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An Update on Key Areas of Progress In Bladder Cancer

Urothelial carcinoma remains one of the most common malignancies, with about 81,000 new diagnoses and approximately 17,000 associated deaths in 2022 alone.1 Survival numbers are dependent on early diagnosis and drop with delayed diagnosis and/or advanced stages of disease.1 Both muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are associated with substantial morbidity and reduced quality of life.2,3


Fortunately, new insights into the biology of urothelial carcinoma have expanded our treatment armamentarium and improved outcomes for many patients. In this update, I highlight recent and ongoing studies in three important areas: personalizing therapy, treating NMIBC that is unresponsive to bacillus Calmette-Guérin (BCG), and developing bladder-sparing therapies for MIBC.

Personalization of therapy

The clinical and biological heterogeneity of bladder cancer traverses traditional grade and stage categories.4 Advanced approaches such as transcriptomics have enabled us to better characterize tumor (somatic) characteristics, which can help us predict risk for relapse or progression and treatment response. Personalizing bladder cancer treatment based on tumor and patient characteristics makes sense and could improve clinical outcomes, but only if we rationally design clinical trials to incorporate appropriate and consistent definitions and endpoints. Although we have seen progress in this area, there is still room for improvement. Fortunately, regulatory bodies such as the U.S. Food and Drug Administration (FDA) have recognized this and are actively seeking to promulgate high quality trials and studies.

Previously, in 2019, the FDA held a workshop on neoadjuvant studies in MIBC.5 Attendees emphasized the need to go beyond pathologic complete response as a sole primary endpoint and capture more granular data on tumor biology, treatment specifics, and patient characteristics and outcomes. Such information will help personalize therapy. Experts also cited the need to study neoadjuvant immune-oncologic and targeted therapies for earlier-stage MIBC, treatments for cisplatin-ineligible patients, and endpoints that have not been well characterized in MIBC, such as event-free survival and overall survival (OS).

In 2021, the FDA convened a public workshop on clinical trial design in NMIBC to address the implications of the chronic BCG shortage, best practices for clinical trials in BCG-naïve and BCG-exposed NMIBC, rational definitions of disease and risk, the appropriate use of biopsy, and endpoints for studies of neoadjuvant and adjuvant therapies.6 Insights from workshop attendees—who included experts from the FDA, academia, and international bladder cancer groups and societies—will lead to guidance that supports a more uniform playing field for researchers. In addition, explicit FDA support for research in NMIBC should inspire the industry to invest the resources needed for high-quality clinical trials.

In June 2022, the FDA also released guidance for the industry on developing adjuvant drugs and biologics to treat MIBC.7 The agency called on researchers to develop consistent eligibility criteria, methods of disease assessment, definitions of disease recurrence, and timepoints for the evaluation of disease-free survival (DFS). Such consistency will make it easier to interpret study findings and use them to guide treatment selection in the clinic.

On a molecular level, one of the most intriguing biomarkers for personalizing therapy is circulating cell-free tumor DNA (ctDNA), a marker of occult or residual carcinoma. Because ctDNA has a short half-life,8 it provides real-time information on treatment response and risk for post-treatment recurrence or early clinical relapse. Detectable ctDNA after definitive treatment for urothelial carcinoma is a negative prognostic indicator.9-11 In one study, ctDNA positivity at each of the following time points was highly prognostic for recurrence: after transurethral resection of bladder tumor, during chemotherapy before cystectomy, and after cystectomy.11 When comparing ctDNA positive versus negative patients, recurrence rates differed markedly (42% vs. 3%, 75% vs. 7%, and 76% vs. 0%, respectively [all P < .001]). Indeed, ctDNA positivity before or during neoadjuvant chemotherapy was a better prognostic marker than pathologic downstaging or radiologic imaging.

