Clinical Challenges: PD-1 Blockade in Non-Muscle Invasive Bladder Cancer - MedPage Today

In January 2020, the FDA approved the use of pembrolizumab (Keytruda) for patients with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are either ineligible for or have elected not to undergo cystectomy.

The approval came after a somewhat split Oncologic Drugs Advisory Committee vote of 9-4, where even some members who voted yes expressed concerns about the approval.

"One reason there seems to be some debate about the use of pembrolizumab in this patient population is if you have BCG-unresponsive high-risk disease that keeps coming back, the question is whether the patient should just get the bladder removed," said Vinay Prasad, MD, MPH, of the University of California San Francisco (UCSF).

The current guideline-recommended treatment for BCG-unresponsive NMIBC is radical cystectomy. However, surgery is associated with decreased quality of life and high complication rates. In addition, the FDA approval is worded in such a way that the regimen could be used in patients who elect not to undergo cystectomy.

"There is always a bit of a gray area," Prasad said. "There are clearly some patients where you would recommend surgery and others where you clearly would not, but there is a group of patients that fall into this gray zone, whether that is because they are ineligible or because they just don't want to do it."

Realistically, he added, if you tell some patients that they could try a new medication that might allow them to not need cystectomy, many will try it, and some will have success.

The NMIBC indication for pembrolizumab was approved based on results from the open-label, single-arm, multicenter, phase II KEYNOTE-057 study. The efficacy analysis included 96 eligible patients who were assigned to receive pembrolizumab, and 41% of patients had a complete response at 3 months.

Durability of response is an important outcome, however. The KEYNOTE-057 researchers reported that about half of responders had at least a 12-month duration of response at data cutoff. Updated results reported in February 2021 showed that about one-third of responders remained in remission for longer than 18 months and about one-quarter for longer than 24 months.

"All the treatments we give these patients with BCG-refractory disease have about a 25-30% chance of controlling the disease for 1-2 years," said Richard E. Greenberg, MD, chair of Urologic Oncology at Fox Chase Cancer Center in Philadelphia. "If you can control the disease for 2 years that is considered a success."

The challenge, though are the potential costs of that delay.

"Untreated carcinoma in situ or high-grade noninvasive papillary disease that is BCG-refractory tends to ultimately progress, and a missed progression invades the muscle and becomes systemic," explained Greenberg, who is a member of the National Comprehensive Cancer Network's Bladder/Penile Cancers Panel. "There is no good marker to predict which patients will benefit from something like pembrolizumab."

The situation deserves an in-depth discussion with the patient involving the risks and benefits of different treatment options for treating this high-grade disease while it is non-lethal, Greenberg added. "There is always the option of aggressive surgical treatment to remove the bladder and the source of the whole problem."

Outside of the risk of progression, the other potential concern is financial: Bladder cancer is estimated to have one of the highest lifetime treatment costs of all cancers, and the use of pembrolizumab in BCG-unresponsive, high-risk NMIBC would only add to that total, Prasad said.

In a commentary in JAMA Oncology, Prasad and colleague Jennifer Gill, MS, also of UCSF, wrote that it costs approximately $300,000 to treat a BCG-unresponsive patient with NMIBC with a full course of pembrolizumab and $200,000 based on the average duration of response.

"Comparatively, BCG costs about $2,000 per patient, and the median total charges for radical cystectomies are approximately $53,000," the authors said.

Prasad noted that based on the results of KEYNOTE-057, this means that more than half of patients may choose the expensive regimen with pembrolizumab and have little or no benefit.

And although clinicians do not like to use cost as a decision breakpoint in terms of how best to treat a patient, there is no question that a drug like pembrolizumab is significantly more expensive than the intravesical agents, Greenberg said.

He noted that on the whole, he does not see many NMIBC patients who are eligible for pembrolizumab and that he would likely use all other options for BCG-refractory disease before that.

Prasad said he believes the use of pembrolizumab for this indication is growing and will continue to grow: "It is on the upswing and will likely continue to gain market share in this space."

There is no question that some fraction of cases of this cancer are "exquisitely susceptible" to pembrolizumab, he added. "If the drug cost $200 a year, I think the uptake would be exuberant. This question of when to use it comes into play when considering the cost and the side effects."

Prasad also said that the ongoing disruptions to the supply of BCG could also increase the use of pembrolizumab in this space.

Last Updated November 01, 2021

• Leah Lawrence is a freelance health writer and editor based in Delaware.

Disclosures

Greenberg reported no relevant conflicts of interest.

Prasad reported relationships with Arnold Ventures, Johns Hopkins Press, Medscape, MedPage, UnitedHealthcare, EviCore, and New Century Health, and noted that his Plenary Session podcast has Patreon backers.