Immunotherapy for the Treatment of Urothelial Cancer

Currently, the evidence does not support routine use of biomarkers to guide BCG therapy in NMIBC. Cystoscopy (with biopsy/transurethral resection (TUR) of bladder tumor as needed), urine cytology, and periodic upper tract imaging should be used to detect recurrence.

PD-L1 expression by IHC should be used to guide therapy in patients with mUC who are cisplatin-ineligible but eligible for carboplatin. Patients with PD-L1 negative tumors should receive carboplatin-based combination chemotherapy in this setting, while those with PD-L1 positive tumors can receive either immune checkpoint blockade or carboplatin-based chemotherapy (LE: 2). Clinical trial data otherwise does not currently support the use of PD-L1 expression to select patients with platinum-refractory disease for therapy.

MSI-H/dMMR testing should be considered in patients with upper tract and bladder urothelial cancer, especially for patients of younger age and/or with relevant personal or family history to rule out Lynch syndrome, which has implications for genetic counseling (LE: 3). The presence of MSI should not change the use of ICIs in advanced urothelial cancer.

BCG is recommended for all eligible patients with high-risk NMIBC (including cases with CIS or papillary tumors) (LE: 1).

BCG is also recommended for patients with intermediate-risk NMIBC. However, due to global shortages of BCG, and when BCG is unavailable, the panel recommends intravesical chemotherapy as the first-line therapy for intermediate-risk NMIBC (LE: 1).

If patients experience recurrence of intermediate-risk NMIBC after a course of intravesical chemotherapy, the panel recommends BCG as second-line intravesical therapy (LE: 1).

BCG is not recommended for the treatment of patients with low-risk NMIBC (LE: 1).

BCG should not be administered to patients with active infection or gross hematuria, but BCG may be administered to patients experiencing asymptomatic bacteriuria.

Best supportive measures should be employed to ensure that patients receive a full, adequate course of BCG.

The following treatments are approved for adult patients with Bacillus Calmette Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors: pembrolizumab monotherapy (LE:2), nadofaragene firadenovec-vcng monotherapy (LE:2), or nogapendekin alfa inbakicept-pmln in combination with BCG. The decision as to which of these agents should be used should be based on shared decision making, taking into account factors such as efficacy, adverse events and also patient preferences regarding scheduling and administration routes.

The full results of CheckMate 274 are eagerly awaited to guide the potential use of immunotherapy in the adjuvant setting. Active investigation is ongoing into various neoadjuvant and adjuvant strategies, either as single agents or in combination with chemotherapy, radiotherapy, or novel agents.

For patients with mUC, first-line treatment options include enfortumab vedotin plus pembrolizumab (preferred) regardless of whether patients are cisplatin-eligible or cisplatin-ineligible (LE:2), or gemcitabine, cisplatin, plus nivolumab in patients who are cisplatin-eligible (LE:2). Both of these regimens have been shown to improve OS compared with platinum-based chemotherapy alone.

In patients with with locally advanced or mUC that has not progressed with first-line platinum-containing chemotherapy, avelumab maintenance therapy improves OS (LE: 2).

Pembrolizumab is recommended for the treatment of patients with platinum-refractory mUC who have not received prior ICI treatment based on a significant OS benefit in a randomized phase III trial (LE: 2). Avelumab and nivolumab also have approvals in this setting (LE:3).

Participation in clinical trials should be discussed with all patients at any stage of bladder cancer.

SITC’s guidelines for the management of ICI-related AEs should be consulted for the treatment of irAEs in patients with bladder cancer.

Patient navigation and PRO tools can help eliminate barriers to oncologic care, enhance patient decision-making, and improve the patient experience during their cancer care. This has been demonstrated in screening outcomes for a variety of malignancies and confirmed in recent studies of NMIBC and MIBC. Combining patient-focused information and educational resources with comprehensive patient-provider conversations can contribute to improved QOL both during treatment and surveillance.

Comprehensive conversations with patients about all aspects of medical treatment, including financial obligations, could involve multiple clinical and institutional providers. Conversations should continue throughout patient-provider relationships that reflect the evolving nature of treatment timing, options, and patient concerns.

Urothelial cancer-specific outcome measures for BCG and ICI treatments should be developed, validated, and utilized as tools for patient navigation.

ICI-specific measures should address a range of treatment protocols and QOL, including ICI alone, combinations with chemotherapy and/or radiation, or any other combination of therapies. Such measures should recognize the often-lengthy nature of bladder cancer treatment and surveillance, along with the potential for adverse effects to occur after the period of initial treatment.

Practical patient information and education resources are needed for both BCG and ICI treatment. As more patients are treated with ICIs, written and digital educational materials are needed. Patient information resources in written and digital formats are available from bladder cancer and medical education organizations, in addition to materials provided by the providing clinic.

There is now an opportunity to develop, study, and deploy digital/mobile technologies to increase patient awareness and reporting of BCG- and ICI-related AEs. Innovation in patient-provider communication and application of technology to PRO/QOL communication could affect patient care for initial and follow-up of patients with urothelial cancer.