Safety, Tolerability Profile for Low-Dose Lenvatinib Is Similar to Standard Dose in RCC


Findings from a phase 2 trial evaluating lenvatinib given at 2 different starting doses, 14 mg versus 18 mg, in combination with everolimus, suggest the lower dose is similar to the standard dose in terms of efficacy and safety with minimal differences observed between the 2 arms.

Sumanta Pal, MD

Although standard second-line therapy for advanced renal cell carcinoma (RCC) includes lenvatinib (Lenvima) administered at 18 mg/day plus everolimus (Afinitor) administered at 5 mg/day, efforts to identify the optimal dose for this combination continue. Findings from a phase 2 trial (NCT03173560) evaluating lenvatinib given at 2 different starting doses, 14 mg versus 18 mg, in combination with everolimus, suggest the lower dose is similar to the standard dose in terms of efficacy and safety with minimal differences observed between the 2 arms.1

“Our study demonstrated that noninferiority cannot be claimed for the 14-mg dose versus the 18-mg dose,” lead author Sumanta Pal, MD, said in a presentation of the data during the International Kidney Cancer Symposium 2020, held virtually on November 6-7, 2020. “We observed a very slight difference in objective response rate [ORR], 32.1% for the 14-mg dose versus 34.8% in the 18-mg dose.”

Previously, in a multicenter phase 1/2 study (NCT01136733), patients were randomized 1:1:1 to receive either lenvatinib (18 mg/day) plus everolimus (5 mg/day), single-agent lenvatinib (24 mg/day), or single-agent everolimus (10 mg/day). Patients in the lenvatinib combination arm demonstrated 14.6 months of progression-free survival (PFS) compared with 5.5 months for single-agent everolimus.2 However, in this study, dose interruptions were reported in 89% of patients treated with the combination and treatment discontinuation was reported in 29%, suggesting a need for diligent monitoring and optimization of management strategies.

The current study evaluated patients with advanced clear cell kidney cancer who had progressed on prior treatment with 1 VEGF inhibitor. Patients were randomized to receive the combination with either 14 or 18 mg/day of lenvatinib based on the MSKCC prognostic model as well as by exposure to prior PD-1 or PD-L1–directed therapy.

“Importantly, [in the investigational arm] if the drug was tolerated for a span of 4 weeks without intolerable grade 2 or any grade ≥3 treatment-emergent adverse events [TEAEs] that required dose reduction, the lenvatinib dose would be increased to 18 mg/day, [which was a coprimary end point],” said Pal, clinical professor, Department of Medical Oncology and Therapeutics Research, and codirector, Kidney Cancer Program, City of Hope Comprehensive Cancer Center in Duarte, California. The other coprimary end point was efficacy with an objective response rate (ORR) as of week 24. Secondary end points included overall ORR, PFS, and overall survival (OS). From a primary efficacy end point, Pal said the study used a one-sided P value that had to be ≤ .045 in order for noninferiority to be declared. The primary safety end point was based on a superiority test.

Initially, the study was designed to be double-blinded, Pal said, but because of a computer error affecting dose reassignment, which affected 33 patients, the sponsor Eisai unblinded the study to ensure patient safety and continued the study as an open-label trial. Although 306 patients were planned for the study, investigators enrolled 32 additional patients to replace those patients affected by the computer error.

As a result, the analysis sets were divided into a full analysis set (N = 343), a per-protocol analysis set (n = 331), a per-protocol safety analysis set (n = 309), and a safety analysis set (n = 341).

Patient characteristics at baseline were similar between the 2 treatment arms, with an overall median age of 61 to 62 years, most patients were considered favorable risk based on the MSKCC prognostic model, and the majority of patients (82.8%) underwent prior nephrectomies. Between 24% to 29% of patients received prior PD-1/PD-L1 treatment and most patients received either 1 or 2 prior lines of anticancer treatments.

At the 24-week investigator assessment, Pal described the difference between the 2 doses as marginal (32.1% vs 34.8% with 18-mg lenvatinib) with an odds ratio of 0.88 (90% CI, 0.59-1.32, P = .2676). “Keep in mind that we were looking for a P value of less than .045,” Pal said.

Reviewing tumor response, Pal reported an overall ORR of 34.6% for the 14-mg arm and 40.6% for the 18-mg arm. The median duration of response observed for both arms was also similar with 11.5 months in the 14-mg arm (95% CI, 7.5-19.2) versus 11.7 months in the 18-mg arm (95% CI, 9.1-not evaluable).

“Meaningful differences across baseline characteristics are difficult to tease out,” Pal said, “but patients with baseline hypertension or those patients who had prior PD-1 or PD-L1–directed therapy may benefit [to] a greater extent [from] lenvatinib at 18 mg.”

PFS for patients in the 14-mg arm was 11.1 months (95% CI, 9.0-12.9) compared with 14.7 months (95% CI, 11.1-20.3) in the 18-mg arm. OS will require further follow up, said Pal, because in the 14-mg arm, the OS was 27.0 months (95% CI, 18.3-not evaluable) compared with not evaluable (95% CI, 23.8-not evaluable) in the 18-mg arm.

Regarding tolerability, patients in the 14-mg arm had intolerable grade 2 or any grade ≥3 TEAEs at a rate of 82.8% versus 79.6% for the 18-mg arm, which was a difference of 3.2 percentage points (95% CI, –5.5 to 11.9; P = .47). Median duration of treatment was 7.72 months in the lower-dose arm versus 8.18 months in the higher-dose arm. The proportion of patients who received the median lenvatinib dose as a percentage of the planned dose was 76% at 14 mg and this was similar for the 18-mg dose. Dose reductions were also similar between the 2 treatment arms, which was about 65%, said Pal. Time to first dose reduction was approximately 2 months.

Regarding TEAEs that led to study-drug discontinuation, a higher percentage was observed in the 14-mg arm versus the 18-mg arm but rates of dose interruptions were higher in the 18-mg arm versus the 14-mg arm. Rates of study-drug reductions due to TEAEs were similar for both arms. The most common TEAEs (≥20%) in either treatment arm were diarrhea, hypertension, proteinuria, and decreases in appetite. The rate of patients who experienced serious TEAEs (≥2%) was also similar between the 2 treatment arms (49.1% vs 48.8%).

“PFS and OS seemed to trend towards favoring the 18-mg dose,” Pal said. With no significant differences in the proportion of patients with grade 2 or grade 3 TEAEs and no true differences in safety across the treatment populations, Pal concluded that the data support the current dosing regimen of lenvatinib at 18 mg/day plus everolimus at 5 mg/day.


1. Pal S, Puente J, Heng DYC, et al. Phase 2 trial of lenvatinib at 2 starting doses + everolimus in renal cell carcinoma. Presented at: International Kidney Cancer Symposium 2020. November 6-7, 2020; Virtual.

2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

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