"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
For successful care of muscle-invasive bladder cancer (MIBC), patients should be evaluated by a multidisciplinary team that includes a urologist, radiation oncologist, and medical oncologist. Depending on whether the patient is a surgical candidate, a variety of standard-of-care options exist, noted Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic.
For those patients who are candidates for surgery, the standard of care for MIBC is neoadjuvant chemotherapy followed by cystectomy. Neoadjuvant cisplatin-based chemotherapy improves overall survival (OS) in cisplatin-eligible patients. Two trials, SWOG-8710 and BA06 EORTC 30894, showed that neoadjuvant cisplatin-based chemotherapy followed by cystectomy is superior to radical cystectomy alone in improving patient outcomes.
In SWOG-8710, neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) followed by radical cystectomy increased the likelihood of tumors being downstaged to pT0 and was associated with a 33% reduction in the risk of death compared with radical cystectomy alone among patients with locally advanced bladder cancer.
In BA06 EORTC 30894, a neoadjuvant regimen of cisplatin, methotrexate, and vinblastine (CMV) reduced the relative risk of death by 16% in patients with MIBC treated by cystectomy and/or radiotherapy.
The Advanced Bladder Cancer Meta-analysis Collaboration showed a 6% absolute improvement in OS with adjuvant chemotherapy at 5 years. The EORTC 30994 trial assessed immediate versus deferred chemotherapy (at the time of relapse) with investigator's choice of M-VAC, dose-dense M-VAC, or gemcitabine-cisplatin after cystectomy in patients with high-risk (pT3-pT4 or N+ M0) bladder cancer.
Immediate adjuvant chemotherapy led to a median OS of 6.7 years compared with 4.6 years with deferred chemotherapy at the time of relapse. The trial was underpowered because of the difficulty in accruing patients and closed early. The strategy of adjuvant systemic therapy offers the potential for maximizing the impact on patient outcomes by administering chemotherapy at the earliest point in the natural history of the disease.
Despite use of chemotherapy and surgery, however, MIBC has a high risk of recurrence and death. The desired state in MIBC is to improve disease-free survival (DFS) and ultimately OS with personalized treatments and remove barriers to access [to care], said Gupta. "Fifty percent of patients are deemed ineligible for chemotherapy, and 30% refuse it. Lack of neoadjuvant treatment options for cisplatin-ineligible patients is a barrier we see every day."
Adjuvant Immunotherapy
"Incorporating immunotherapy in the adjuvant paradigm is the next rational step," she continued. Two studies have reported results in the setting of high-risk muscle-invasive urothelial cancer, with high risk defined as ≥pT2 disease or node-positive disease after neoadjuvant chemotherapy, or ≥pT3 or node-positive disease if patients were deemed ineligible for chemotherapy. IMvigor010, which compared atezolizumab with observation, did not show a DFS or OS benefit with atezolizumab.
Nivolumab became a standard of care for patients with high-risk muscle-invasive urothelial carcinoma after radical surgery based on the initial results from the CheckMate-274 trial, which compared nivolumab with placebo, showing a doubling of median DFS (22.0 vs 10.9 months) in the nivolumab arm with the OS data immature.
The benefit to nivolumab was even more pronounced in patients with PD-L1 expression ≥ 1%. "Notably, patients in CheckMate-274 who received prior neoadjuvant cisplatin-based chemotherapy or any other neoadjuvant chemotherapy derived greater benefit than those who did not," Gupta said.
Extended follow-up of Checkmate-274 (median 36.1 months) showed that nivolumab continues to demonstrate improvements in DFS, non-urothelial tract recurrence-free survival, and distant metastasis-free survival (DMFS) versus placebo.
In the intent-to-treat population, median DFS with nivolumab was doubled compared with placebo, said the study's lead investigator, Matthew Galsky, MD, director of Genitourinary Medical Oncology and co-director of the Center of Excellence for Bladder Cancer at the Tisch Cancer Institute at Mount Sinai in New York City.
