In NEJM: Practice-Changing Trial in Urothelial Cancer

Nick Mulcahy

February 17, 2017

ORLANDO, Florida — For the first time in decades, there is a major advance in the second-line treatment of patients with advanced urothelial carcinoma whose disease has recurred or progressed after initial chemotherapy, according to new trial results published today in the New England Journal of Medicine.

Patients receiving the immunotherapy pembrolizumab (Keytruda, Merck) lived about 3 months longer than those treated with standard second-line chemotherapy (10.3 months vs. 7.4 months; hazard ratio for death, 0.73; P = .002), report the study authors, led by Joaquim Bellmunt, MD, PhD, from the Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School in Boston, Massachusetts.

"The results…represent a major breakthrough for urothelial cancer patients showing for the first time — after 30 years of no major advances in second-line bladder cancer — an agent that prolongs survival," Dr Bellmunt told Medscape Medical News.

The results are "very welcome news" for clinicians caring for these patients, who have a poor prognosis, he added.

In the phase 3 randomized trial, known as KEYNOTE-045, the response rate was higher with pembrolizumab than with chemotherapy (21.1% vs. 11.4%; P = .001), and the estimated rate of response duration of 12 months or longer was also higher with pembrolizumab (68% vs 35%).

Notably, among the 542 patients randomly assigned 1:1 between the two groups, treatment was ongoing in 36 of 57 patients with a response (63%) in the pembrolizumab group and in 2 of 31 (6%) with a response in the chemotherapy group.

The immunotherapy was also less toxic than chemotherapy in terms of all adverse events (60.9% vs 90.2% of patients had at least one event) and severe adverse events (15.0% vs 49.4%).

The trial will have a "practice-changing effect," writes Guru Sonpavde, MD, from the University of Alabama at Birmingham Comprehensive Cancer Center in an accompanying editorial.

However, Dr Sonpavde also has sobering words about the improved clinical scenario.

"As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable. Patients who require salvage therapy remain incurable," he writes.

Patients who require salvage therapy remain incurable. Dr Guru Sonpavde

Still, the combination of improved survival and lower toxicity adds up to an "improved therapeutic index" for these patients, who are generally elderly and have comorbidities, Dr Sonpavde continues.

Two other checkpoint inhibitors, atezolizumab and nivolumab, are already approved by the US Food and Drug Administration for patients with locally advanced or metastatic urothelial cancer who have progressed while receiving standard platinum-based chemotherapy. However, both of these were accelerated approvals based on response rates in single-group, phase 2 studies.

Pembrolizumab now has data showing an overall survival benefit from a phase 3 clinical trial, and these data are likely to lead to a full approval and its use as a new standard of care, says Dr Sonpavde.

Also, today here at the Genitourinary Cancers Symposium (GUCS) 2017, KEYNOTE-045 investigators presented additional study data on health-related quality of life (HRQoL). Pembrolizumab was associated with substantially better HRQoL for a longer duration than was investigator-choice chemotherapy. "Along with superior overall survival, these data support pembrolizumab as a new standard-of-care in this population, write the authors in their meeting abstract.

Progression-Free Survival Surprise

In KEYNOTE-045, patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy receive pembrolizumab (a monoclonal antibody against programmed death-1 [PD-1]) at a dose of 200 mg every 3 weeks (n = 270) or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine (n = 272).

The authors explain that after first-line platinum-based chemotherapy, there is no internationally accepted standard of care in the second line.

Single-agent paclitaxel and docetaxel are commonly used worldwide, they write, and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care. However, in that study, vinflunine did not extend survival in the intention-to-treat population (J Clin Oncol. 2009;27:4454-4461) and is not approved in the United States.

"Because the median overall survival with second-line therapy is only 6 to 7 months, effective options are needed in patients with previously treated advanced urothelial carcinoma," the authors summarize.

The co-primary endpoints in the trial were overall survival and progression-free survival.

Notably, the duration of progression-free survival did not significantly differ between the pembrolizumab group and the chemotherapy group (hazard ratio for death or disease progression, 0.98; P = .42).

The median progression-free survival was 2.1 months (95% confidence interval [CI], 2.0 - 2.2 months) in the pembrolizumab group and 3.3 months (95% CI, 2.3 - 3.5 months) in the chemotherapy group.

However, editorialist Dr Sonpavde says that extension of survival without the extension of progression-free survival that was observed with pembrolizumab "suggests a delayed benefit in the majority of patients."

He also writes that the new results "provoke some questions," including whether there is a preferred agent among pembrolizumab, nivolumab, and atezolizumab.

In the absence of a randomized trial comparing these agents, it is "not possible to choose among them objectively," he says. Still, Dr Sonpavde argues that pembrolizumab is the only agent with proven efficacy in a phase 3 trial.

Other issues that are not definitively answered at this point include when these checkpoint inhibitors should be discontinued and whether there is a biomarker that informs the selection of patients for treatment (in KEYNOTE-045, the benefit of pembrolizumab appeared to be independent of PD ligand-1 expression).

More trials and results in urothelial cancer are on the way as checkpoint inhibitors have also been shown to be active as first-line therapy, Dr Sonpavde points out.

Currently, randomized phase 3 trials are assessing use of checkpoint inhibitors as first-line therapy in combination with platinum-based chemotherapy and cytotoxic T-lymphocyte–associated 4–inhibiting immune modulators as well as adjuvant therapy after surgery for high-risk disease.

Dr Bellmunt was especially enthusiastic about these new trials using immunotherapies for this difficult-to-treat cancer. "An emerging and brilliant future is coming for our patients," he said.

The study was funded by Merck. Dr Bellmunt has financial ties with Merck and Genentech. Multiple other authors have ties to Merck and other pharmaceutical companies. Dr Sonpavde has financial ties with Pfizer, Genentech, and Novartis and other pharmaceutical companies.

Genitourinary Cancers Symposium (GUCS) 2017. Abstract 282. Presented February 17, 2017.

N Engl J Med. Published online February 17, 2017. Study full text, Editorial

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