Immunotherapy Beats Chemo for Bladder Cancer

In a phase III trial, Merck's PD-1 inhibitor pembrolizumab (Keytruda) prolonged survival in patients with advanced urothelial carcinoma whose disease worsened while on or after receiving platinum-based chemotherapy.

“It is really the first study that shows a benefit of immunotherapy in overall survival” in these patients, says Ashish Kamat, MD, a urologic oncologist at The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the trial.

Patients who received the checkpoint-blocking agent in the open-label, 542-person KEYNOTE-045 study had a median overall survival of 10.3 months, compared with 7.4 months for those who received paclitaxel, docetaxel, or vinflunine—a 27% reduction in the risk of death. Response rates to pembrolizumab were also higher (21% versus 11%) and more durable, with 68% of responders still showing a benefit after 1 year, compared with 35% of those who responded to chemotherapy.

A team led by Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center at Dana-Farber Cancer Institute in Boston, MA, described the trial results in a new paper, reporting fewer and less severe side effects in those treated with pembrolizumab than those who received chemotherapy. The investigators also presented unpublished safety data at the 2017 American Society of Clinical Oncology's Genitourinary Cancers Symposium in Orlando, FL, showing that patients taking the immunotherapy scored better on health-related quality-of-life metrics.

Based on these results, Merck has petitioned the FDA to approve pembrolizumab as a second-line therapy to treat locally advanced or metastatic urothelial carcinoma. The company is also seeking approval for first-line use in patients who are ineligible for cisplatin, given that preliminary data from a phase II single-arm trial showed that 24% of patients had a durable response. Regulatory decisions are expected by mid-June.

If granted the label expansion, pembrolizumab would be in direct competition with the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) and the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech), both of which were approved within the past year as second-line therapies.

“The good thing,” says Bellmunt, is that after decades without progress in drug development for urothelial carcinoma, “we have three new options for our patients.” However, deciding which drug to use could be tricky because few factors differentiate them.

One potential inconvenience of nivolumab is that it's given every 2 weeks, whereas atezolizumab and pembrolizumab are given every 3 weeks. “That's a noticeable difference to patients from a quality-of-life standpoint,” says Peter H. O'Donnell, MD, a bladder cancer specialist and KEYNOTE-045 investigator at the University of Chicago in Illinois.

In terms of efficacy and tolerability profiles, the three immunotherapies are “all in the same ballpark,” says Kamat—although pembrolizumab is the only agent with proven survival superiority over chemotherapy.

Although there's some early indication that PD-L1 expression, chemokine signatures, or genomic subtype could have prognostic value for some agents, at this point, “it's a lot of noise,” Kamat says. “We don't know yet what is going to be predictive, if anything at all.”

That's why O'Donnell expects many oncologists will continue using what they've become most comfortable with—and for many that's atezolizumab, the first immunotherapy to earn approval for bladder cancer. “Pembrolizumab is coming third to the game,” he says, “even though it has randomized phase III data.” –Elie Dolgin