"In the population with PD-L1 expression ≥ 1%, median DFS with nivolumab reached 52.6 months -- more than six times the median DFS in the placebo arm," he said. "We can say that there's a benefit in the all-comer population and that the effect size is larger in patients with tumors with high PD-L1 expression. You can't say with the study design whether patients with low PD-L1 expression benefit. There's remarkable consistency in effect size regardless of the primary, secondary, or exploratory endpoints. Included in those endpoints is DMFS. The effect size with DMFS is quite similar to what you see with DFS."
Closer inspection of data from IMvigor10 suggests that adjuvant atezolizumab may be associated with improved outcomes compared with observation but only in those in patients who are positive for circulating tumor (ct)DNA and who are at a high risk of relapse, according to an analysis that appeared in Nature. Patients who were positive for ctDNA had improved DFS and OS in the atezolizumab arm versus the observation arm, whereas there was no difference in DFS or OS between treatment arms for patients negative for ctDNA.
"Even though that analysis is retrospective and exploratory, they showed that patients that had detectable ctDNA at baseline, a measure of the presence of microscopic residual disease, benefited from adjuvant atezolizumab in that study," said Galsky. "If you believe in that result, then you believe that adjuvant immunotherapy works; it's just that there is an issue with patient selection, which would make the IMvigor10 and CheckMate-274 [results] more similar than different."
Short of OS data with either agent, which can take time to mature, he said, "clinicians have to make the decision based on the package of data for the patient that is sitting in front of them today. Do the benefits outweigh the risks? I think the package of data supports a favorable risk-benefit balance."
Treatments for upper-tract urothelial cancer represent an unmet need, as outcomes tend to be poor with existing treatments. In the Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer (POUT) trial of patients with upper-tract urothelial cancer, adjuvant platinum-based chemotherapy demonstrated a significant improvement in DFS versus surveillance, with an HR of 0.45.
In patients who received gemcitabine-cisplatin in POUT, the HR was 0.35, and in those who received gemcitabine-carboplatin, the HR was 0.66 (P=0.21). In trials of adjuvant immunotherapy in MIBC, both atezolizumab and nivolumab failed to produce a statistically significant benefit in DFS in patients with upper-tract disease, Gupta noted. These subgroup analyses need to be explored in future studies.
Emerging Role of Neoadjuvant Immunotherapy
Neoadjuvant chemotherapy plus immunotherapy is effective in patients who are eligible for cisplatin prior to radical cystectomy. Across the trials examining chemo-immunotherapy, the combination was generally safe and showed promising rates of pathologic complete response (pCR). Single-agent immunotherapy and single-agent chemotherapeutic agents such as enfortumab vedotin (EV) have also shown efficacy in MIBC, with rates of pCR comparable to those with neoadjuvant chemotherapy alone. These strategies are being explored in several trials highlighted below.
Data from the Bladder Cancer Signal Seeking Trial (BLASST-1) reinforce the efficacy of nivolumab when given in combination with gemcitabine and cisplatin as neoadjuvant treatment in patients with MIBC prior to standard-of-care radical cystectomy. The recurrence-free survival rate with combination immuno-chemotherapy was 85.4%, and the PFS rate, including death from any cause, was 83%, said Gupta, one of the study's co-authors.
"We found really impressive results, with pathologic downstaging in 66% and a pathologic complete response rate of 50%," she said. "It was well tolerated. There were no delays to surgery and no side effects other than those expected from chemotherapy. Nobody required steroids for any immune-related side effects."
The authors also conducted a genomic analysis of tissue obtained from residual tumors to identify predictors of response, and found that mutations in ERCC2, ARID1A, DSP, HMCN1, ERBB2, ERBB3, STAG2, and BRCA2 were present in responders.
BLASST-1 is ongoing. Patients are receiving neoadjuvant treatment with nivolumab in combination with gemcitabine-cisplatin every 3 weeks for four treatment cycles over 12 weeks followed by standard-of-care radical cystectomy.
Recently reported data from the EV-103 Cohort H study demonstrated a pCR rate of 36.4% with single-agent EV in cisplatin-ineligible patients with MIBC. "For patients who are not candidates for cisplatin, this appears to be a promising option," Gupta said, noting that the efficacy of single-agent immunotherapy calls into question the need to add chemotherapy to immunotherapy.
