‘Encouraging’ results with transurethral resection, systemic therapy for bladder cancer
Click Here to Manage Email Alerts
Transurethral resection of bladder tumor plus systemic therapy induced clinical complete response among a large subset of patients with muscle-invasive bladder cancer, according to phase 2 study results.
The findings — presented during the virtual ASCO Annual Meeting — showed 1-year bladder-intact survival is possible for these patients. However, the durability of responses and the role genomic biomarkers can play in clinical management require longer follow-up, researchers concluded.
“This approach is not yet ready for prime time. We need longer follow-up and we need to interpret this study in the context of some other contemporary studies that are assessing variations on this approach,” Matthew D. Galsky, MD, professor of medicine (hematology and medical oncology) and professor of urology at Icahn School of Medicine at Mount Sinai, told Healio.
“However, what we can state thus far is that (a) clinical response in this setting should be rigorously and consistently defined and approached as one would approach a biomarker in general; (b) the clinical complete response rate to this treatment regimen is relatively high; and (c) a subset of patients have now been observed [for more than] 1 year with an intact bladder and no evidence of local or systemic recurrence.”
Clinicians have known for decades that some patients with muscle-invasive bladder cancer who receive neoadjuvant chemotherapy achieve pathological complete response, Galsky said.
“If one could identify these patients prior to surgery, a subset of patients might be able to receive definitive therapy with transurethral resection of bladder tumor (TURBT) plus systemic therapy alone,” he said.
However, key challenges have prevented this approach from moving forward, Galsky said.
“Clinical response to neoadjuvant chemotherapy — that is, what can be defined using imaging, cystoscopy and potentially repeat biopsies of the bladder — is a poorly and inconsistently defined entity and has rarely been assessed prospectively,” Galsky said.
There also is a potential disconnect between clinical response assessment and pathological response.
“This concern does undermine the possibility that patients who have microscopic residual disease not detected on initial clinical restaging, and who experience a local recurrence, cannot achieve similar long-term outcomes with delayed surgery vs. immediate cystectomy,” Galsky said. “Salvage surgery has been a critical component of organ-sparing approaches for all other organ sites. Finally, our systemic therapy regimens ideally would be further improved to increase the likelihood that patients might experience long-term bladder intact survival.”
Galsky and colleagues conducted their trial to assess the efficacy of gemcitabine, cisplatin and the anti-PD-1 monoclonal antibody nivolumab (Opdivo, Bristol Myers Squibb) with selective bladder sparing for patients with clinically localized muscle-invasive bladder cancer.
The analysis included 76 cisplatin-eligible patients (median age, 69 years; 79% male) with cT2-T4aN0M0 urothelial bladder cancer treated at seven sites between August 2018 and November 2020. More than half (56%) of patients had cT2 disease, whereas 32% had cT3 and 12% had cT4.
Patients received four cycles of gemcitabine, cisplatin and nivolumab. They underwent subsequent clinical restaging, including urine cytology, MRI/CT of the bladder, cystoscopy and biopsies of the bladder and prostate.
Patients who achieved a clinical complete response — defined as normal cytology and imaging and no evidence of tumors on biopsies of the bladder — could receive nivolumab every 2 weeks for eight cycles, followed by surveillance, without surgical removal of the bladder. All other patients underwent cystectomy.
Researchers established co-primary endpoints, aiming to determine clinical complete response rate and define the performance characteristics of clinical complete response to predict benefit from treatment.
“Because patients with a clinical complete response could opt for cystectomy after cycle four vs. no cystectomy, a composite endpoint of benefit was employed: benefit was defined as either being 2 years metastasis free if the bladder was left intact, or having a pathological complete response if the bladder was removed after cycle four,” Galsky said.
Researchers also sought to determine whether tumor mutational burden and prespecified genomic alterations — such as ERCC2, FANCC, RB1 or ATM — in baseline TURBT tissue correlated with benefit from treatment among patients who achieved clinical complete response.
At ASCO, Galsky and colleagues reported clinical complete response rate data, as well as an interim analysis of 1-year outcomes.
Sixty-four patients (84%) had completed restaging after four treatment cycles. These included 31 patients (48%) who achieved clinical complete response — one of whom opted to undergo immediate cystectomy and had pTaN0M0 stage disease — and 33 (52%) patients who did not achieve clinical complete response.
Median follow-up for patients who achieved clinical complete response was 13.7 months (range, 2.5-24).