Strikingly, in the ABACUS trial of patients with cisplatin-ineligible MIBC, no relapses occurred among patients who tested negative for ctDNA at baseline or after receiving neoadjuvant atezolizumab prior to cystectomy (ctDNA positivity was 63% at baseline, 47% after atezolizumab, and 14% after cystectomy).12 Biomarker assays in this study were exploratory and were not conducted in all patients, but the results nonetheless suggest that the use of ctDNA assays may help us personalize therapy in the future. Notably, in the phase 3 IMvigor010 trial of patients with high-risk MIBC, atezolizumab after cystectomy was associated with a significant improvement in survival only in the subgroup of patients who were ctDNA-positive after surgery.13 In this subgroup, DFS and OS each improved by nearly 40% among patients who received adjuvant atezolizumab compared with those who underwent observation only, and outcomes were best among patients who became ctDNA-negative after receiving atezolizumab. Although ctDNA was assessed prospectively in this study, the subgroup analysis was exploratory. We therefore eagerly await results from the phase 3 placebo-controlled IMvigor011 trial (NCT04660344), which specifically evaluates adjuvant atezolizumab therapy in patients who are ctDNA-positive after cystectomy. Primary results are anticipated in 2024.

BCG-unresponsive bladder cancer

For patients with high-grade NMIBC (intermediate high-risk papillary tumors or CIS), intravesical BCG after TURBT is an established and effective therapy to help prevent recurrence and reduce the likelihood of progression. Nonetheless, recurrence or progression do occur, creating a pressing need for alternative treatments. Such therapies also could benefit patients who cannot access BCG due to the ongoing global shortage.

Several recent and ongoing studies in BCG-unresponsive disease are particularly noteworthy. At ASCO 2022, we saw encouraging data from an interim analysis of the phase 2, single-arm CORE-001 study, in which patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS) received the investigational oncolytic vaccine CG0070 in addition to intravenous pembrolizumab. Among 16 evaluable patients, 14 (87.5%) showed a complete response (CR) to treatment at 3-month assessment, all of whom remained in CR for up to 12 months of follow-up.14 This is a striking improvement on the prior benchmark of 20% to 25% for CR to therapies for BCG-unresponsive NMIBC with CIS. CG0070, an adenovirus serotype 5 engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), selectively replicates within tumor cells that have mutated or deficient retinoblastoma (RB) gene, which leads to cell lysis and immunogenic cell death. Early safety data in CORE-001 were promising: no grade 3, 4, or serious adverse events (AEs) were attributed to treatment. The study continues to recruit patients, with final results expected in 2023.

Also at ASCO 2022, we also saw intriguing data from the multicenter, open-label, phase 3 QUILT-3.032 trial, in which patients with BCG-unresponsive high-grade NMIBC with CIS or papillary disease received intravesical therapy with BCG and N-803, an investigational high-affinity interleukin (IL)-15 immunostimulatory fusion protein.15 N-803 promotes the proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells, which are thought to suppress the immune system’s antitumor response.16,17 In the QUILT-3.032 study, primary endpoints were met for patients with both CIS (CR rate, 71% [59/83 patients]; median duration of response, 24.1 months) and papillary disease (53% of patients were disease-free at 18 months). Among 160 evaluable patients, more than 90% had avoided cystectomy after 2 years of follow-up. Four (3%) patients had grade 3 or worse treatment-related AEs, but no serious AEs were classified as treatment-related or immune-related—the most common AEs were dysuria, pollakiuria, and hematuria, each of which affected approximately 20% of treated patients. This rate is remarkably low, especially in light of the fact that single-agent BCG typically leads to AEs in more than 50% of patients.

Results from both CORE-001 and QUILT-3.032 are very promising. Although CG0070 and N-803 are investigational and not ready for prime time, their performance in these studies shows how we are raising the bar for our patients with BCG-unresponsive NMIBC. While cross-study comparisons are fraught with pitfalls, discussions with patients often center around the fact that pembrolizumab monotherapy produced a 12-month CR rate of just under 18% when evaluating all patients with BCG-unresponsive NMIBC who received at least one treatment dose in the registrational KEYNOTE-057 trial.18

Many other studies in BCG-unresponsive NMIBC are accruing or ongoing. A phase 1 study (NCT05014139) investigates intravesical enfortumab vedotin (currently approved for treating metastatic urothelial carcinoma) in BCG-unresponsive NMIBC. Other studies are evaluating erdafitinib in patients with FGFR mutations or fusions (phase 2; NCT04172675); intravenous pembrolizumab plus standard intravesical chemotherapy with gemcitabine (phase 2; NCT04164082); intravesical durvalumab (NCT03759496); intravenous durvalumab plus the 5-peptide cancer vaccine S-488210/S-488211 (phase 1/2; NCT04106115); intravesical photodynamic therapy (phase 2; NCT03945162); the non-viral gene therapy EG-70 (phase 1/2; NCT04752722); and cetrelimab (a PD-1 inhibitor), TAR-200 (continuous intravesical release gemcitabine) or both agents in combination (phase 2; NCT04640623).

