In 1980, scientists discovered something rather unexpected – the tuberculosis vaccine, Bacillus Calmette-Guérin (BCG) was effective in reducing the recurrence of non-muscle invasive bladder cancer (NMIBC).
More than four decades later, BCG remains the standard of care (SoC) and the most effective therapy for these patients, with recent studies suggesting it to be effective in at least 70% of patients to prevent recurrence, while some experts predict the number may be even higher, potentially even closer to 80%.
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Given its high levels of efficacy, sponsors are investigating combination therapies including BCG to see if immunotherapies can boost that well-established effectiveness. There have, however, been difficulties in the past decade as only Merck is producing BCG, leading to ongoing shortages.
Questions are being raised about this, given the high-level adverse events that patients suffer on immune checkpoint inhibitors and chemotherapies, as well as the cost factor. With the already high response of BCG alone, and given recently approved gene therapies and others that are in the pipeline, some experts are taking issue with these approaches.
Despite these concerns, sponsors are pushing on with trials in the hope of expanding the first-line treatment market.
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By GlobalDataCheckpoint inhibitors in combination with BCG
Many big pharma companies are investigating the use of their checkpoint inhibitors alongside BCG in patients with NMIBC.
This includes AstraZeneca’s Imfinzi (NCT03528694), Pfizer’s sasanlimab (NCT04165317), Roche’s Tecentriq (atezolizumab) (NCT03799835) and Merck’s Keytruda (NCT03711032).
AstraZeneca’s POTOMAC trial is an open-label, multicentre, global Phase III trial enrolling approximately 1,300 adult patients with high-risk NMIBC following resection, who are BCG-naïve. The trial has a primary completion date of October 2024.
Pfizer’s trial is a Phase III, multinational, randomised, open-label trial enrolling 1,070 patients with NMIBC who are BCG-naïve. The trial has a primary completion date of June 2024.
Roche’s ALBAN trial is a Phase III, open-label, randomised, global trial enrolling around 500 patients with high-risk NMIBC who are BCG-naïve. The trial’s primary completion date was in April 2024.
Finally, Merck’s KEYNOTE-676 trial is a Phase III, open-label, randomised, global trial that is enrolling 1,400 patients with high-risk NMIBC following BCG induction, or who are BCG-naïve. The trial has a primary completion date of December 2025.
Despite these candidates all having the same target, there is a chance that one will be superior to others, says Dr. Vignesh Packiam, director of clinical and translational research in urologic oncology at Rutgers Cancer Institute, New Jersey, but only time will tell which candidate may be best.
“In other cancers, for unclear reasons, patients seem to do better with certain immunotherapies than others; that has been shown in adjuvant trials for kidney cancer and bladder cancer,” Packiam says. “It is therefore challenging to rationally predict which of these medications is going to be more successful. We will just have to see what the trials show.”
Packiam adds that given the efficacy of BCG alone, he would want to see a dramatic difference – 20% more reduction in recurrence in the first-line setting – with these therapies given the cost and occurrence of adverse events.
There are alternative therapies being used in combination with BCG that are looking more promising, says Israel Stern, oncology and haematology analyst at GlobalData.
“Standard of care BCG induction and maintenance works well, especially given recent developments in identifying patients at an earlier stage,” explains Stern. “For patients who do progress and don't wish to undergo full bladder removal, there are options which currently appear more effective than BCG plus checkpoint inhibitor, and that is Immunity Bio’s Anktiva plus BCG. This combination is being evaluated in a Phase I/II study of BCG naïve patients, which could also be a more promising approach.”
One of the investigators in KEYNOTE-676, Dr Sandip Prasad, director of Genitourinary Surgical Oncology at Morristown Medical Centre, part of the Atlantic Health System, was more positive about the use of checkpoint inhibitors, adding that it is important to try and bolster efficacy in BCG-naïve populations given the lack of treatments available on the market in BCG unresponsive setting.
“Induction BCG is very effective and maintenance BCG is generally quite effective. If you can eliminate one of those treatments, maintenance specifically, or you can demonstrate durability, that will be an important endpoint,” Prasad explains.
Prasad goes on to explain that removing the need for BCG maintenance would both alleviate the ongoing BCG shortages and improve patients’ quality of life.
Adding mitomycin to the mix
Another candidate being investigated alongside BCG is mitomycin, an antineoplastic antibiotic first discovered by Japanese microbiologists in the 1950s.
The University of Sydney is conducting the Phase III study (NCT02948543) using mitomycin as an adjuvant intravesical therapy for high-risk NMIBC.
Mitomycin is currently used as a treatment for NMIBC patients where BCG is not available, although it is not as effective. It has been investigated in prospective trials in a combination with BCG, but Packiam explains there were concerns about toxicity.
“Outcomes for NMIBC are improving, so it is possible that that the combination strategy may be more optimal now than in the prior era. Based on previous studies, my concerns would be about toxicity of that specific combination.”
The dosing regime in the trial is interesting, according to Prasad, who says he is looking out for this data in the hope that a similar trial model could be replicated in the US.
“Doing these types of rigorous studies, rather than retrospective, single institution studies we have seen before, these types of Phase III randomised studies are critically needed. I am excited to see these results, not because they will necessarily become the new SoC, but I think it will drive forward additional opportunities to use other agents in combination.”
Another strain of BCG
Given the BCG shortages, there is little point in investigating combination therapies unless the BCG supply can be improved. The National Cancer Institute-supported Southwest Oncology Group (SWOG) is investigating different strains of BCG in a Phase III trial (NCT03091660).
The trial is comparing the currently used TICE strain with the Tokyo-172 strain. Not only is it evaluating the two strains head-to-head, it is also evaluating whether an additional intradermal injection of BCG can augment the body's immune response to intravascular BCG.
“It is important to take the time to recruit large numbers of patients for these types of studies, because upfront BCG works well. Therefore, you need to have a lot of patients to show superiority, if that is what you are looking for, and to really demonstrate that effect. This trial is also a way of directly addressing the BCG shortage,” Prasad, who is a member of SWOG, adds.
The study has enrolled 1,000 patients across the US and has a primary completion date set for December 2024.
“This is a fantastic trial and was very well received,” adds Packiam. “It would be very helpful to have other strains available in the US. There is a lot of excitement and anticipation as we wait for this data to read out. It is the hope that trials like this will allow for other strains to be approved in the US.”
