Abstract
Summary To date, intravesical instillation of Bacillus Calmette–Guérin (BCG) is the standard adjuvant treatment for most intermediate- and all high-risk bladder nonmuscle invasive urothelial carcinomas (NMIBC) after complete transurethral resection. Although BCG immunotherapy successfully reduces both recurrence and progression rates in affected patients, there are certain limitations associated with its application. Major issues are the relatively high failure rate in up to 40% of patients, the adverse effects of the instillations, and the shortage in BCG supply, requiring concerted alternative strategies. Furthermore, radical cystectomy, the currently suggested salvage treatment for patients failing BCG therapy, is often an overtreatment for a significant proportion of patients. Checkpoint inhibitor (CKI) immunotherapy has proven to be highly effective in a subset of advanced bladder cancer patients and is currently tested in various clinical scenarios alone and in combination with BCG in the adjuvant setting. CKIs’ mechanism is to a large part similar to that reported for BCG—that is, activation of the immune system and elimination of cancer cells in the bladder. Furthermore, CKIs could synergistically enhance the effect of the immune system attracted by BCG and are generally associated with acceptable rates of adverse reactions. Thus, they may represent an ideal alternative to or partner for BCG immunotherapy in NMIBC. In case the recent encouraging results of currently ongoing trials translate into tangible improved outcomes, the combination of CKI and BCG immunotherapy can be expected to represent a valid treatment strategy for well-selected nonmuscle invasive bladder cancer patients in the future.
Highlights
Bacillus Calmette–Guérin (BCG) instillation immunotherapy is the standard adjuvant treatment for most intermediate and all high-risk nonmuscle invasive urothelial carcinomas (NMIBC) after transurethral resection of the bladder (TUR/B) Intravesical BCG with maintenance therapy has proven effective in reducing recurrence as well as progression rates, but up to 40% of patients eventually become BCG unresponsive Radical cystectomy is the standard treatment for BCG unresponsive and intolerant patients, but is associated with significant morbidity rates often representing overtreatment in a subset of patients Checkpoint inhibition (CKI) immunotherapy has become an effective standard therapy for metastatic bladder cancer and could represent a promising alternative therapy in high-risk and BCG unresponsive bladder cancer alone or in combination with BCG
A multitude of clinical trials assessing Checkpoint inhibitor (CKI) therapy in BCG unresponsive patients as well as firstline combination therapy with BCG are being conducted, and—depending on outcomes of these trials—addition of CKI to BCG may become a standard option in the future, thereby, reducing the need for radical cystectomy
From mechanistic studies in patients receiving CKIs, we know that tumors with sufficient PD-L1 expression, high in mutational burden/neoantigen load, and inflamed tumors are the most likely to respond to CKIs [27]
Summary
Bacillus Calmette–Guérin (BCG) instillation immunotherapy is the standard adjuvant treatment for most intermediate and all high-risk nonmuscle invasive urothelial carcinomas (NMIBC) after transurethral resection of the bladder (TUR/B) Intravesical BCG with maintenance therapy has proven effective in reducing recurrence as well as progression rates, but up to 40% of patients eventually become BCG unresponsive Radical cystectomy is the standard treatment for BCG unresponsive and intolerant patients, but is associated with significant morbidity rates often representing overtreatment in a subset of patients Checkpoint inhibition (CKI) immunotherapy has become an effective standard therapy for metastatic bladder cancer and could represent a promising alternative therapy in high-risk and BCG unresponsive bladder cancer alone or in combination with BCG. Nonmuscle invasive urothelial cancer— Bacillus Calmette–Guérin instillation or checkpoint inhibitor. Interim results of the KEYNOTE-057 phase II trial evaluating pembrolizumab in high-risk bladder cancer patients unresponsive to BCG reported complete response rates of 40% at 3 months Further immunotherapy phase II and phase III trials testing CKI alone or in combination with BCG in the BCG unresponsive or naïve setting are currently ongoing and will determine which patients benefit most from CKI therapy in the adjuvant setting
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