As novel bladder-sparing therapies for BCG-unresponsive bladder cancer become available, it is only logical that they will also be evaluated and eventually used in BCG-exposed and BCG-naïve high-risk patients. This can help mitigate gaps in care due to the ongoing BCG shortage and further improve on the already high efficacy we see with single-agent BCG.

Bladder-sparing strategies in MIBC

The standard treatment for non-metastatic MIBC has been neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, cystectomy can be associated with perioperative complications and morbidity as well as reduced quality of life, and it may not be the appropriate or best treatment option for patients with comorbidities. In addition, 5-year survival after cystectomy is only approximately 50%, leaving considerable room for improvement.19,20 Traditionally, trimodal therapy (TMT: maximal transurethral resection of bladder tumor [TURBT] followed by radiation therapy and radiosensitizing chemotherapy) was reserved for patients who were ineligible for cystectomy, but TMT is increasingly being chosen by fitter, younger individuals who prioritize saving their bladder. However, it must be emphasized that appropriate patient selection is paramount; in published datasets, only about 20% of patients were eligible for conventional TMT regimens.21

Immuno-oncologic drugs are moving earlier in the bladder cancer trajectory, as they have in other cancers, and multiple clinical trials are now evaluating immune checkpoint inhibitors as part of bladder-sparing TMT. Researchers are also studying bladder-sparing combinations of chemotherapy and immunotherapy.22,23 We have also made strides in the molecular classification of MIBC with the publication, in 2020, of a consensus classification system consisting of six molecular profiles based on more than 1,700 transcriptomic profiles.24 Advances in biomarker detection, novel drug delivery systems, imaging techniques, and radiotherapy techniques will help us further refine bladder-sparing therapies for MIBC in the future.25

DNA damage repair (DDR) mutations are associated with pathologic downstaging after neoadjuvant chemotherapy and thus could help identify candidates for bladder-sparing therapy. In the phase 2 RETAIN study, which included 71 patients with cT2-T3 N0M0 urothelial carcinoma, a combination of genomic and clinical factors was used to select patients to undergo active surveillance (rather than cystectomy) after receiving accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC).26 The patients chosen for active surveillance had at least one alteration in the DDR genes ATM, ERCC2, FANCC, or RB1 and no clinical evidence of disease based on restaging TURBT specimens and imaging after neoadjuvant therapy. In the interim analysis of this study, after a median follow-up of almost 15 months, 89% of patients selected for active surveillance had retained their bladder, 50% had a recurrence, and 50% of recurrences were NMIBC, while 7% were locally advanced or metastatic disease. In contrast, only 55% of patients in the intention-to-treat population retained their bladders. Data on the study’s primary endpoint of 2-year metastasis-free survival are pending. Another phase 2 trial (Alliance A031701; NCT03609216) is evaluating gemcitabine plus cisplatin in patients with MIBC, including patients with deleterious DDR mutations, who will be selected for bladder preservation. This study is currently recruiting, with an estimated enrollment of 271 patients. Primary results are expected in 2027.

Our ultimate goal when treating MIBC is to be able to personalize recommendations for chemotherapy versus immunotherapy as part of multimodal treatment, further refining patient selection by using molecular profiling to distinguish between individuals whose bladders we can safely save and those for whom cystectomy plus chemotherapy remains the best option for preventing metastatic disease. Longitudinal studies that capture granular data on efficacy, safety, and quality of life will help us understand which patients are the best candidates for bladder-sparing approaches.

Written by: Ashish M. Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas

Published Date: August 2022

References:

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