Editor’s Note:
Bladder cancer is a common tumor in the urinary system, with muscle-invasive bladder cancer (MIBC) accounting for approximately 20% of all bladder cancers. Nearly half of non-muscle-invasive bladder cancer (NMIBC) patients may relapse into MIBC. Currently, various explorations in neoadjuvant therapy, including chemotherapy, immunotherapy, and their combination, have been conducted. The recent ESMO conference revealed several advancements in research. Professor Wei Yu from Peking University First Hospital shares the latest developments in neoadjuvant therapy and bladder preservation for bladder cancer.
The achievements in genitourinary tumors at this ESMO conference are substantial. Novel treatment approaches, including immunotherapy, ADC drugs, and more advanced therapies, have been explored in the field of urothelial carcinoma. These include the application of new drugs in the perioperative treatment of MIBC and integrated intravesical treatment for NMIBC. These strategies provide additional tools for clinical practice, and with further research and clinical application, more patients are expected to benefit from these latest treatments.
Professor Wei Yu: Advances in Neoadjuvant Therapy and Bladder Preservation in Bladder Cancer, Oncology, 17 minutes
Latest Research Advances in Neoadjuvant Therapy
Regarding neoadjuvant therapy for MIBC, traditional regimens are typically based on platinum-based chemotherapy, with a complete pathological response (pCR) rate of about 30% to 40%. In the era of immunotherapy, recent studies indicate that immunotherapy can also achieve pCR in some patients. This raises questions about which patients will benefit more from immunotherapy and whether combination therapy can provide better tumor control, delaying recurrence and progression. Three clinical trials presented at this ESMO conference address these questions: PD-L1 atezolizumab for neoadjuvant therapy in NMIBC, the ddMVAC regimen combined with PD-L1 immunotherapy, and neoadjuvant therapy with EV for MIBC.
Efficacy of Atezolizumab as Neoadjuvant Treatment
ADC drugs have seen significant success in late-stage treatment; however, can a single-agent ADC still be effective in the neoadjuvant setting? The ABACUS-2 study presented at this conference analyzed the efficacy and safety of PD-L1 atezolizumab. The study enrolled patients with T1-4a N0-1 M0 diagnosed with NMIBC, classified into subtypes such as squamous cell carcinoma, adenocarcinoma, and sarcomatoid carcinoma. Patients received atezolizumab for two cycles before undergoing radical cystectomy, with the primary endpoint being pCR. The previous PURE-01 study also explored a similar concept, showing that pembrolizumab could achieve pCR in 50% of patients with the Ba/Sq subtype of the EU classification. However, further data are needed to support these findings, as the clinical diagnosis of this subtype still poses challenges.
The ABACUS-2 preliminary results indicate that the pCR rate is close to 40% in the intention-to-treat (ITT) population after two cycles of atezolizumab treatment. Particularly noteworthy is the 75% pCR rate in sarcomatoid carcinoma, although this subgroup had only six patients. Previously, platinum-based chemotherapy had a very low pCR rate in the treatment of sarcomatoid carcinoma, not exceeding 20%. In terms of safety, the overall incidence of grade 3 or higher treatment-related adverse events (TRAEs) was low, similar to previous
experiences.
In conclusion, for NMIBC, it is crucial to strengthen the ability to differentiate central pathology at the time of diagnosis, preferably by experienced pathologists. Atezolizumab demonstrates a good pCR rate, though not remarkable. For patients with sarcomatoid carcinoma, who respond poorly to traditional chemotherapy, the pCR rate can reach 75%. Therefore, further exploration of molecular mechanisms based on pathological subtypes is needed to select appropriate immunotherapy for patients, providing them with opportunities for neoadjuvant treatment.
Exploring the ddMVAC Regimen Combined with PD-L1 Immunotherapy
For MIBC, current neoadjuvant treatments include chemotherapy, immunotherapy, and combination approaches. With improved management of chemotherapy and immunotherapy side effects, can a more potent combination of chemotherapy and immunotherapy lead to better pCR for patients? The NEMIO study at this year’s ESMO conference explored this question. The study included patients with cT2-4 N0-1 and randomly treated them with ddMVAC chemotherapy combined with durvalumab or ddMVAC chemotherapy combined with durvalumab and tremelimumab.
