Immunotherapy After Chemo May Slow Metastatic Bladder Cancer Progression

By Marilynn Larkin

April 16, 2020

NEW YORK (Reuters Health) - In patients with metastatic bladder cancer, progression-free survival was prolonged by switching to pembrolizumab immediately after platinum-based chemotherapy, in a phase-2 trial.

"Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration, followed by observation until progression," note Dr. Matthew Galsky of Icahn School of Medicine at Mount Sinai in New York City and colleagues. "'Switch maintenance' therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons."

Dr. Galsky and colleagues randomized 108 patients (median age, about 66; about 75% men; 90% white) to pembrolizumab 200 mg IV q3 weeks versus placebo for up to 24 months. The primary outcome was progression-free survival.

As reported in the Journal of Clinical Oncology, the objective response rate was 23% with pembrolizumab and 10% with placebo.

Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months vs. 3.0 months; hazard ratio, 0.65).

Median overall survival was 22 months with pembrolizumab and 18.7 months with placebo.

Among patients initially randomized to placebo who experienced disease progression, 27 (52%) crossed over to pembrolizumab and 12 did not (seven died prior to receiving any further systemic therapy and five opted for further treatment off study). The objective response rate with pembrolizumab among those 27 patients was 22%.

The median progression-free survival from crossover was 2.7 months; median overall survival was 15.8 months.

Treatment-emergent grade 3-4 adverse events occurred in 59% of patients receiving pembrolizumab and 38% of those receiving placebo. Immune-related adverse events requiring systemic steroids occurred in 20% of those initially randomized to pembrolizumab.

One fatal treatment-related adverse event (hepatitis) occurred in the pembrolizumab group.

"Changing standard of care should be really based on larger trials that demonstrate patients live longer with this approach," Dr. Galsky told Reuters Health by email. "However, while our study was the first to test this approach and the first to report the results demonstrating a potential benefit, in January 2020 a press release indicated that a trial with a similar immunotherapy (PD-L1 inhibitor avelumab rather than the PD-1 inhibitor pembrolizumab we tested) demonstrated an improvement in survival with the switch maintenance approach." (

"The avelumab study has not yet been presented or published and we need to wait for those full results," he said. "However, it is the first randomized phase 3 trial in several decades showing a survival benefit in the first-line treatment of patients with metastatic bladder cancer."

"We now have two randomized studies supporting this approach and once the results of the other study are presented/published, depending on the degree of benefit, it is highly likely that this will become a standard treatment approach," he said. "Physicians should await the results of the latter study, so that we can interpret the results of the two studies in total, before changing their current approach."

Dr. Daniel Geynisman, Assistant Professor, Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, commented in an email to Reuters Health, "The trial was relatively small and the absolute benefit was not staggering, but this is a proof-of-concept trial upon which other phase-3 trials have built."

Like Dr. Galsky, he noted "Adding immunotherapy as maintenance treatment for patients with advanced urothelial carcinoma who have been treated with first line platinum-based chemotherapy will likely become a standard of care option over the next three to six months as data are presented from phase-3 trials evaluating this approach with the endpoints of progression-free survival and overall survival."

"However," he added, "other phase-3 trials are maturing that examine combined chemo-immunotherapy approaches upfront, rather than sequentially, and may also become a treatment option for many patients."

"Careful patient selection and biomarker discovery will be critical to personalizing therapy for newly diagnosed patient with advanced urothelial carcinoma," he concluded.

The study was funded by Merck. Dr. Galsky and nine coauthors have received fees from the company.

SOURCE: Journal of Clinical Oncology, online April 9, 2020.