little bit more concern of comorbidities and being able to manage toxicities.

Transcript edited for clarity.