Lenvatinib Plus Pembrolizumab Shows Activity in Advanced Urothelial Cancer

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THE COMBINATION of lenvatinib plus pembrolizumab has demonstrated antitumor activity in patients with advanced urothelial cancer, including patients receiving later-line treatment. Results of a phase Ib/II trial showed an objective response rate of 25% and a median progression-free survival of 5.4 months.According to data presented at the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium,of the 20 patients enrolled on study, 1 remains in complete remission.

Nicholas J. Vogelzang, MD, FASCO, FACP

Nicholas J. Vogelzang, MD, FASCO, FACP

“This response rate warrants further investigation,” said Nicholas J. Vogelzang, MD, FASCO, FACP, a medical oncologist at Comprehensive Cancer Centers of Nevada. “The lenvatinib plus pembrolizumab combination will be studied in a phase III trial in urothelial carcinoma.”

As Dr. Vogelzang reported, urothelial cancer accounts for 90% of all bladder cancers. Pembrolizumab monotherapy is currently approved in the first-line setting for patients with urothelial cancer who are ineligible for cisplatin with programmed cell death ligand 1 (PD-L1) expression or ineligible for platinum-based chemotherapy regardless of PD-L1 status. Pembrolizumab monotherapy is also approved in the second-line setting for all patients with metastatic urothelial cancer who have received prior chemotherapy.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factors, fibroblast growth factor receptors, and platelet-derived growth factors, as well as RET and KIT receptors. It is approved as a monotherapy in radioiodine-refractory differentiated thyroid cancer and unresectable hepatocellular carcinoma, as well as with everolimus in advanced renal cell carcinoma after one prior antiangiogenic therapy. In preclinical models, lenvatinib combined with a programmed cell death protein 1 monoclonal antibody has shown enhanced antitumor activity.

As Dr. Vogelzang explained, this trial was a phase II study design and part of a larger phase Ib/II study involving mostly patients with kidney or endometrial cancer. At the time of data cutoff (March 1, 2018), 20 patients with metastatic urothelial cancer were enrolled, he noted. Eligibility criteria included confirmation of disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received lenvatinib at 20 mg per day orally and standard-dose pembrolizumab at 200 mg intravenously every 3 weeks.

The study’s primary endpoint was objective response. Key secondary endpoints included objective response based on immune-related Response Evaluation Criteria in Solid Tumors as well as duration of response, progression-free survival, and safety.

Antitumor Activity Shown

AS DR. VOGELZANG reported, the median age of enrolled patients was 72 years, and the population was predominantly male (70%). Although 30% of patients had a good baseline ECOG performance status (0), the remaining 70% were classified as ECOG 1, which carries an average life expectancy of approximately 12 months, commented Dr. Vogelzang.


  • In a phase Ib/II trial of patients with advanced urothelial cancer, the combination of lenvatinib plus pembrolizumab demonstrated a response rate of 25% and a median progression-free survival of 5.4 months.
  • Half of treated patients experienced grade 3 or 4 toxicities, with the most common any-grade treatment-related adverse events being proteinuria, diarrhea, fatigue, hypertension, and hypothyroidism.
  • Lenvatinib plus pembrolizumab will be studied in a phase III trial in urothelial carcinoma.

A total of 20% of patients were treatment-naive, whereas the remaining 80% had received chemotherapy. No patients enrolled on the study had been administered prior immunotherapy. Finally, PD-L1 status using the Merck criteria was positive in 50%.

The objective response rate was 25%, including a partial response in 20% of patients and a complete response in 5%. Stable disease occurred in 45% of patients, and the overall clinical benefit rate was 40%.

“The majority of patients had a response,” said Dr. Vogelzang. “Although there were only five objective responses, there were an additional seven patients or more who experienced minor regressions of disease, so this is clearly an active regimen.”

Of the four patients who are still alive, one had PD-L1–positive disease, whereas the remaining three had PD-L1–negative disease. The other patients on the study either did not respond to treatment or experienced disease progression after a short duration of response. One patient who is still alive withdrew consent due to toxicity, said Dr. Vogelzang, although the patient remains disease-free.

The median progression-free survival was 5.4 months, and the 12-month progression-free survival rate was 26%. The median follow-up time for progression-free survival was 11.7 months.


TREATMENT-RELATED adverse events occurred in 90% of patients, with 50% of patients experiencing grade 3 or 4 toxicities. The most common any-grade treatment-related toxicities were proteinuria (45%), diarrhea (40%), fatigue (30%), hypertension (30%), and hypothyroidism (30%). As Dr. Vogelzang explained, the side effect of fatigue/hypothyroidism was synergistic with both lenvatinib and pembrolizumab. Reduced appetite with nausea, pancreatitis, skin rash, vomiting, and dry mouth were also noted.

Treatment-related adverse events leading to study dose adjustment occurred in 75% of patients, including 20% with treatment withdrawal or discontinuation. Dose reduction occurred in 35%, and interruption of therapy, almost always lenvatinib, occurred in 60%.

“The one fatal event was gastrointestinal hemorrhage, likely related to perforation,” said Dr. Vogelzang. “This event appeared to be connected to lenvatinib and not something caused by a checkpoint inhibitor, but it’s impossible to be precise.”

The lenvatinib plus pembrolizumab combination will be studied in a phase III trial in urothelial carcinoma, the study authors noted. A phase III trial in endometrial cancer is already open, and the lenvatinib plus pembrolizumab combination in renal cell carcinoma is also under investigation.


  • Lenvatinib plus pembrolizumab is currently under investigation in a phase III trial in endometrial cancer and in a trial in renal cell carcinoma.
  • A phase III study of lenvatinib plus pembrolizumab in urothelial cancer is planned.

Question on Dose

ONE MEMBER of the audience asked “Why did you choose such a high dose, and could a lower dose of lenvatinib help to reduce toxicity?”

“It is true that the dose is too high,” Dr. Vogelzang responded. “In renal cell studies, the starting dose is 18 mg, and that’s clearly easier to tolerate. Lenvatinib is active as low as 4 mg. Many of us start with lower doses and go higher depending upon hypertension and diarrhea.” ■

DISCLOSURE: Dr. Vogelzang owns stock in Caris Life Sciences; has received honoraria from Pfizer and UpToDate; has consulted for Amgen, AstraZeneca, Bayer, Caris Life Sciences, Fuji.lm, Genentech/Roche, Heron, Pfizer, and Tolero Pharmaceuticals; is a speaker for AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Exelixis, Genentech/Roche, and Sanofi; has received research funding from Endocyte, Merck, Suzhou Kintor Pharmaceuticals, US Oncology, and Viamet Pharmaceuticals; and has received travel/expenses from AstraZeneca/MedImmune, Bayer/Onyx, Exelixis, Genentech/Roche, Pfizer, and US Oncology.


1. Vogelzang NJ, Encarnacion CA, Cohn AL, et al: Phase Ib/II trial of lenvatinib plus pembrolizumab in urothelial cancer. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 11. Presented March 1, 2019.