The following article features coverage from the International Kidney Cancer Symposium 2021. Click here to read more of Cancer Therapy Advisor’s conference coverage.

A proactive approach to managing adverse reactions (ARs) is “critical” when treating patients with lenvatinib plus pembrolizumab, according to a poster presentation at the International Kidney Cancer Symposium (IKCS) 2021.1

Researchers found that, in the phase 3 CLEAR trial, the median time to first onset of key ARs was within 5 months of starting lenvatinib-pembrolizumab treatment.

“Close monitoring of patients at the beginning of treatment is therefore critical, as ARs can often be managed with additional medical therapy if they are diagnosed early,” the researchers wrote in their poster.

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The team analyzed ARs associated with lenvatinib plus pembrolizumab in the CLEAR trial ( identifier: NCT02811861), which was designed to compare lenvatinib plus pembrolizumab, lenvatinib plus everolimus, and sunitinib alone in patients with treatment-naïve, advanced renal cell carcinoma. 

Of the 1069 patients enrolled in the study, 355 were assigned to receive lenvatinib plus pembrolizumab.

AR Incidence and Onset

The most common ARs of any grade that occurred in more than 50% of patients on lenvatinib-pembrolizumab were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%).

ARs with a shorter median time to first onset were hypertension (3.0 weeks), dysphonia (3.0 weeks), and fatigue (4.4 weeks). ARs with a longer median time to onset included diarrhea (20.0 weeks), weight loss (17.4 weeks), and decreased appetite (14.6 weeks).

Grade 3 or higher ARs with a shorter median time to onset included hypertension (28.7%, 3.1 weeks), proteinuria (7.7%, 5.1 weeks), rash (4.5%, 8.1 weeks), and hypothyroidism (1.4%, 9.1 weeks). 

Grade 3 or higher ARs with a longer median time to onset included stomatitis (2.0%, 14.3 weeks), fatigue (9.4%, 19.4 weeks), musculoskeletal pain (3.7%, 20.7 weeks), diarrhea (9.9%, 21.4 weeks), decreased appetite (4.0%, 23.6 weeks), weight loss (8.0%, 51 weeks), and nausea (2.6%, 62 weeks).

Dose Reductions, Discontinuations

ARs led to dose interruptions of lenvatinib, pembrolizumab, or both in 78% of patients. Permanent discontinuation of lenvatinib, pembrolizumab, or both occurred in 37% of patients.

The lenvatinib dose was reduced in 69% of patients. The median time to the first dose reduction of lenvatinib was 1.87 months (range, 0.10-37.98 months), and the median time to the first dose interruption of lenvatinib was 4.14 months (range, 0.07-30.59 months).

The researchers noted that certain ARs, such as diarrhea, may be attributable to either lenvatinib or pembrolizumab, so it is important to determine which drug is causing the AR.

“The timing of first onset of such ARs may be critical in making this determination,” the researchers wrote. “Since lenvatinib is administered daily and has a shorter half-life, dose interruption of lenvatinib may be considered as a first-line approach to determine whether clinical resolution can be obtained. If there is no clinical improvement, an immune-mediated AR may be considered.”

The researchers recommended using “optimal medical management” in accordance with the prescribing information for lenvatinib and pembrolizumab.2,3 For example, for many ARs — such as musculoskeletal pain, fatigue, nausea, and diarrhea — the recommendation is to withhold lenvatinib for persistent or intolerable grade 2-3 severity. Once AR severity decreases to grade 1 or lower, lenvatinib can be resumed at a lower dose.

“Clinicians play a critical role in the prompt identification and management of ARs,” the researchers wrote. “Prompt management of ARs may potentially reduce treatment interruption(s) and/or lenvatinib dose reduction and allow patients to continue receiving therapy.”

Disclosures: This research was supported by Eisai Inc., and Merck Sharp & Dohme Corp. Some study authors declared affiliations with Eisai and Merck.

Read more of Cancer Therapy Advisor’s coverage of IKCS 2021 by visiting the conference page.


1. Motzer R, George S, Merchan JR, et al. Characterization and management of adverse reactions in patients with advanced renal cell carcinoma receiving lenvatinib + pembrolizumab (CLEAR study). Presented at IKCS 2021. Abstract CTR14.

2. Lenvima (lenvatinib). Prescribing information. Eisai Inc. Accessed November 6, 2021.

3. Keytruda (pembrolizumab). Prescribing information. Merck. Accessed November 6, 2021.

This article originally appeared on Cancer Therapy Advisor