Addressing the BCG Shortage: Gemcitabine/Docetaxel Is an Effective Substitute Treatment for NMIBC

Bacillus Calmette-Guérin (BCG) therapy is commonly used as ongoing maintenance for non-muscle-invasive bladder cancer (NMIBC) to reduce the risk of progression. However, a BCG shortage has been ongoing since 2019 due to increased use and the minimal number of US-based suppliers, leading researchers to study potential replacements for BCG. A recent study compared the efficacy of sequential intravesical gemcitabine plus docetaxel with BCG and examined its potential as a replacement treatment. GU Oncology Now spoke with lead author Vignesh T. Packiam, MD, an assistant professor in the Department of Urology at the University of Iowa Carver College of Medicine, about the results of the study as well as the current BCG shortage.

Can you provide a brief overview of the trial and what its findings were?

Dr. Packiam: The standard treatment for high-grade NMIBC for more than 40 years has been BCG. Over the last decade, there’s been an intermittent and worsening BCG shortage, which has resulted in an unmet need for an effective alternative to BCG for patients with high-grade NMIBC. BCG has been compared with a single-agent chemotherapy inside the bladder and has generally outperformed all  single-agent chemotherapy drugs when they’re used instead of BCG.

At the University of Iowa, we developed a doublet regimen using 2 chemotherapies, gemcitabine and docetaxel, which was initially used for patients who didn’t have a successful response to BCG. As the shortage got worse, we found that this drug was very effective in patients who had previously untreated NMIBC that we would traditionally treat with BCG.

Last year, we published a report looking at more than 100 patients who received gemcitabine/docetaxel for newly diagnosed NMIBC and found very promising outcomes, with good treatment efficacy and safety. But a major limitation of that study was the lack of a comparison group to compare those outcomes against. Our most recent study is a comparison of patients with newly diagnosed high-risk NMIBC who were treated with either gemcitabine/docetaxel (the new treatment) or BCG (the historical treatment) over the last decade.

The study showed that there was no difference in clinical or pathologic characteristics between the 2 groups. Ultimately, treatment efficacy was similar, with superior high-grade recurrence-free survival seen in patients who received gemcitabine/docetaxel compared with those who received BCG. There was also similar toxicity from the agents in both groups and superior tolerance of the induction treatment in the gemcitabine/docetaxel group compared with the BCG group. The study showed that in the setting of the ongoing BCG shortage, gemcitabine and docetaxel is an effective alternative agent that can be used by urologists.

Why gemcitabine and docetaxel? Were any other treatment combinations tested first?

Dr. Packiam: Many different combinations have been tested over the years. Some of the earliest combinations paired different chemotherapies with BCG, but, unfortunately, those combinations were highly toxic and poorly tolerated by patients.

Dr. Mike O’Donnell, of the University of Iowa, was the one who developed these different regimens; he thought to combine gemcitabine with mitomycin-C and found that the combination offered promising results. Unfortunately, in 2009, there was a shortage of mitomycin-C. That shortage led to Dr. O’Donnell trying the combination of gemcitabine and docetaxel, which resulted in a very effective treatment. Since we started using the treatment, some studies have looked at the interaction of those 2 specific chemotherapies, and some studies show that the bladder wall and bladder tumors are more susceptible to the docetaxel if they’re pretreated with gemcitabine first, which supports the sequence of the 2 medications.

What caused the current BCG shortage?

Dr. Packiam: BCG is not a traditional medication that’s just manufactured. It’s actually an attenuated virus or mycobacterium that was initially used as the vaccine for tuberculosis. BCG is serially cultured over time, which can cause some issues in production. In the United States, there were only 2 companies that produced BCG up until 2012, when 1 of those 2 companies, Sanofi, stopped production of BCG due to contamination issues at their plant. Since 2012, we’ve only had a single supplier of BCG in the United States, Merck, and over time they too have had production issues that have become intermittently worse over time. The most recent severe shortage was in 2019 and 2020.

Besides gemcitabine and docetaxel, are there any other treatments currently being looked at as an alternative to BCG?

Dr. Packiam: There are many treatments being looked at right now; most of the clinical trials that are underway are looking at a combination of BCG with other agents. Most of them combine BCG with immunotherapy such as pembrolizumab, although there are others. The trouble with those treatments is that you still need a supply of BCG in order to be able to give those agents.

There’s another pretty exciting trial being run by the Southwest Oncology Group that’s studying a different strain of BCG called the Tokyo-172 strain. If that trial is successful, it could potentially allow the United States to have access to another strain of BCG, so that’s another strategy to try to beat the BCG shortage.

Could gemcitabine and docetaxel ever replace BCG completely, or is it considered a temporary treatment?

Dr. Packiam: That’s a super exciting area of research right now. There’s an ongoing, multicenter, noninferiority trial being run by the ECOG-ACRIN Cancer Research Group called BRIDGE, which aims to randomize 870 patients between BCG and gemcitabine/docetaxel. If the results of that trial show that gemcitabine/docetaxel is noninferior to BCG, it very well could replace BCG as a first-line option for patients with NMIBC, which is exciting because it would be the first change to that treatment paradigm in almost 50 years.