More than three-quarters (78%) of patients who achieved clinical complete response remained recurrence free at 1 year.
The 48% pathological complete response rate is reassuring and “aligned well” with researchers’ assumptions when they designed the trial, Galsky said.
Although data are not mature to determine long-term bladder-intact survival among patients who opted not to undergo immediate cystectomy, results thus far are “encouraging,” he added.
“The standard approach for patients with muscle-invasive bladder cancer is to receive local therapy with surgery or radiation along with systemic therapy,” Galsky said. “However, based on years of clinical observations, we know that a subset of patients will do well with TURBT plus systemic therapy and, therefore, we must acknowledge the limitations of the knowledge base in this area to date, acknowledge our potential biases and proceed with the series of prospective investigations simultaneously integrating novel technologies to refine the role of this treatment approach among those we employ as standard treatment for muscle-invasive bladder cancer.”
Eight of 31 patients who achieved clinical complete response developed local recurrence, and six underwent cystectomy (pT0N0, n = 1; pTaN0, n =1; PTisN0, n = 1; pT2N0, n = 2; pT4N1, n = 1).
Researchers observed associations between two variables — tumor mutational burden (10 or more mutations/megabase) and ERCC2 mutations — and clinical complete response or pT0 (P = .02 for both).
“The role of additional genetic, genomic and radiomic biomarkers to refine selection of patients for this approach needs to be defined, [and] this is being done through our study and a couple of others,” Galsky said. “However, I do want to emphasize that all of this work should be built on a foundation of rigorously and consistently defining clinical response.”
Perspective
Back to TopAndrea Necchi, MD
Efforts to improve outcomes for patients with muscle-invasive bladder cancer started with improvements in disease downstaging, moved toward improving systemic therapy by adding new drugs like immunotherapy, and continued with improvements in consolidation of local tumor control through introduction of newer strategies.
The study by Galsky and colleagues is designed to achieve what I would call the new target step: curing bladder cancer by avoiding any radical local therapy on the primary tumor.
Initial data for this approach from the RETAIN BLADDER study were very promising in terms of metastases-free survival and OS, particularly for biomarker-selected patients.
In the study by Galsky and colleagues, a substantial number of patients presented with larger tumors, and the definition of complete response included residual low-grade disease.
In this case, we have a maintenance immunotherapy period after clinical complete response. It is interesting to highlight that patient adherence to any novel therapeutic strategy outside of surgery or radiotherapy is very high, suggesting if we provide patients with an intelligent option within well-designed and well-conducted clinical trials, patients are with us. That is important information to have when we think about and design future studies in the same clinical setting.
The role of biomarkers is still undefined. We saw an association between ERCC2 mutations and response, but the same association was not confirmed for the other genes assessed. We still need validation prior to using these mutations as part of routine practice.
It is clear if we avoid radiotherapy to the primary tumor, we lose a substantial proportion of patients achieving complete response. Also, based on treatment eligibility, this strategy may apply to only about half of the patient population. However, patients who achieved a complete response had a substantial ability to maintain that response long term.
As the field moves forward, we should look at biomarkers, tumor imaging and use of new drugs. Biomarkers are critical. We should look outside of the tumor — in particular with use of circulating tumor DNA, which is one of the best candidate biomarkers for next-generation studies. The concept of minimal residual disease also is important, and it may apply to immune-radiotherapy or chemoradiotherapy protocols in the near future.
Multiparametric MRI appears to be a feasible and promising strategy to design treatment paths for patients with muscle-invasive bladder cancer.
Finally, we have to consider incorporating new drugs into rational therapeutic sequences — in particular antibody-drug conjugates and fibroblast growth factor receptor inhibitors, which are changing the paradigm for bladder cancer.
Are we able to circumvent any radical local therapy to the bladder tumor?
With the introduction of immunotherapy over standard chemoradiation protocols or newer protocols, we desperately need harmonization of terminology and definition of trial endpoints, starting with complete response but also including survival endpoints.
We need longer follow-up to confirm associations with outcomes, and we need to substantially raise the bar of therapeutic efficacy for strategies that aim to spare patients any radical local therapy because the benchmark of chemoradiation is still hard to beat.
We also desperately need results of randomized trials to assess and quantify the magnitude of benefit by adding immunotherapy over standard chemotherapy and chemoradiation protocols.
Collapse
Galsky MD, et al. Abstract 4503. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
Click Here to Manage Email Alerts