Several phase III neoadjuvant chemo-immunotherapy trials are ongoing or have completed enrollment, in which standard-of-care, cisplatin-based chemotherapy is being combined with a variety of immunotherapy agents.
"Once the results of these trials are reported, we will learn whether complete responses and event-free survival are better with the combination compared with chemotherapy alone, and also whether the combination of EV and pembrolizumab leads to better pCR and event-free survival compared to chemotherapy alone, and can [therefore] replace chemotherapy," she said.
The trials will also inform whether immunotherapy or EV-pembrolizumab is superior to upfront surgery in cisplatin-ineligible patients. Unfortunately, she noted, patients in the control arms in these trials are not permitted to receive adjuvant nivolumab, which has been recently approved for patients with MIBC.
When it comes to combination chemo-immunotherapy, it should be noted that on April 3, 2023, the FDA granted accelerated approval to the combination of EV and pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma ineligible for cisplatin, on the basis of the EV-103/KEYNOTE-869 study. With the approval of this combination for patients with metastatic urothelial cancer, results from ongoing chemo-immunotherapy combinations in the neoadjuvant space are eagerly awaited.
Circulating Tumor DNA, Biomarkers
The role of ctDNA will be clarified in the coming years; it has been shown to be highly prognostic in MIBC and served as a biomarker of response to atezolizumab in the IMvigor010 study. IMvigor011 is assessing the treatment of patients with high-risk MIBC who are ctDNA-positive and randomizing them to adjuvant atezolizumab or placebo; in another trial, patients with cDNA-negative high-risk disease are being randomized to immediate nivolumab versus initiation when they become cDNA-positive.
Bladder-sparing Strategies and Trimodality Therapy
Since patients value bladder preservation when possible, "trimodality therapy [TMT] is a valid option for bladder preservation as an alternative to radical cystectomy, which is considered the gold standard," Gupta noted.
Although randomized controlled trials comparing TMT with cystectomy are lacking, in cohort analyzes and meta-analyses long-term OS appears similar, she said, adding that 5-year DFS rates with TMT can approach 85% in patients who are good candidates for it. Neoadjuvant chemotherapy prior to TMT is currently being explored, which may further improve outcomes.
Bladder-sparing approaches remain an unmet need in MIBC. In the phase II RETAIN BLADDER study, neoadjuvant dose-dense M-VAC and bladder preservation was studied in patients with cT2-T3N0M0 urothelial cancer with alterations in DNA damage repair-response genes.
After 2 years of follow-up, 46% of patients survived and retained their bladders without developing metastatic disease. The 2-year metastasis-free survival rate was 77%. Two ongoing trials, Alliance and RETAIN-2, will further clarify the role of bladder preservation in select patients.
Immunotherapy with concurrent chemoradiation is also being studied as a part of TMT. In the CCT BL13 trial, patients are being randomized to surveillance or adjuvant durvalumab after TMT. The role of antibody drug conjugates in TMT is unclear. The RAD-SG trial led by investigators at Cleveland Clinic, including Gupta, is exploring sacituzumab govitecan in patients with MIBC who are ineligible for cisplatin to test the safety and feasibility of using it concurrently with radiation.
Currently, no validated biomarkers exist to identify response to immunotherapy approaches. Artificial intelligence is being used in an attempt to develop comprehensive biomarkers of response and resistance to immunotherapy through investigation of pre- and post-treatment tissues obtained from patients on chemotherapy alone, chemo-immunotherapy, and immunotherapy alone. Biomarker-based adaptive trials are needed, Gupta emphasized.
Read previous installments in this series:
Part 1: Urothelial Cancer: Diagnostic Evaluation
Part 2: Staging of Urothelial Cancer: Cystoscopy and CT Evaluation Remain Standard
Part 3: Non-Muscle-Invasive Bladder Cancer: Intravesical BCG and Beyond
Part 4: Case Study: Recurrence of Urothelial Cancer Challenging in Patient With Morbid Obesity