November 03, 2017
3 min read

Lenvatinib plus pembrolizumab active in metastatic clear cell renal cell carcinoma

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MIAMI — The combination of lenvatinib and pembrolizumab exhibited antitumor activity among patients with metastatic clear cell renal cell carcinoma, according to study results presented at International Kidney Cancer Symposium.

The combination also appeared well tolerated.

Lenvatinib (Lenvima, Eisai) — an oral multikinase inhibitor — is approved for use in combination with everolimus (Afinitor, Novartis) for treatment of patients with advanced renal cell carcinoma who received prior vascular endothelial growth factor-targeted treatment.

Pembrolizumab (Keytruda, Merck), an anti-PD-1 monoclonal antibody, is approved for treatment of certain advanced malignancies.

Preclinical studies suggested lenvatinib increased antitumor activity of PD-1 blockade, including a decrease in tumor-associated macrophage population and upregulation of PD-1 signal inhibitors.

Chung-Han Lee , MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues conducted a phase 1b/phase 2 trial to assess the combination of lenvatinib and pembrolizumab in select solid malignancies.

The phase 1b portion of the trial — results of which were previously reported — included 13 patients whose disease progressed after treatment with approved therapies. The population included eight patients with renal cell carcinoma, two with non-small cell lung cancer, two with endometrial cancer and one with melanoma.

The phase 2 portion of the trial included 30 patients (median age, 62 years; range, 42-76; 83.3% men) with metastatic clear cell renal cell carcinoma. Patients had received zero (n = 12), one (n = 10) or two (n = eight) prior lines of systemic therapy. All had measurable disease per immune-related RECIST criteria, and had ECOG performance status of 0 or 1.

Twelve (40%) patients had one metastatic site, seven patients (23%) had two metastatic sites, and 11 patients (37%) had three or more metastatic sites. The most common sites of metastases were lung (73%), liver (23%), lymph nodes (23%) and bone (20%).

Nearly all patients (93%) underwent prior nephrectomy, and seven patients (23%) underwent prior radiotherapy.

Patients received 20 mg oral lenvatinib daily plus pembrolizumab 200 mg via IV every 3 weeks.

Objective response rate at 24 weeks served as the primary endpoint. Key secondary endpoints included PFS, duration of response and safety.

Median treatment duration was 9.5 months (range, 1.1-19.1).

Median follow-up was 9.7 months.

At 24 weeks, 63% (95% CI, 44-80) of patients achieved objective response. All responses were partial responses.

Researchers reported a higher ORR among treatment-naive patients (83%; 95% CI, 52-98) than previously treated patients (50%; 95% CI, 26-74).


During the study period, 19 patients (63%) achieved partial response; they included 10 (83%) treatment-naive patients and nine (50%) previously treated patients.

Ten patients (33%) achieved stable disease; these included two (17%) treatment-naive patients and eight (44%) previously treated patients.

Median duration of response in the full study population was not estimable.

Twelve patients in the cohort had PD-L1-positive tumors, 14 patients had PD-L1-negative tumors, and four patients did not undergo PD-L1 testing.

When researchers assessed ORR at 24 weeks by PD-L1 status, results showed a higher percentage of patients with PD-L1-negative tumors (71%; 95% CI, 42-92) than PD-L1-positive tumors (58%; 95% CI, 28-85) achieved objective response. Researchers also reported a longer median duration of response among patients with PD-L1-negative tumors (not estimable vs. 10.3 months).

In the full cohort, median PFS had not been reached as assessed by immune-related RECIST criteria (95% CI, 9.9-not estimable) or RECIST v1.1 criteria (95% CI, 9.7-not estimable).

Toxicities appeared consistent with those previously reported with the two agents evaluated. Most were managed with supportive medications, or dose modifications or interruptions.

The most common treatment-emergent adverse events included constipation (27%), palmar-plantar erythrodysesthesia (27%), vomiting (27%), decreased weight (27%), dyspnea (23%), pain in extremity (23%), back pain (20%), myalgia (20%) nasal congestion (20%) and rash (20%).

Eighteen patients (60%) experienced treatment-emergent adverse events that required lenvatinib does reductions. Five patients experienced treatment-emergent adverse events that required discontinuation of either study drug. These events included one case each of autoimmune nephritis, back pain, oral mucositis, proteinuria and rhabdomyolysis.

Four patients (13%) experienced grade 3 lipase increase, one experienced grade 3 vomiting and one experienced grade 3 dyspnea. One patient experienced grade 4 lipase increase.

A phase 3 trial designed to compare lenvatinib plus pembrolizumab and lenvatinib plus everolimus with the multikinase inhibitor sunitinib (Sutent, Pfizer) for first-line treatment of metastatic clear cell renal cell carcinoma is underway. – by Mark Leiser

For more information:

Lee C-H, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at: International Kidney Cancer Symposium; Nov. 3-4, 2017; Miami.

Disclosure: The authors report funding from Eisai and support from Merck.