A Failed Strategy for an Effective Bladder Cancer Drug

Nick Mulcahy

February 17, 2020

SAN FRANCISCO — It seemed like a sensible measure for desperate times, but reducing the standard frequency of doses of bacille Calmette-Guérin (BCG; Merck) for the treatment of high-grade bladder cancer resulted in worse outcomes in a randomized clinical trial.

The study was conceived and undertaken in response to the worldwide shortage of BCG, an immunotherapy with no highly comparable alternative and a limited number of manufacturers.

However, less frequent BCG dosing resulted higher rates of disease recurrence, and the NIMBUS trial investigators stopped patient enrollment immediately after learning of the inferiority from its independent safety committee.

Lead study author Marc-Oliver Grimm, MD, Jena University Hospital, Germany, reported the disappointing results here at the Genitourinary Cancers Symposium (GUCS) 2020.

The optimal number of treatments or instillations of BCG is unknown, explained Grimm.

So NIMBUS investigators from 10 European countries set out to test whether a reduced frequency — and thus reduced dose — of BCG instillations was inferior (or not) to accepted standards. The team aimed to enroll 824 BCG naïve patients with high-grade non-muscle invasive bladder cancer (NMIBC).

However, an intention-to-treat analysis among 345 randomized patients showed a notable difference in the number of recurrences: 27% in the reduced arm vs 12% in the standard arm, reported Grimm.

"The experimental arm is clearly inferior," he told the meeting audience.

"More early recurrences occurred in the experimental arm, suggesting inferior efficacy of the reduced frequency BCG induction schedule," he added.

The study treatment arms consisted of a standard dose arm (induction cycle BCG at weeks 1-6; maintenance cycles at months 3, 6, 12 — weeks 1, 2, 3) and a reduced dose arm (induction cycle at weeks 1, 2, 6 only; maintenance cycles at months 3, 6, 12 — only weeks 1 and 3).

Alexander Kutikov, MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said the new trial is "very important."

"Standard BCG dosing protocols have always been viewed as entirely arbitrary by the urologic community," he told Medscape Medical News. "This trial tried to answer a critical question: Can we get the same results at lower costs, while expanding less resources and making treatment less burdensome to patients? Level 1 evidence produced a resounding 'no.' "

A Kaplan Meier survival analysis for time to recurrence, the study's primary endpoint, revealed that 33% of patients in the reduced dose arm had disease recurrence at 24 months vs 14% of the standard frequency arm (hazard ratio, 0.391; 95% confidence interval, 0.231 - 0.662).

New Results Should Not Be Confused With AUA Advisory

NIMBUS is not the first study to examine reduced BCG in this setting.

Lower doses of BCG were used in a randomized trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) that showed no difference in progression rates between full-dose and 1/3 dose BCG (Eur Urol. 2013;63:462-72). However, this trial also showed that recurrence rates were higher with the reduced dose.

BCG is a bacteria-based immunotherapy that has been used in the treatment of bladder cancer for the past 40 years, but is now in short supply globally.

The supplier of BCG for the NIMBUS study was Medac GmbH, a privately owned German pharmaceutical company.

BCG is indicated in the United States for early stages of bladder cancer — specifically for the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder and the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection.

BCG is infused into the bladder through a catheter, and thus comes into direct contact with the cancer cells and activates the immune system. BCG must come in contact with the cancer cells to work and therefore is an intravesical therapy.

The US Food and Drug Administration added BCG to its official list of drugs in short supply last year. Merck, which is the sole supplier in the United States and other countries, says the shortages are due to an increasing global demand.

Last year, the American Urological Association (AUA) and a group of bladder cancer–related organizations issued an advisory about the BCG shortage.

It outlined strategies to maximize the care for patients with NMIBC, including patients with high-risk NMIBC and patients with high-grade T1 and CIS who are receiving induction therapy. These patients "should be prioritized for use of full-strength BCG," reads the advisory.

But, the advisory said that, if the full dose is not available, "these patients and other high-risk patients should be given a reduced 1/2 to 1/3 dose, if feasible."

At GUCS 2020, Sam Chang, MD, Vanderbilt University, Nashville Tennessee, pointed out that the AUA advisory, which recommended a reduced 1/2 or 1/3 dose for 6 weeks, is not the same as the NIMBUS regimen.

"It's a totally different regimen," he told Medscape Medical News. "To me, a good question is: Why did they [NIMBUS investigators] choose that regimen? What's the biology behind doing that? Why not do it every other week? I don't know what the rationale was."

The study was funded by the EAU Foundation for Urological Research, Medac, Lyon Cancer Fund, and Jena Research Cancer Fund. The study abstract did not list financial disclosures of the investigators. Drs Kutikov and Chang have disclosed no relevant financial relationships.

Genitourinary Cancers Symposium (GUCS) 2020: Abstract 436. Presented February 14, 2020.

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