Pembrolizumab Plus Chemo Shows Promise in Urothelial Carcinoma

Primo N. Lara Jr, MD

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with chemotherapy induced objective responses in one-third of patients with previously treated metastatic urothelial carcinoma, according to preliminary data from an ongoing trial presented at the 2017 Genitourinary Cancers Symposium.

Four of the first 12 patients treated responded to pembrolizumab when combined with docetaxel or gemcitabine. Three of the four responses occurred with the combination of pembrolizumab and docetaxel. There were no unexpected toxicities and adverse events were generally manageable.

“Pembrolizumab plus either full-dose docetaxel or gemcitabine is feasible in platinum-treated urothelial cancer patients,” Primo N. Lara Jr, MD, a urologic oncologist at the University of California, Davis, and colleagues concluded in a poster presentation. “Encouraging antitumor activity for chemoimmunotherapy was seen in this ongoing study, particularly with the pembrolizumab/docetaxel cohort. Expansion cohorts are currently accruing. Further investigation of this approach is warranted.”

No standard second-line therapy exists for metastatic urothelial carcinoma that progresses during or after treatment with frontline platinum-based chemotherapy Although immune checkpoint inhibitors, such as pembrolizumab, have revolutionized systemic therapy in the postchemotherapy setting, the drugs have relatively modest single-agent activity—16% response rate with atezolizumab (Tecentriq) in platinum-treated urothelial cancer and <25% with pembrolizumab, Lara and colleagues noted.

Chemotherapy has been hypothesized to enhance tumor neoantigen expression, resulting in a “priming” effect for treatment with PD-1 targeted immunotherapy.

“We hypothesized that pembrolizumab has an acceptable safety and tolerability profile when given in combination with docetaxel or gemcitabine in patients with advanced or metastatic platinum-treated urothelial cancer,” the investigators wrote.

To test the hypothesis, Lara and colleagues conducted a preliminary clinical trial designed primarily to determine the maximum-tolerated dose of pembrolizumab in combination with docetaxel or gemcitabine. Secondarily, clinical researchers performed a preliminary assessment of overall response rate and progression-free survival.

Eligible patients had locally advanced or metastatic urothelial cancer that was not amenable to curative surgery. Previous treatment with as many as 2 prior chemotherapy regimens for advanced/metastatic disease was permitted. The median patient age was 66 years (range, 45-84).

All patients received pembrolizumab and were assigned to also receive either docetaxel or gemcitabine. Treatment consisted of pembrolizumab at 200 mg on day 1 every 3 weeks plus either docetaxel at 75 mg/m² on day 1 or gemcitabine at 1000 mg/m² on days 1 and 8. Six patients were accrued to each treatment arm. Response assessment occurred every 6 weeks.

The four objective responses included 1 complete response in a patient treated with docetaxel, and 3 partial responses (2 with docetaxel, 1 with gemcitabine). In addition to the objective responses, 2 patients had stable disease, resulting in a disease control rate of 50%. Four of the six patients who benefited from treatment (response plus stable disease) received docetaxel in addition to pembrolizumab.

Dose-limiting toxicity (DLT) in the docetaxel arm consisted of a single case of grade 3 hypophosphatemia. DLT in the gemcitabine arm consisted of 1 case of grade 3 diarrhea.

Seven of the 12 patients had at least 1 grade 3/4 adverse event, the most common being anemia (5 patients); fatigue and neutropenia (4 each); sepsis, hypophosphatemia, and hyponatremia (2 each); and rash (1). No treatment-related deaths occurred. Three patients died of disease progression.

As a single agent, pembrolizumab was granted priority reviews by the FDA for use as a first- and second-line treatment for patients with locally advanced or metastatic urothelial cancer. The FDA is scheduled to make a final decision on both applications on or before June 14, 2017.

The frontline application, which is for cisplatin-ineligible patients, is based on data from the open-label phase II KEYNOTE-052 study. In the first 100 patients enrolled in the study, the objective response rate with pembrolizumab was 24%, which included a 6% complete response rate. After a median follow-up of 8 months, the median duration of response was not yet reached (range, 1.4+ to 9.8+ months), and 83% of patients responded to therapy for at least 6 months.

The second-line application, which is for patients who progress following platinum-containing chemotherapy, is based on data from the phase III KEYNOTE-045 study, in which single-agent pembrolizumab reduced the risk of death by 27% compared with chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment. The median overall survival for patients receiving pembrolizumab was 10.3 months (95% CI, 8.0-11.8 months) compared with 7.4 months (95% CI, 6.1-8.3 months) for those who received a chemotherapy regimen (HR, 0.73; 95% CI, 0.59-0.91).

Lara P, Beckett L, Li Y, et al. Combination checkpoint immunotherapy and cytotoxic chemotherapy: pembrolizumab plus either docetaxel or gemcitabine in patients with advanced or metastatic urothelial cancer. J Clin Oncol 35, 2017 (suppl 6S; abstract 398).

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The 12 patients had a median progression-free survival of 4.8 months, including 5.7 months in the docetaxel group and 3.7 months in the gemcitabine group.