Pembrolizumab Plus Lenvatinib Elicits Responses in Urothelial Cancer

Nicholas J. Vogelzang, MD

Combining lenvatinib (Lenvima) and pembrolizumab (Keytruda) led to a 25% overall response rate (ORR) in patients with urothelial carcinoma and was also associated with a manageable safety profile, according to results of a phase Ib/II trial that were presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium.

"The majority of patients had a response, and although there were 5 objective responses, there were an additional 7 patients or more who had minor regressions of disease; clearly [it's] an active regimen," said Nicholas J. Vogelzang, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada in Las Vegas.

Pembrolizumab is approved as a monotherapy for the treatment of patients with newly diagnosed locally advanced or metastatic urothelial cancer who are ineligible for cisplatin and demonstrate PD-L1 positivity (combined positive score ≥10). The PD-1 inhibitor is also approved in the second-line setting for advanced or metastatic urothelial cancer following platinum-containing chemotherapy.

In preclinical studies, lenvatinib enhanced antitumor activity when used in combination with an anti—PD-1 agent.

Vogelzang explained that the urothelial cancer study was part of a larger phase Ib/II trial, which mostly consisted of patients with kidney cancer and endometrial cancer. The phase Ib/II multicenter, open-label trial enrolled 20 patients with metastatic urothelial cancer. Participants in the trial had received up to 2 prior systemic treatment regimens and had an ECOG performance status of 0 or 1.

Patients were administered 20 mg daily of oral lenvatinib plus 200 mg of pembrolizumab given intravenously every 3 weeks. Vogelzang noted that the approved indication of lenvatinib combination therapy in the treatment of renal cell carcinoma was for 18 mg instead of 20 mg.

The primary endpoint was ORR as of 24 weeks according to immune-related RECIST criteria (irRECIST), with secondary endpoints including ORR by data cutoff, duration of response (DOR), and progression-free survival (PFS), all by irRECIST, as well as safety profile.

Of the 20 patients, the median age at baseline was 72 years (range, 40-87); 70% of the patients were male and 70% had an ECOG performance status of 1. Fifty-five percent of patients had received only 1 prior regimen, but 20% were treatment-naïve. Half of the patients were positive for PD-L1 expression and 40% were negative; PD-L1 expression testing was not completed in the other 10%.

Prior treatment included platinum-based chemotherapy for all of the previously treated patients. None had received prior immunotherapy or VEGF therapy.

At 24 weeks, the ORR was 25% (95% CI, 9%-49%) by both irRECIST and modified RECIST v1.1 (mRECIST) criteria. One patient achieved a complete response (CR) as their best response and 4 had partial responses (PRs). An additional 9 patients (45%) achieved stable disease (SD). The clinical benefit rate (CR + PR + SD ≥23 weeks) was 40% (95% CI, 19%-64%) by both irRECIST and mRECIST criteria. Four patients were not evaluable and 2 had progressive disease.

As of data cutoff, 4 patients remain alive, only 1 of whom was PD-L1 positive, and the others were PD-L1 negative. One of these patients withdrew consent but is still alive. “The remaining patients did not respond or progressed after a short duration of response,” Vogelzang noted.

After a median follow-up of 11.7 months, the median PFS was 5.4 months (95% CI, 1.3-not estimable) by both sets of criteria. At 6 months, the PFS rate was 35% (95% CI, 12%-59%) and at 1 year the PFS rate was 26% (95% CI, 7%-51%).

Treatment-related adverse events (TRAEs) were experienced by 90% of patients, 50% of which were grade 3/4. Six TRAEs were serious and 1, a case of gastrointestinal hemorrhage likely due to perforation, resulted in death. Vogelzang said that he believed that this was due to treatment with lenvatinib rather than pembrolizumab.

The most common TRAEs of any grade included proteinuria in 45%, diarrhea in 40%, hypertension in 35%, fatigue in 30%, hypothyroidism in 30%, decreased appetite in 25%, and nausea in 25%.

TRAEs led to dose adjustments of a study drug for 75% of patients and withdrawal or discontinuation in 20%. Study drug interruption, usually for lenvatinib, was needed for 60% of patients.

Vogelzang suggested that these results warrant further investigation of the combination regimen for patients with urothelial cancer. The lenvatinib plus pembrolizumab combination will be explored further in a phase III trial for patients with urothelial cancer, and is also being studied in endometrial cancer and renal cell cancer.

Vogelzang NJ, Encarnacion CA, Cohn AL, et al. Phase 1b/2 trial of lenvatinib plus pembrolizumab in urothelial cancer. J Clin Oncol. 2019;37(suppl 8; abstr 11).