Lenvatinib Plus Everolimus Under Investigation Vs Cabozantinib in PD-1–Pretreated mRCC

Andrew W. Hahn, MD

The combination of lenvatinib (Lenvima) plus everolimus (Afinitor) is under evaluation vs cabozantinib (Cabometyx) in the phase 2 LenCabo trial (NCT05012371) for patients with metastatic renal cell carcinoma (RCC) who have progressed on prior treatment with a PD-1/PD-L1 immune checkpoint inhibitor, according to a presentation at the 2022 International Kidney Cancer Symposium.

Both single-agent cabozantinib and the combination of lenvatinib plus everolimus have received FDA approval for patients with metastatic RCC following progression on angiogenesis targeted therapies. Lenvatinib and cabozantinib have similar, but distinct, mechanisms of action, and the agents have not been compared head-to-head in a randomized clinical trial.

“We hypothesize that lenvatinib plus everolimus will produce a longer progression-free survival [(PFS) benefit] compared to cabozantinib in patients with metastatic RCC that progressed on a prior PD-1/PD-L1 checkpoint inhibitor,” lead study author Andrew W. Hahn, MD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues, wrote in a poster presentation overviewing the trial.

The trial is enrolling patients with histologically confirmed metastatic/advanced clear cell RCC who progressed on a PD-1/PD-L1 checkpoint inhibitor and 1 to 2 prior lines of treatment. Patients are required to have measurable disease per RECIST v1.1 criteria. Notably, patients with treated or stable brain metastases for at least 4 weeks are permitted to enroll.

Key exclusion criteria include prior treatment with lenvatinib, a c-MET inhibitor, or an mTOR inhibitor; radiotherapy within 14 days of enrollment; major surgery within 28 days of enrollment; active inflammatory bowel disease; or uncontrolled medical conditions, such as systolic blood pressure greater than 140 mmHG or diastolic blood pressure above 90 mmHG on anti-hypertensives.

Enrolled patients will be randomly assigned 1:1 to receive 18 mg of lenvatinib plus 5 mg of everolimus per day or cabozantinib monotherapy at 60 mg daily. Treatment will continue until disease progression or unacceptable treatment-related toxicity. Crossover between arms is permitted.

Stratification factors include IMDC risk group and prior receipt of VEGF-targeted therapy.

PFS is serving as the trial’s primary end point. Secondary end points include objective response rate, disease control rate, overall survival, health-related quality of life, and safety. An exploratory end point will assess whether c-MET, AXL, VEGF, mTOR, or FGFR alterations are associated with response to treatment.

PFS will be monitored through a Bayesian optimal phase 2 design, and an interim analysis will be performed when 50 patients are enrolled. The null hypothesis is that both arms will produce a median PFS of 7.4 months. An alternate hypothesis says that lenvatinib plus everolimus will generate a median PFS of 12.8 months.

LenCabo is currently enrolling patients at The University of Texas MD Anderson Cancer Center. The trial will open at Moffitt Cancer Center and The University of Virginia Emily Couric Clinical Cancer Center within the next 6 months.

Reference

Hahn AW, Chahoud J, Skelton WP, et al. A phase II study of lenvatinib plus everolimus versus cabozantinib in patients with metastatic renal cell carcinoma (mRCC) that progressed on a PD-1/PD-L1 checkpoint inhibitor (LenCabo). Presented at: International Kidney Cancer Symposium; November 4-5, 2022; Austin, TX. Abstract 51.