Lenvatinib Plus Pembrolizumab Makes an Impression in Advanced RCC

Robert J. Motzer, MD

The combination of lenvatinib (Lenvima), a kinase inhibitor, and pembrolizumab (Keytruda), a PD-1–blocking monoclonal antibody, has demonstrated strong efficacy results with a manageable safety profile in patients with advanced renal cell carcinoma (RCC). On August 10, 2021, the FDA approved the doublet for the first-line treatment of adult patients with RCC.¹

The approval was based on data from the phase 3 CLEAR; KEYNOTE-581 trial (NCT02811861), which compared lenvatinib plus pembrolizumab with single-agent sunitinib (Sutent). Results showed that patients treated with the combination (n = 355) achieved a median progression-free survival (PFS) of 23.9 months (95% CI, 20.8-27.7) compared with 9.2 months (95% CI, 6.0-11.0) in patients receiving sunitinib (n = 357; HR, 0.39; 95% CI, 0.32-0.49; P < .0001). Median overall survival (OS) was not reached in either cohort (HR, 0.66; 95% CI, 0.490.88; P = .0049) and the objective response rate (ORR) in the lenvatinib plus pembrolizumab arm was 71% (95% CI, 66%-76%) vs 36% (95% CI, 31%-41%) in the sunitinib arm.2 Further, the complete response rates were 16% and 4% in the combination and sunitinib arms, respectively.

In an interview with OncologyLive®, Robert J. Motzer, MD, the head of the Kidney Cancer Section of the Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York, and a Giants of Cancer Care® award winner in the genitourinary cancer category, spoke about the “exceptional” efficacy of the combination and how it fits into the evolving RCC treatment landscape.

Please describe the rationale for combining these agents for patients with RCC.

Lenvatinib is a tyrosine kinase inhibitor [TKI] that mainly targets the VEGF receptor. It’s a very potent oral TKI. It also targets other kinases, including fibroblast growth factor and platelet-derived growth factor receptors. It’s considered to be an oral antiangiogenesis drug, meaning clinically it has effect on the vasculature that surrounds and feeds tumors with a blood supply. Pembrolizumab is a PD-1 inhibitor that is widely used in many malignancies. It’s an intravenous checkpoint inhibitor that augments immune activity directed toward tumors. The combination of the 2 [agents] was largely fostered by [their] mechanisms of action. There were preclinical studies done [the results of which] suggested the 2 together had a high level of activity. Additionally, there has been a history of other TKI and IO [immuno-oncology] combinations that clinically have shown positive outcomes in phase 3 trials.

Was there any aspect of the trial results that you found surprising?

The activity of lenvatinib plus pembrolizumab was exceptional. The ORR was over 70%, with 16% [of patients experiencing] complete responses. In addition, the PFS was exceptional. The median PFS was 23.9 months by independent review compared with only 9.2 months with sunitinib. [The trial] met the primary end point of PFS and had a very high response rate, and there was a benefit in OS as well. The high response rate, median PFS, and the OS were really exceptional gains for that regimen. In fact, the response rate and the median PFS are really the longest we’ve seen in any of the first-line trials for RCC.

How does this approval potentially alter the treatment paradigm for patients with advanced RCC?

I’ve been in the field for over 30 years. When I was first an attending [physician] at Memorial Sloan Kettering the median PFS for the cytokines that we had at that time was only 4 months. The response rate was approximately 12%. The median OS was only between 9 to 12 months. You can see there’s been one benefit over another with TKI monotherapy, with IO therapy. Now with these TKI and IO combinations you can see [that with] the degree of response rates, [including] the complete responses and a median PFS of almost 24 months, how much of a therapeutic gain it is for our patients.

What are some strategies clinicians can employ to manage the immune-mediated adverse effects (AEs) that can arise from this combination?

The immune-related AEs are relatively modest in frequency with lenvatinib plus pembrolizumab. Usually they are managed by either delaying the pembrolizumab, or if they’re moderately severe or highly severe, then we use steroids for management. But for the most part with TKI/IO therapy there are a relatively modest number of immune-related AEs.

A majority of the AEs that we see with levantinib plus pembrolizumab are more directed toward levantinib as a TKI, and include diarrhea, hypertension, some fatigue, and some skin toxicity, [among others]. Those largely make up the predominant AEs of the regimen and are mostly managed by local symptomatic management. For example, with diarrhea [we use] Imodium [Ioperamide], dose reduction, or dose delay. With this program, there are a high number of [individuals who] wound up having a dose reduction of the levantinib on the program, approximately 60%, [because of] AEs over the course of their therapy.

What does the future hold for lenvatinib plus pembrolizumab?

There are 2 ongoing studies that are industry sponsored that have levantinib plus pembrolizumab as the backbone of the regimen. These studies are combining levantinib plus pembrolizumab with other immunotherapies or with the new busulfan inhibitor. For levantinib plus pembrolizumab the efficacy with this particular [combination] would be tough to beat, but there are some trials that are adding additional agents to the combination.

References

1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed August 17, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma
2. Lenvima. Prescribing information. Eisai Inc; 2021. Accessed August 17, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206947s019lbl.pdf