NCCN Recommends Frontline Lenvatinib/Pembrolizumab for Advanced RCC

CancerNetwork spoke with Eric Jonasch, MD, about the NCCN’s recommendation and how thee multidisciplinary approach will play a role.

As part of its recommendations for advanced renal cell carcinoma (RCC), the National Comprehensive Cancer Network (NCCN) suggests the combination use of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for the frontline setting.

The recommendation was based on findings from the phase 3 CLEAR trial (NCT02811861), designed to evaluate the combination of Lenvatinib with either pembrolizumab or everolimus (Afinitor), compared with sunitinib (Sutent) for the treatment of patients with advanced RCC receiving therapy in the frontline setting.2

In the study, the median progression-free survival (PFS) with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P < .001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; P < .001).

A median overall survival was not reached in any of the three treatment arms; however, the data indicated the end point was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

Objective response rate was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1).

“All of these various factors, together, show that this is one of the strongest regimens that's been tested so far in this particular setting, in advanced kidney cancer. And so the NCCN panel felt that these data deserve preferred status,” explained Eric Jonasch, MD, professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, and vice-chair of the NCCN Guidelines Panel for Kidney Cancer.

CancerNetwork spoke with Jonasch about the NCCN’s recommendation, and how thee multidisciplinary approach will play a role.

CancerNetwork: How does this recommendation affect the multidisciplinary approach to frontline RCC care?

Jonasch: The multidisciplinary team that takes care of renal cell carcinoma patients would include a medical oncologist, a surgeon, a radiation oncologist. As the systemic therapy options become stronger, the role, for example, of upfront surgical removal of the primary kidney, also known as cytoreductive nephrectomy, starts swinging more in favor of initiating systemic therapy. The role for radiation is still fairly specific in terms of types of metastases, for example to the brain or bone. So, the radiation oncologist needs to understand what the potential toxicities of these regimens are, vis a vis the administration of radiation within the context of this treatment regimen.

CancerNetwork: Is there anything from that standpoint that nurses need to know?

Jonasch: For lenvatinib plus pembrolizumab specifically, two-thirds of the patients did require dose reduction. And a bit more than 10% of patients did ultimately end up having discontinuation of both drugs. So, this is a regimen where the initial dose of lenvatinib is fairly high. It's pretty clear that the majority of individuals are going to need some type of dose reduction. It's critical that, although the data are very strong with regards to the efficacy, an ongoing dialogue occurs between the patients and the treating team, including the nursing team, to make sure that the patients know that they should communicate about side effects, that they have an understanding of how to dose reduce or to hold the drug so that you can really help that patient maximize their quality of life.

CancerNetwork: Is there anything in particular patients should know about this recommendation?

Jonasch: Just that the preferred regimens should be prioritized when considering a treatment. Having said that, a skilled oncologist can further prioritize those therapies, even within the preferred category. Or there might be some circumstances that will make a preferred regimen not appropriate for a particular patient.

So, this is obviously a conversation that needs to occur between the patient and the physician. The physician can then explain what the different regimens are in these various categories, explain why one would be chosen over the other and whether there may be other choices that are not preferred, but that might actually be ideal for that particular patient for various reasons.

CancerNetwork: What do you think patients with front-line renal cell carcinoma have to look forward to now that we, you know, obviously have another preferred option in the regime?

Jonasch: We are seeing that overall survival has increased consistently over the past five years, as more and more of these combination regimens have been approved. So, the chance of having a prolongation of survival has become a reality for many patients. The chance of a complete disappearance of disease is no longer a fantasy, but a reality. There is a small percentage of individuals who are cured in 2021, which is amazing. I would have been afraid to say that five years ago.

But, having said that, we are dealing with regimens that carry a real burden of toxicity, and can have an impact on quality of life. So, maintaining that dialogue between the treating team, the patient and the patient’s family to make sure that we can maximize quality of life while we're improving quantity of life is critical.


1. National Comprehensive Cancer Network. Kidney Cancer. Version 3.2021.

2. Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. N Engl J Med. doi:10.1056/NEJMoa2035716.

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