Vogelzang Discusses Significant PFS Benefit of Lenvatinib/Pembrolizumab in RCC

Nicholas J. Vogelzang, MD

Chairman of Medical Oncology, Comprehensive Cancer Centers

Clinical Professor

University of Nevada, Reno School of Medicine

UNLV School of Medicine

Las Vegas, NV

Targeted Oncology^TM: What was the study design and goals of the CLEAR study (NCT02811861)?

VOGELZANG: The CLEAR study compared sunitinib [Sutent] monotherapy with lenvatinib [Lenvima] and everolimus, and with pembrolizumab [Keytruda] and lenvatinib. I want to note that lenvatinib was given at 20 mg daily. The primary end point was progression-free survival [PFS], that is the end point that sunitinib was approved [by the] FDA. Secondary end points were overall survival [OS], objective response rate [ORR], safety, and duration of response.

What were the results of the study in terms of its primary end point of PFS?

This was published in the New England Journal of Medicine, and interestingly, lenvatinib and pembrolizumab was clearly superior to lenvatinib and everolimus, and superior to sunitinib.¹ But, lenvatinib and everolimus came in at 14.7 months, superior to sunitinib, which was exactly what was expected of it, namely a PFS of 9.2 months. So, if anything, you should no longer use sunitinib. Sunitinib has been beat up [in trials] and is no longer used. But lenvatinib and everolimus was quite effective.

Let’s focus on the lenvatinib and pembrolizumab arm compared with sunitinib. The hazard ratio was stunning, at 0.39, at a P value of .001. So, no matter which way you cut it, lenvatinib is a superior drug compared with sunitinib, and the combination of lenvatinib and pembrolizumab reached a PFS of 24 months in the first line. That’s an unheard-of number. I haven’t used the regimen so far because it wasn’t FDA approved until [more recently].² But it’s a very impressive figure, and it needs to be considered seriously in the first line.

Among the subgroups, there were no obvious differences [in PFS].¹ There were a large number of favorable-risk patients, and only a small number of poor-risk patients. Even in the poor-risk patients, there was a substantial favorable hazard ratio [of 0.18], albeit in a small number. So you have to think long and hard about this regimen as supplanting nivolumab [Opdivo] plus ipilimumab [Yervoy]. I am beginning to lean in that direction. It didn’t matter whether patients were PD-L1 positive or negative, the number of organs involved, male/female, or age.

What were the OS outcomes for lenvatinib/pembrolizumab versus sunitinib?

For OS, this is where it gets a little tricky. The OS is not reached for any of the subgroups yet. Now, the median OS is favoring lenvatinib/pembrolizumab. But sunitinib caught up, and why is that? Well, probably because physicians started using a second-line therapy. If the patients were randomized to sunitinib, they got a checkpoint inhibitor and probably what was available, either axitinib [Inlyta], lenvatinib, or cabozantinib [Cabometyx]. So, this clouds the water a little bit.

The hazard ratio [for lenvatinib/pembrolizumab versus sunitinib is 0.66 and the P value is .005]. But the end point of OS has not been reached, and not unexpectedly, because the patients receiving sunitinib tend to be treated successfully in the second line.

What was the ORR of patients with lenvatinib/pembrolizumab?

Another measurable end point was ORR, and lenvatinib/pembrolizumab comes in at 71% ORR, with a complete response [CR] rate of 16.1%, and this is where I start wavering on my nivolumab/ipilimumab stand. Now, granted that there are favorable-risk patients here, but that number is better than I would expect. I’m beginning to think that pembrolizumab/lenvatinib is a good choice, and maybe better than axitinib/pembrolizumab. We will see. Follow-up will be important, but you could argue right now that CR rate—granted that it includes favorable risk patients in it—is pretty impressive.

What was the tolerability of lenvatinib and pembrolizumab in this study?

We have to factor into the discussion that patients receiving lenvatinib/pembrolizumab stayed on treatment for 17 months, and that’s both good and bad. That’s a long time to be on lenvatinib, and all patients gets adverse events [AEs] for a long time. [The percentage of patients with treatment-emergent] grade 3 or higher AEs is about 80%, leading to dose reductions in about 70%, and treatment discontinuation rate is about 15% to 20% [for both the lenvatinib/pembrolizumab and lenvatinib/everolimus arms].

Remember, these are [more fit patients]. These are patients who are in the clinical trial, so they all had to enter with high-quality eligibility. So, just be aware the AEs in community practice are probably going to be greater than this.

AEs of the lenvatinib/pembrolizumab combination include diarrhea occurring in 54%; hypertension, 52%; stomatitis, 32%; hypothyroidism, 42%; and then there are other AEs, such as dysphonia, 24%. But there are a number of daily AEs that the patients have to deal with, including decreased appetite and nausea. Proteinuria is not uncommon, and physicians [should] worry a little bit about the toll that the hypertension might be taking on the kidney. There is significant hypertension and along with that is proteinuria, and most of these patients only have 1 kidney.

_References:

_{1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

_{2. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Published August 10, 2021. Accessed March 23, 2022. https://bit.ly/3D3z0b9}