Bladder cancer accounts for over 200,000 deaths every year globally, with non-muscle invasive bladder cancer (NMIBC) making up 75% of all bladder cancer cases. High-risk NMIBC is characterised by poor prognosis, with half of patients recurring despite effective treatment with the attenuated vaccine standard of care (SOC), bacillus Calmette-Guerin (BCG). NMIBC is becoming more prominent in society as its incidence is correlated with older age groups, with the median age being 70 when the disease is diagnosed. If patients with high-risk NMIBC fail to respond to BCG and progress, further treatment includes radical cystectomy with or without platinum-based chemotherapy. As the global population is ageing, trials have been initiated to observe if there is any synergistic effect of using BCG in combination with programmed death receptor-1 (PD-1) checkpoint inhibitors to enhance the overall response rate and duration of response to reduce the burden on healthcare systems globally.
Pfizer’s sasanlimab is a monoclonal antibody (mAb) that binds to PD-1, activating T-cells and facilitating an immune response against cancer cells. The CREST Phase III trial compared sasanlimab in combination with BCG (n=352) against BCG maintenance (m=352) or BCG induction and maintenance (n=351) in BCG treatment-naïve high-risk NMIBC. Results have demonstrated that sasanlimab + BCG maintenance reduced the risk of disease-related events by 32% compared to the existing SOC. The probability of event-free survival after three years since the trial start was 82.1% for the sasanlimab + BCG combo compared to 74.8% for BCG alone. In a subset analysis of high-risk NMIBC patients who have carcinoma-in-situ, a very early form of the disease, the sasanlimab + BCG combo treatment arm achieved a complete response (CR) of 91.7%, which was significantly higher than the CR rate with BCG induction and maintenance alone (67.7%). These results indicate that early implementation of the combination could significantly improve the duration of response to BCG in early high-risk NMIBC disease.
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Competing immunotherapies are also vying to prove clinical improvements in similar conditions. KEYNOTE-676 seeks to demonstrate clinical improvements of MSD’s Keytruda (pembrolizumab) in high-risk NMIBC patients with disease persistence after BCG induction. Although Keytruda has a venerable status owing to its prominent clinical evidence and defined safety profile, sasanlimab has a head start with proven benefits to clinical performance in an area of unmet need. While sasanlimab will likely carve a significant patient market share in high-risk treatment-naïve NMIBC patients, it is unlikely to capture any market share beyond this group. Johnson & Johnson’s TAR-200 investigational therapy delivers a sustained release of gemcitabine for high-risk NMIBC carcinoma-in-situ patients who don’t respond to BCG induction and maintenance. TAR-200 demonstrated an overall CR rate of 82.4% in 85 patients. The drug release system received FDA approval for patients with BCG-unresponsive high-risk NMIBC who are ineligible to receive radical cystectomy and a further label expansion offering an alternative for those who are eligible, which will greatly increase its market share. TAR-200 is forecast to reach $983m in sales by 2031 in the US, with sasanlimab expected to reach $190m.
