Lenvatinib/Pembrolizumab Combo Demonstrates Strong Antitumor Activity in Metastatic RCC

Chung-Han Lee, MD, PhD

Findings from a planned interim analysis of the Ib/II Study 111 showed that lenvatinib (Lenvima) plus pembrolizumab (Keytruda) induced a disease control rate of 94% in patients with metastatic clear cell renal cell carcinoma (RCC) who regressed following treatment with a PD-1/PD-L1 inhibitor.¹

Lead author Chung-Han Lee, MD, PhD, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York, presented results from the phase II portion of the study during the 18th International Kidney Cancer Symposium in Miami, Florida. “Almost all patients did end up showing at least some shrinkage of their tumors,” he said.

Investigators are conducting an ongoing phase II study evaluating lenvatinib plus pembrolizumab in patients with metastatic RCC. Patients were assigned to 20 mg daily lenvatinib plus 200 mg intravenous pembrolizumab every 3 weeks until progression or toxicity.

This analysis included 33 patients who experienced regression after treatment with a PD-1/PD-L1 inhibitor. Lee said the trial is still recruiting patients and hopes to eventually accrue a population of 100.

The objective response rate (ORR) at week 24, the primary endpoint, was 61% (95% CI, 42%-77%).

Confirmed ORR by investigator review was 64% (95% CI, 45%-80%) and was made up of all partial responses. An additional 10 patients (30%) had stable disease and 2 (6%) were not evaluable for response.

The duration of response was 9.1 months (95% CI, 6.1-not evaluable). The median time to response in responders was 1.6 months (95% CI, 1.1-14.0).

Lee said that, according to investigator assessment by immune-related (ir)RECIST, the median progression-free survival (PFS) was 11.3 months (95% CI, 7.3-not evaluable). “Results were similar when we looked at it with RECIST v1.1, with a median PFS of 11.2 months and a 95% CI of 5.6 months to not yet evaluable,” he added.

Lee said the safety results were “fairly characteristic” of patients treated with a VEGF/immune checkpoint inhibitor combination. One patient (3%) died of a suspected treatment-related adverse event (TRAE) and 18 (55%) experienced grade 3/4 TRAEs.

Six patients (18%) experienced any-grade hypothyroidism and 2 each (6%) experienced colitis, hyperthyroidism, or severe skin reaction. One patient developed pneumonitis.

The FDA issued a breakthrough therapy designation to the combination of lenvatinib and pembrolizumab for the treatment of patients with advanced and/or metastatic RCC in January 2018 based on earlier results from Study 111.²In the RCC cohort of the study, patients treated with the combination had an objective response rate (ORR) of 63.3% (95% CI, 43.9%-80.1%), based on an earlier data cutoff of March 1, 2017.³

The phase Ib portion of Study 111 enrolled 13 patients with metastatic solid tumors, 8 of whom had RCC that progressed after treatment with approved therapies and who had an ECOG performance status ≤1. The phase II RCC cohort at this analysis, whose results were presented at the European Society for Medical Oncology 2017 Congress, included 22 patients.

Tumor assessments were performed using irRECIST criteria every 6 weeks until week 24, and then every 9 weeks.

The combined phase Ib and phase II results (N = 30) had an ORR at 24 weeks of 83% (95% CI, 52%-98%) in the treatment-naïve cohort, and 50% (95% CI, 26%-74%) in those patients who received previous treatment. All responses were partial responses. Two patients in the treatment-naïve group and 8 in the previously-treated population had stable disease. One patient in each cohort had primary progressive disease.

References:

1. Lee C, Shah A, Makker V, et al. Phase 2 study of lenvatinib plus pembrolizumab for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell (MCC) renal cell carcinoma (RCC): results of an interim analysis. Presented at: the 18th International Kidney Cancer Symposium; November 15-16, 2019; Miami, Florida.
2. Eisai and Merck receive breakthrough therapy designation from FDA for Lenvima (lenvatinib mesylate) and Keytruda (pembrolizumab) as combination therapy for advanced and/or metastatic renal cell carcinoma [news release]. Tokyo, Japan and Kenilworth, NJ; Eisai Co., Ltd. And Merck: January 9, 2019. bit.ly/35b9DSi. Accessed November 16, 2019.
3. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma.Ann Oncol. 2017;28(suppl 5;abstr 847O). doi: 10.1093/annonc/mdx371.002.