Managing Adverse Reactions in Patients With RCC Treated With Lenvatinib/Pembrolizumab

Robert J. Motzer, MD

An analysis from the phase 3 CLEAR trial (NCT02811861) of patients with advanced renal cell carcinoma (RCC) treated with the lenvatinib (Lenvima) plus pembrolizumab (Keytruda) regimen showed adverse reactions (ARs) most often occurred within the first 5 months of treatment.¹

The study authors, led by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, suggested in a poster presented at the 2021 International Kidney Cancer Symposium that proactive management of treatment-emergent adverse events (AEs), including treatment interruption, was crucial for patients receiving the regimen.

“Clinicians play a critical role in the prompt identification and management of ARs in patients with [advanced] RCC treated with lenvatinib plus pembrolizumab,” Motzer et al wrote in their poster. “Prompt management of ARs may potentially reduce treatment interruption(s) and/or lenvatinib dose reduction and allow patients to continue receiving therapy.”

In the analysis, AEs were defined by 12 different AR groupings: fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, dysphonia, proteinuria, and weight decrease.

Of the 352 patients treated with at least 1 dose of the combination in the original CLEAR trial,² the total exposure was 542.9 person-years. The most common ARs of any grade reported were fatigue in 63.1%, diarrhea in 61.9%, musculoskeletal pain in 58.0%, hypothyroidism in 56.8%, hypertension in 56.3%, stomatitis in 43.2%, and decreased appetite in 40.6%. The most common grade 3 or higher ARs were hypertension in 28.7%, diarrhea in 9.9%, fatigue in 9.4%, weight decrease in 8.0%, and proteinuria in 7.7%.¹

The exposure-adjusted incidence of the most common ARs was 567 (1.08/total exposure) for diarrhea, 480 (0.91/ total exposure) for musculoskeletal pain, 370 (0.70/total exposure) for fatigue, and 340 (0.65/total exposure) for hypertension.

No difference was noted overall in the safety profile between patients who were 65 years or older and those who were under 65 years old.

The median time to first onset of all ARs was approximately 5 months.

The median time to first onset of hypertension of any grade was 3.0 weeks, with a minimum time of 0.1 weeks and a maximum time of 126.9 weeks. A total of 9.1% interrupted their lenvatinib dose due to hypertension, 11.9% reduced their dose of lenvatinib, and 0.9% discontinued lenvatinib. Pembrolizumab was interrupted in 3.1% and discontinued in 0.3%. With dysphonia, the median time to onset was 3.0 weeks, with a minimum of 0.1 weeks and a maximum of 129.3. Only 0.6% interrupted or reduced their dose of lenvatinib. Among patients experiencing fatigue, the median time to onset was 4.4 weeks, with a minimum of 0.1 weeks and a maximum of 128.3 weeks. Lenvatinib was interrupted in 11.1%, reduced in 9.7%, and discontinued in 0.6%. Pembrolizumab was interrupted in 7.4% and discontinued in 0.3%.

On the other end of the spectrum, the median time to onset of diarrhea was 20.0 weeks, with a minimum of 0.3 weeks and a maximum of 118.0 weeks. Lenvatinib was interrupted in 17.6%, reduced in 16.2%, and discontinued in 1.4%. Pembrolizumab was interrupted in 10.2% and discontinued in 1.1%. The minimum time to onset of weight decrease was 1.1 weeks, the maximum was 114.1 weeks, and the median was 17.4 weeks. Lenvatinib was interrupted in 2.6%, reduced in 2.8%, and discontinued in 0.3%.Pembrolizumab was interrupted in 1.4% and discontinued in 0.6%.

The median time to first onset of grade 3 or higher hypertension was 3.1 weeks, with a minimum of 0.1 weeks and a maximum of 126.9 weeks. Proteinuria of grade 3 or higher had a median of 5.1 weeks to onset, with a minimum of 2.0 weeks and a maximum of 108.1 weeks. Rash of grade 3 or higher had a median of 8.1 weeks to onset, with a minimum of 2.4 weeks and a maximum of 113.9 weeks. The median time to first onset of grade 3 or higher hypothyroidism was 9.1 weeks, with a minimum of 5.9 weeks and a maximum of 60.1 weeks.

On the other end of the spectrum, grade 3 or higher nausea had a median time to first onset of 62.0 weeks, with a minimum of 14.4 weeks and a maximum of 91.1 weeks. The median time to first onset of weight decrease was 51.0 weeks, with a minimum of 15.1 weeks and a maximum of 98.9 weeks.

AR Management

For management of ARs in patients treated with the regimen, Motzer et al suggested baseline monitoring of blood pressure, urine protein levels, and thyroid and liver function. In the study, AEs were managed with dose modifications of lenvatinib, with reductions reported in 69% of patients. Lenvatinib was discontinued in 26% of patients, and pembrolizumab in 29%. Both were discontinued in 13%. The median time to first dose reduction of lenvatinib was 1.87 months (range, 0.10-37.98) and 4.14 months (range, 0.07-30.59) to first interruption.

According to the lenvatinib prescribing information, in the case of a persistent or intolerable grade 2 or 3 AR, it is recommended to withhold the drug until the AR improves to grade 1 or less, then resume therapy at a reduced dose.3 Permanent discontinuation is recommended in the case of a grade 4 AR. The original trial also recommended an antidiarrheal agent at the time of treatment initiation or the onset of symptoms.²

From the standard 20-mg start dose of lenvatinib, given once daily, the first recommended reduction is to a 14-mg dose, followed by 10 mg, then 8 mg.³

In the case of hypertension, blood pressure should be monitored after 1 week of treatment, then every 2 weeks for the first 2 months, followed by monthly thereafter, the study authors recommended.1 Lenvatinib should be withheld and later reduced in the case of grade 3 hypertension that does not alleviate with antihypertensive therapy. In the original study, if a patient was not already on an antihypertensive therapy, starting one would be indicated.²

High-grade corticosteroids were taken by 14.8% of the patients in the original trial to manage immune-mediated AEs. If a grade 4 immune-mediated AE occurs, prescribing information recommends pembrolizumab be discontinued.⁴

Understanding which agent is the causative agent for the AR helps to determine which agent to reduce or withhold. If there is no improvement, an immune-mediated AE may be considered, the study authors suggest.¹

_REFERENCES:

_{1. Motzer R, Geore 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: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract CTR14.}

_{2. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

_{3. Lenvima. Prescribing information. Eisai Inc; 2021. https://bit.ly/3m0SzcW}

_{4. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2021. https://bit. ly/3rYb0Tj}