Researchers have characterized common adverse reactions (ARs) to combination treatment with lenvatinib and pembrolizumab in patients with advanced renal cell carcinoma.

The team also reviewed management strategies for these adverse reactions. Their work was published in The Oncologist.

The researchers characterized adverse reactions using data from 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study ( Identifier: NCT02811861).

Key adverse reactions, which occurred in at least 30% of patients, included fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), hypertension (56.3%), stomatitis (43.2%), decreased appetite (40.6%), rash (37.2%), nausea (35.8%), dysphonia (29.8%), proteinuria (29.8%), and weight decrease (29.8%).

The median time to the first onset of all key adverse reactions ranged from 3 weeks (for hypertension and dysphonia) to 20 weeks (for diarrhea).

Grade 3 or higher adverse reactions that occurred in at least 5% of patients included hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decrease (8.0%), and proteinuria (7.7%).  Clinically relevant adverse reactions included myocardial infarction (3%) and angina pectoris (1%).

The researchers noted that the prescribing information for lenvatinib recommends dose reductions or discontinuations in the context of certain adverse reactions. For most grade 4 adverse reactions, lenvatinib should be discontinued.

Lenvatinib should be withheld for any grade 3 adverse reactions or for grade 2 adverse reactions that are persistent or intolerable. When the ARs become grade 1 or lower, or return to baseline, lenvatinib can be resumed at a reduced dose. The dosage can be reduced progressively to 14 mg, 10 mg, and 8 mg, each step once daily.

The CLEAR study protocol deviated from the recommendations in the prescribing information, allowing patients to resume lenvatinib at a reduced dose for most adverse reactions if they downgraded to tolerable grade 2 or lower adverse reactions.

On the other hand, dose reduction is not recommended for pembrolizumab. The treatment should be withheld in the case of most immune-related adverse reactions (irARs) that are grade 3 or grade 2 and persistent/intolerable. Pembrolizumab can be resumed after the irAR has improved to grade 0 or 1 and any corticosteroid dose has been tapered.

Pembrolizumab should be discontinued in the case of life-threatening grade 4 irARs, recurrent severe irARs that require systemic immunosuppressive treatment, irARs that do not resolve within 12 weeks of the last dose, or if the corticosteroid doses cannot be reduced to 10 mg or lower of prednisone or the equivalent per day within 12 weeks.

Corticosteroid tapering should start when the irAR improves to grade 0 or 1 and should continue over 4 weeks or more. For severe and life-threatening irARs, start with intravenous corticosteroids and follow with oral steroids. If the irARs are not controlled by corticosteroids, other immunosuppressive treatment should be used.

“Close monitoring of patients treated with lenvatinib plus pembrolizumab is critical because ARs can occur at any time and can be managed with additional medical therapy if they are diagnosed promptly,” 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 LLC. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Motzer R, George S, Merchan JR, et al. Characterization and management of adverse reactions from the CLEAR study in advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab. Oncologist. Published online March 2, 2023. doi:10.1093/oncolo/oyac269

This article originally appeared on Cancer Therapy Advisor