Dual VEGF and PD-1 Inhibition in Advanced Solid Tumors

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In a phase Ib/II trial reported in the Journal of Clinical Oncology, Taylor et al found the combination of the VEGF inhibitor lenvatinib and the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab showed activity across a range of advanced solid tumors. As stated by the authors, there is evidence to suggest that modulation of VEGF-mediated immune suppression through angiogenesis inhibition could augment the immunotherapeutic activity of immune checkpoint inhibitors.

The study included 137 patients with metastatic solid tumors in a dose-finding phase Ib cohort (n = 13) and an initial phase II expansion cohort (n = 124). Pembrolizumab was given at 200 mg every 3 weeks. The primary outcome measure was objective response rate at week 24 at the recommended phase II dose.

Response Rates

Two dose-limiting toxicities—consisting of grade 3 arthralgia and grade 3 fatigue—were observed at the initial lenvatinib dose level of 24 mg/d plus pembrolizumab. No dose-limiting toxicities were observed in dose de-escalation, with the recommended phase II dose being established as lenvatinib at 20 mg/d plus pembrolizumab.


  • Lenvatinib plus pembrolizumab was active across a range of advanced solid tumors.
  • Response rates ranged from 25% to 63%.

Objective response at 24 weeks with this regimen was observed in 19 (63%) of 30 patients with renal cell carcinoma (median response duration = 20.0 months); 12 (52%) of 23 with endometrial cancer (median response duration = not reached); 10 (48%) of 21 with melanoma (median response duration = 12.5 months; 8 (36%) of 22 with squamous cell carcinoma of the head and neck (median response duration = 8.2 months); 7 (33%) of 21 with non–small cell lung cancer (median response duration = 10.9 months); and 5 (25%) of 20 with urothelial cancer (median response duration = not reached).

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (58%), diarrhea (52%), hypertension (47%), hypothyroidism (42%), and decreased appetite (39%). Grade 3 or 4 treatment-related adverse events occurred in 67% of patients, with the most common being hypertension (20%), fatigue (12%), diarrhea (9%), proteinuria (8%), and increased lipase (7%). Adverse events led to treatment discontinuation in 20% of patients. Two deaths were considered related to treatment, due to pulmonary hemorrhage in a patient with non–small cell lung cancer and gastrointestinal hemorrhage in a patient with urothelial cancer.

The investigators concluded, “Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.”

Matthew H. Taylor, MD, of Knight Cancer Institute, Oregon Health & Science University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Eisai Inc and was also supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit

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