Audrey Sternberg

Combination therapy with lenvatinib (Lenvima) plus everolimus (Afinitor) demonstrated potential as an option for patients with clear cell renal cell carcinoma (RCC) who progressed following treatment with an immune checkpoint inhibitor (ICI), according to findings presented during the 2021 Genitourinary Cancers Symposium.

The findings were generated from an exploratory analysis of a phase 2 trial (NCT03173560) involving patients with RCC who progressed during or after treatment with a VEGF inhibitor. The primary goal of the trial was to examine the safety and efficacy of lenvatinib at 2 different starting doses combined with a fixed dose of everolimus.

“Because of changes to the treatment landscape, first-line treatment often includes immune checkpoint inhibitor therapy, and therefore, it is important to examine the antitumor response and safety of lenvatinib [plus] everolimus in this patient subgroup,” the study investigators, who were led by Sumanta K. Pal, MD, wrote in their post presentation.

Out of 343 patients enrolled in the trial, 90 received ICIs in a prior line of therapy. These patients received 14 mg (n = 49) or 18 mg (n = 41) of daily lenvatinib plus 5 mg of daily everolimus. Patients in the 14 mg starting dose group were escalated to 18 mg in the absence of intolerable adverse events (AEs) or dose reductions at 4 weeks. The trial’s primary end points were the objective response rate (ORR) at week 24 and the rate of grade 2 or higher AEs. Progression-free survival (PFS), ORR, and overall survival (OS) were amongst the secondary outcome measures.

The median PFS in patients receiving prior ICI therapy was 12.0 months (95% CI, 8.9-16.7) in the 14 mg group and 12.9 months in the 18 mg group (95% CI, 8.4-not evaluable [NE]), with a hazard ratio of 1.27 (95% CI, 0.74-2.20). By independent imaging review (IIR), the median PFS was numerically shorter with the lower starting dose of lenvatinib, at 11.0 months (95% CI, 34.8%-67.6%) and 12.9 months (95% CI, 8.9%-16.7%).

Median OS was 17.1 months (95% CI, 10.6-NE) with the 14 mg starting dose of lenvatinib and 18.0 months (95% CI, 13.1-NE) with 18 mg lenvatinib, for a hazard ratio of 1.28 (95% CI, 0.75-2.18).

The ORRs were higher for patients receiving 18 mg lenvatinib at 51.3% (95% CI, 34.8%-67.6%) versus 30.2% (95% CI, 17.2%-46.1%) for those in the 14 mg lenvatinib group.

By IRR, the ORRs at week 24 in the 14 mg and 18 mg groups were 39.1% (95% CI, 31.4%-46.8%) and 34.8% (95% CI, 27.3%-42.3%), respectively (odds ratio, 1.20; 95% CI, 0.82-1.76). Also, by IRR, the corresponding overall ORRs were 39.7% (95% CI, 32.1%-47.4%) and 38.7% (95% CI, 31.0%-46.4%), with an odds ratio of 1.04 (90% CI, 0.71-1.53).

“The exploratory end point results of [the 24-week ORR] by IRR demonstrated a numerical benefit for the lenvatinib starting dose of 14 mg versus 18 mg (both in combination with everolimus),” the investigators wrote. “However, this advantage disappeared when evaluating the ORR by IIR with additional follow-up–as the overall ORR by IIR was similar between the study-treatment arms.”

The investigators stated that there was a high level of concordance (>80%) between investigator assessment and IIR for both the overall ORR and the ORR at week 24.

The safety profile for the subset of patients with prior ICI experience was similar to the overall patient population. In the 14 mg and 18 mg groups, the most common any-grade treatment-emergent AEs included (61.2% vs 70.7%, respectively) decreased appetite (44.9% vs 51.2%), stomatitis (30.6% vs 43.9%), nausea (32.7% vs 43.9%), hypertension (42.9% vs 39.0%), fatigue (34.7% vs 34.1%), asthenia (30.6% vs 29.3%), vomiting (32.7% vs 51.2%), and proteinuria (32.7% vs 43.9%).

The investigators concluded by stating that, “when taken together, the efficacy results by investigator [assessment] and IIR are supportive of the higher lenvatinib 18 mg starting dose compared with 14 mg.”

Lenvatinib is approved in combination with everolimus for the treatment of patients with RCC following prior VEGF-inhibitor therapy based on results of the phase 1/2 Study 205 (NCT01136733).

1. Pal SK, Puente J, Yick Chin Heng D, et al. Phase II trial of lenvatinib (LEN) at two starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma (RCC): Results by independent imaging review (IIR) and prior immune checkpoint inhibition (ICI). 

. 2021;39(suppl 6):307. doi:10.1200/JCO.2021.39.6_suppl.306

2. Lenvima. Prescribing information. Eisai; 2015. Accessed February 11, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206947s018lbl.pdf

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