Research Frontiers Does lowering the starting dose of lenvatinib affect the efficacy of advanced RCC?

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Guide

Based on the results of Study 205, lenvatinib (18 mg) in combination with everolimus (5 mg) has been approved in Europe and the United States for the second-line treatment
of patients with advanced renal cell carcinoma (RCC) who have progressed after a previous antiangiogenic therapy 。 In order to reduce the occurrence of adverse events (TEAEs) during treatment, the US research team conducted a large-scale lenvatinib dose optimization study and published the results in European Urology.

Research background

To explore the optimal dosing regimen for lenvatinib, the research team, in collaboration with the U.
S.
Food and Drug Administration (FDA), developed a pharmacokinetic/pharmacodynamic model of tumor growth that showed that a lower starting dose of lenvatinib (14 mg) may be equal
to or better than the conventional starting dose of lenvatinib (18 mg) in patients with advanced RCC.
This study aims to validate model predictions and assess whether the efficacy and safety of low starting doses of lenvatinib in patients with advanced RCC are comparable (with conventional dosing regimens
).

Study design

This is a randomized, open-label, phase II trial conducted worldwide in patients with advanced RCC
who have progressed to disease following prior targeted therapy (or anti-PD-1/PD-L1 therapy) with a vascular endothelial growth factor (VEGF).
Patients were randomized (1:1) to 14 or 18 mg of lenvatinib starting dose group, all plus everolimus 5 mg/day
.
Unless grade 2 or any ≥ grade 3 TEAEs that cannot be tolerated or require dose reduction occur within the first 28-day cycle, patients in the 14 mg group should increase the lenvatinib dose to 18 mg
on day 1 of cycle 2.
The primary endpoint of efficacy was the objective response rate (ORR_wk24) assessed by the investigator at 24 weeks, with a unilateral p-value ≤0.
045)
in the 14 and 18 mg groups.
The primary endpoint of safety was the proportion
of patients in both groups who developed intolerable grade 2 or any ≥ grade 3 TEAEs within 24 weeks.

Study results

The ORR_wk24 was 32% (95% CI 25-39) in the 14 mg group and 35% (95% CI 27-42) in the 18 mg group, with an odds ratio (OR) of 0.
88 (90% CI 0.
59-1.
32), and a p-value of 0.
3 (no preset non-inferior efficacy cut-off) for the non-inferiority test, so it cannot be concluded that a low starting dose of lenvatinib is not inferior to the conventional starting dose of lenvatinib
。 At data cut-off, there was 1 patient with a complete response (CR) and 53 patients with a partial response (PR) in the 14 mg group, with an ORR of 35% (95% CI 27-42), 2 patients in the 18 mg group, 61 patients with PR, an ORR of 41% (95% CI 33-48), and an OR of 0.
77 (90% CI 0.
52-1.
14).

Table 1 ORR analysis of patients in two groups

The results of safety analysis showed that there was no significant difference in the incidence of grade 2 or any ≥ grade 3 TEAEs that could not be tolerated within 24 weeks between the two groups (14 mg versus 18 mg, 83% vs 80%, p=0.
5).

Most treated patients (≥99%) developed at least one TEAEs, and the incidence of the most common levels of TEAEs of any grade was similar between the 14 mg and 18 mg groups, including diarrhea (68 versus 72 percent), decreased appetite (35 versus 35 percent), hypertension (30 versus 36 percent), stomatitis (34 versus 28 percent), and nausea (31 versus 31 percent
。

Table 2 Analysis of common TEAEs in the two groups

The primary endpoint ORR and secondary endpoints progression-free survival (PFS) and overall survival (OS) were better
in the 18 mg group.
The study had certain limitations
as the study design did not provide a comprehensive comparison of PFS between the two groups.

Conclusion of the study

The results of this study suggest that the efficacy of lenvatinib at low doses (14 mg) differs from the approved dose (18 mg), and although safety results are similar, the approved dosage regimen
of 18 mg lenvatinib plus everolimus 5 mg daily should be used in patients with advanced RCC.

References:

Pal SK, Puente J, Heng DYC,et al.
Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial.
Eur Urol.
2022 Sep; 82(3):283-292.