Proactive Approach for Managing Adverse Reactions Associated With Lenvatinib/Pembrolizumab Needed in Advanced RCC

As lenvatinib plus pembrolizumab combination therapy results in a wide range of adverse effects, some which even led to discontinuation of the treatment, investigators suggest a proactive strategy for patients with advanced renal cell carcinoma.

Treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for advanced renal cell carcinoma (RCC) often resulted in the occurrence of adverse effects (AEs) within 5 months of treatment, leading investigators to develop a proactive approach to managing toxicities, according to results from an analysis of the phase 3 CLEAR study (NCT02811861) presented at the 2021 International Kidney Cancer Symposium North America.

Investigators recommend checking patients’ blood pressure, urine protein levels, and thyroid and liver function prior to treatment. Additionally, utilizing dosing interruptions or modifications for lenvatinib is an important part of managing toxicities.

Dose interruptions of lenvatinib, pembrolizumab, or both due to adverse effects (AEs) occurred in 78% of the patients who were treated with the combination regimen. A total of 69% of patients had their dose of lenvatinib reduced. Permanent discontinuation of either or both drugs in the combination group occurred in 37% of patients, with 26% stopping lenvatinib, 29% stopping pembrolizumab, and 13% stopping both. The median time to first dose reduction of lenvatinib was 1.87 months, and the median time to first dose interruption was 4.14 months.

The median time to onset of AE was found to occur with 5 months of initial treatment, with the shortest median time to onset occurring for hyper tension (3.0 weeks), dysphonia (3.0 weeks), and fatigue (4.4 weeks). The AEs with the longest median times to onset included diarrhea (20.0 weeks), weight decrease (17.4 weeks), and decreased appetite (14.6 weeks).

Findings from the CLEAR study led to the FDA approval of lenvatinib plus pembrolizumab for first-line treatment of advanced RCC in August 2021.

“Close monitoring of patients at the beginning of treatment is therefore critical, as [AEs] can often be managed with additional medical therapy if they are diagnosed early,” the investigators wrote. 

A total of 1069 patients were included in the CLEAR study, 355 of whom were randomized to the combination arm. In terms of baseline characteristics in the combination group, patients had a median age of 64 years and 30.1% had a PD-L1 score greater than 1 and 31.5% had a score less than 1. In total, 21.9% of patients had target kidney lesions, and 71.5% had 2 or more metastatic organ sites. Additionally, 73.8% of patients had a previously underwent a nephrectomy.

Within the CLEAR study, patients experienced improved outcomes after being treated with lenvatinib and pembrolizumab compared with sunitinib (Sutent). The median progression-free survival was 23.9 months in the combination group vs 9.2 months in the sunitinib group (HR, 0.39; 95% CI, 0.32-0.49; P <.001). Patients’ overall survival was significantly longer in the combination group vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005). Additionally, patients had an overall response rate of 71.0% in the combination group vs 36.1% in the sunitinib group (relative risk, 1.97; 95% CI, 1.69-2.29; nominal P <.001).

Patients were given 20 mg of lenvatinib orally once a day and 200 mg of pembrolizumab intravenously every 3 weeks. In the sunitinib arm, patients were given 50 mg of oral sunitinib every day with a 4 weeks on, 2 weeks off schedule. Patients could also receive 18 mg of oral lenvatinib once daily plus 5 mg of oral everolimus once daily.

The most common grade 3 or higher AEs included hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), and weight loss (8.0%). Additionally, common any grade AEs included fatigue (63.1%), diarrhea (61.9%), and musculoskeletal pain (58.0%).

Investigators stated that other strategies should be utilized to better manage AEs, such as administering an anti-diarrheal at the onset of soft bowl movements and monitoring blood pressure. If patients have grade 3 hypertension, lenvatinib should be withheld and only resumed when patients begin to experience the toxicity at grade 2 or lower.

If patients experience a grade 4 AE, lenvatinib and pembrolizumab should both be permanently discontinued. A total of 14.8% of patients in the combination group received high-dose corticosteroids to manage immune-related AEs.

“Clinicians play a critical role in the prompt identification and management of [AEs] in patients with RCC treated with lenvatinib [and] pembrolizumab. Prompt management of AEs may potentially reduce treatment interruption(s) and/or lenvatinib dose reduction and allow patients to continue receiving therapy,” the investigators concluded.


Motzer R, George S, Merchan J, et al. Characterization and management of adverse reactions in patients with advanced renal cell carcinoma receiving lenvatinib + pembrolizumab (CLEAR study). Presented at the 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, Texas. Abstract CTR14.

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