Navigating the Bacillus Calmette-Guerin Shortage for Patients With High-Risk Non-Muscle Invasive Bladder Cancer

Andrew Katims, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses the challenges of treating patients with high-risk non-muscle invasive bladder cancer (NMIBC) during the bacillus Calmette-Guerin (BCG) shortage.

Dr Katims explains the efficacy of BCG therapy and the lack of other options for high-risk patients in this population. He also shares 5-year results from the phase 2 trial evaluating the use of a modified BCG regimen for these patients rather than the standard course.

In this trial, patients received 2 induction courses of BCG, rather than the standard induction plus 3 years of maintenance therapy. At 6 months, there was a 91% complete response rate, with 75 patients evaluable for long-term follow-up. Of those patients, there was a 5-year recurrence-free survival of 69%.

Transcript:

Andrew Katims, MD, MPH: Hello, my name is Andrew Katims. I am a urologic oncology fellow at Memorial Sloan Kettering in New York City.

Oncology Learning Network: What is the standard course of BCG for bladder cancer and how effective is it?

Dr Katims: BCG for non-muscle invasive bladder cancer is the best therapy that we have, especially in a high-risk cohort of non-muscle invasive bladder cancer patients. The recommendations were based off of a SWOG trial, which recommended an induction course, which is 6 cycles, followed by 3 years of maintenance BCG.

Historically, the recurrence -free survival rates are around 60% in patients that have received a full course of induction plus maintenance. Non-muscle invasive bladder cancer is a challenging disease because it has a high rate of recurrence for patients. It's frustrating for patients and in the high-risk population, they're also at risk for progression. Giving them adequate treatment is really important. 

OLN: What are the options, other than BCG, in this treatment landscape?

Dr Katims: Historically, the treatment options for high-risk patients were BCG or early cystectomy. Now that we've had this BCG shortage for several years, multiple other medications have been tried. 

Reduced-dose BCG is probably the most tested one. There's alternative intravesical chemotherapies that have been reported in some retrospective studies, like gemcitabine and docetaxel intravesically, and they appear to be promising. There are some ongoing clinical trials with them now. But unfortunately, none of the intravesical chemotherapies in the high-risk cohort in particular have been as good as BCG has. In the intermediate-risk group, it's a different story. Some of the intravesical chemotherapies do work almost as well or as well as BCG in intermediate risk. 

One of the problems we saw in designing our study and reporting our study, is that the success of the alternative treatments is in these mixed intermediate- and high-risk groups. But when you do subgroup analysis and separate them out, the high-risk group always has inferior oncologic outcomes when they're not receiving BCG. 

OLN: How has the current BCG shortage affected practice and patient care?

Dr Katims: I think it's frustrating for both clinicians and patients alike. Patients are getting substandard therapy for a bad disease. 

Right now, BCG is being produced by a single company, Merck. They have a facility that's producing it that's currently producing it at like 200 % of their capacity. They’re currently building another facility to produce BCG which should be done, they reported, in 2025 or 2026. Hopefully that will provide some relief. 

But it's very challenging and you really have to ration your BCG to the highest risk patients, rather than giving it to all-comers. 

OLN: Please describe the clinical trial you conducted evaluating 2 induction courses of BCG for patients with NMIBC.

The trial was designed several years ago. It was initially designed to identify a 6-month complete response rate. It was the phase 2 trial, a single-arm trial, so patients were enrolled with no comparator group. We selected high-risk non-muscle invasive bladder cancer patients. It was designed to identify a 6-month complete response rate and the rationale behind that initial period is that we've shown in previous studies that having a great response at 6 months corresponds to a good overall response.

Now we have 5-year data, which is what was recently published in our JAMA Oncology paper. It was the same cohort of patients just followed out for longer, so we included 77 patients in our group. All of them had a complete transurethral resection of their bladder tumor to the point where there was no visible tumor, and that's an important point in this study that that we can touch upon a bit later, perhaps. Everyone had a complete visual resection of their tumor, and then they went underwent an induction course, the typical 6 cycles of BCG. They had a cystoscopy, and then they had another induction course, so 12 total cycles of BCG, 2 induction courses. 

Our landmark analysis was at 6 months after their first BCG, and we looked at recurrence-free and cancer-specific survival. We knew that cancer-specific survival would be pretty good in this cohort since it's an early-stage cancer that is being managed to monitor.

Our goal would be, if patients progressed, they would be caught early and treated appropriately. And because of that, our cancer-specific survival was 97%. What was impressive is that our recurrence-free survival for high-grade recurrences at 5 years was 69%, which is right in line with the historically reported values of BCG and maintenance. Obviously, the direct comparison can't be made because it was a single arm study, but at least historically our numbers looked comparable. 

One exciting thing from our group that we noted is the biologic hypothesis of this study is that we believe the first course of BCG primed the immune system to the second course. We thought the first induction course led to this very robust response. And while we didn't test that directly and our numbers were quite small, we did have a group of patients within our cohort that were previously treated with BCG and then enrolled in this study. And when you look at those groups, those that were previously treated had a very good 5-year response, recurrence-free survival rate of 82%, compared to those that were not previously treated with a 65% 5-year recurrence-free survival. It goes in-line with our hypothesis. We didn't directly test it, but we believe that's the mechanism.

OLN: What is the significance of all patients undergoing a complete transurethral resection of the bladder tumor?

The value of a complete transurethal resection, if just reading the paper may be lost, but it's critically important in treating patients with non-muscle invasive bladder cancer and having a successful treatment with BCG.

 BCG is not a chemoablative therapy. It works by eliminating minimal residual disease left in there. To have success with your BCG trials, regardless if you're doing 1 or 2 cycles, you have to have a visually complete resection as much as possible. 

OLN: Are there any other potential modifications to the BCG regimen that may potentially yield acceptable results?

Dr Katims: Not yet. Right now, what's recommended by the American Urologic Association is having a reduced dosage where you get a full induction course or a third of the induction course, followed by one-third dosing. Unfortunately, there have been 2 clinical trials now that have shown that this is inferior in terms of oncologic outcomes. It's still being recommended, but hopefully our study can provide some sort of alternative to that with comparable results to maintenance therapy. 

OLN: Is there anything else you would like to highlight about this trial?

Dr Katims: One thing to mention is, from a numbers perspective, reducing the number of vials per patient to 12, which we mentioned in the study. By using our regimen we can reduce the number of vials per patient to 12 compared to about 27 for BCG plus maintenance.

Source:

Katims AB, Tallman J, Vertosick E, et al. Response to 2 induction courses of bacillus Calmette-Guèrin therapy among patients with high-risk non-muscle-invasive bladder cancer: 5-year follow-up of a phase 2 clinical trial.