Pembrolizumab/Lenvatinib Under Evaluation in Frontline Non–Clear Cell RCC


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Chung-Han Lee, MD, PhD, discusses the goals of the phase 3 KEYNOTE-B61 study and the potential for immunotherapy/TKI combinations in non–clear cell RCC.

Chung-Han Lee, MD, PhD

Chung-Han Lee, MD, PhD

Although non–clear cell renal cell carcinoma (RCC) is known to be a very heterogenous disease that has historically been shown to have resistance to systemic therapies, it is hypothesized that certain approaches designed for clear cell RCC may still produce benefit in this population, according to Chung-Han Lee, MD, PhD.

Previously, data from the phase 3 KEYNOTE-581/CLEAR trial (NCT02811861), which examined the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) in patients with metastatic clear cell RCC, showed promising antitumor activity with a manageable safety profile. These results provided the evidence that inspired the launch of the phase 2 KEYNOTE-B61 trial (NCT04704219), which will examine the combination as a first-line therapy in patients with non–clear cell RCC. The study is currently accruing.

“What we already know from the non–clear cell RCC space, is that pembrolizumab is a very active agent, but not everyone responds [to it]. By adding a TKI to an immune checkpoint inhibitor, we hope to see continued responses,” Lee said. “One of the key questions that we hope to answer is whether there are distinct subpopulations that benefit from this combination, and whether these 2 compounds interact with each other in such a way that provide synergism.”

In an interview with OncLive®, Lee, medical oncologist, Kidney Care, Bladder Care, Prostate Care, at Memorial Sloan Kettering Cancer Center, further discussed the goals of the KEYNOTE-B61 study and the potential for immunotherapy/TKI combinations in non–clear cell RCC.

OncLive®: What inspired the launch of the KEYNOTE-B61 trial?

Lee: Currently, there is a lot of interest in examining novel combinations of immune checkpoint inhibitors and TKIs for non–clear cell RCC. This type of combination has been studied extensively for clear cell RCC, where we have multiple FDA-approved regimens, and several regimens that have gained National Comprehensive Cancer Network designation. [Some of these] combinations include axitinib [Inlyta] plus pembrolizumab, cabozantinib [Cabometyx] plus nivolumab [Opdivo], axitinib plus avelumab [Bavencio], and lenvatinib plus pembrolizumab.

The idea for looking at this within non–clear cell RCC is that historically, this disease has been much more resistant to systemic therapies; however, it can still benefit from treatment with regimens that were approved and designed for clear cell RCC. The [goal of] the KEYNOTE-B61 study is to examine the combination of lenvatinib plus pembrolizumab and gain a further understanding of whether this type of regimen could provide additional benefit within the non–clear cell RCC space.

What is the design of the trial?

This is a single-arm, phase 2 study of 152 patients treated with the combination of lenvatinib, at a daily dose of 20 mg, plus pembrolizumab, at a dose of 400 mg every 6 weeks. The primary end point of the study was ORR by RECIST v1.1 [criteria], and key secondary end points included clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Beyond just looking at those standard efficacy end points, other interesting exploratory end points were built in to look at biomarker analysis to better understand which cohorts may benefit [best] from this combination.

Are patients currently being accrued to this trial?

Yes, this trial is ongoing, and we are just starting the process of accruing patients in North America, Europe, Asia, and Australia. It is too early to speak about any of the results from the trial, but we are encouraged by the data that we have seen in clear cell RCC, where we saw high ORR and a very long DOR. Another investigator-initiated trial examined lenvatinib plus everolimus [Afinitor], and this showed promising efficacy results. As such, we look forward to seeing what this type of combination will do [for these [patients].

What is your take-home message regarding the examination of this combination in this specific disease?

The most critical aspect of this work is to better understand non–clear cell RCC, and to not think about it as an entity that is equivalent to clear cell RCC. [The former] remains a very heterogeneous group of diseases, which may require more tailored therapies. As we learn more about these diseases, we [can hopefully] improve outcomes for our patients.

We need to commend the clinical trial sponsors and their willingness to do dedicated trials for non–clear cell RCC; this has often been an orphan disease group because it is so heterogeneous and results are so varied. Our ability to do large phase 2 clinical trials to explore efficacy, and to hopefully identify subpopulations that may derive further benefit, is critical.


  1. Lee C-H, Li C, Perini RF, et al. KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC). J Clin Oncol. 2021;39(supp 15):TPS4595. doi:10.1200/JCO.2021.39.15_suppl.TPS4595
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