Most patients could complete four cycles of the ddMVAC chemotherapy regimen and undergo radical cystectomy smoothly. Regarding the most concerning aspect, overall immune-related adverse events did not significantly increase for most patients. In terms of pCR rates, the ITT population had a pCR rate of 47.8%, the ddMVAC combined with durvalumab group had a pCR rate of 49.1%, and the ddMVAC combined with dual immunotherapy group had a pCR rate of only 46.6%. The pCR rate for the previous ddMVAC neoadjuvant treatment was 42%. It can be observed that the pCR rate did not significantly increase with the ddMVAC combined with dual immunotherapy approach.
As a neoadjuvant regimen, whether through chemotherapy alone, immunotherapy alone, or the combination of both, overall, the pCR rates are similar. The increase in pCR rates with chemotherapy combined with immunotherapy is not significant. Future research needs to further select suitable patient populations, especially conducting tumor molecular pathology screening, to determine whether patients are suitable for chemotherapy alone, chemotherapy combined with immunotherapy, or immunotherapy alone. Currently, it is believed that the advantage of immunotherapy is not in the pCR rate but possibly in disease-free survival (DFS) and overall survival (OS). Therefore, long-term follow-up on combination therapy is needed to obtain better data results, allowing a better understanding of the roles and positions of chemotherapy and immunotherapy in neoadjuvant treatment.
Exploration of Neoadjuvant Treatment with EV
In addition to the mentioned neoadjuvant approaches, ADC drugs have demonstrated good efficacy in advanced urothelial carcinoma. Particularly, phase III clinical data from the EV combined with PD-1 as first-line treatment suggests survival benefits for metastatic patients. Therefore, can EV, this potent drug, still achieve remarkable results in the neoadjuvant stage? The EV-103 cohort L study conducted an analysis. The research protocol involved neoadjuvant treatment with EV for three cycles, followed by radical cystectomy and an additional six cycles of adjuvant therapy. The primary endpoint was the pathological complete response (pCR) rate.
The study indicated that 82.4% of patients completed the neoadjuvant treatment with three cycles of EV. However, 39.2% of patients experienced grade 3 or higher treatment-related adverse events. Therefore, when initiating ADC drug treatment upfront, close attention is still needed for the occurrence of adverse reactions. The overall pCR rate in the study was 34%, not significantly superior to single-agent immunotherapy, single-agent chemotherapy, or chemotherapy combined with immunotherapy. Therefore, whether to use ADC drugs for neoadjuvant treatment in the future still requires observation of subsequent data from EV and combined immunotherapy to determine whether better pCR rates can be achieved.
Currently, the standard neoadjuvant regimen for MIBC is platinum-based neoadjuvant chemotherapy. In the future, there is a need to explore new biomarkers and combination immunotherapy regimens, as well as the application of ADC drugs in the neoadjuvant setting. Different patient populations may respond differently to various combination regimens, and adverse reactions need to be highly considered in clinical practice. As for NMIBC, exploration is still urgently needed. This conference has presented relevant clinical research on bladder preservation strategies, aiming to provide better treatment options for patients.
Bladder Preservation Strategies for NMIBC Patients
For NMIBC, the main treatment involves transurethral resection of the tumor, followed by postoperative intravesical instillation of drugs. Particularly for high-risk patients, Bacillus Calmette-Guérin (BCG) is commonly used for treatment. However, the choice after BCG failure has always been a clinical challenge, with radical cystectomy usually being recommended. How to better preserve the bladder for these patients is a direction that urgently needs exploration in clinical practice. Since the lesions mainly exist within the bladder, local treatment is an important development direction.
The ESMO conference brought the study of the integrated device TAR-200 for NMIBC patients who do not respond to BCG. This involves intravesical instillation of TAR-200, releasing gemcitabine for treatment. Previous data indicated a high pCR rate, and this study further found that the pCR rate could reach 77%. However, there is still a certain level of toxicity, with 7% of patients experiencing grade 3 or higher treatment-related adverse events (TRAEs). Long-term follow-up needs to be strengthened to improve the long-term pCR rate. Another study involves bladder-controlled release of erdafitinib, primarily for patients with FGFR mutations. The study indicates that the pCR rate for these patients can reach 87%, but some patients had to stop treatment due to adverse events.
Therefore, for NMIBC patients who have failed BCG, controlled-release gemcitabine can be used in the general population, or erdafitinib can be used for patients with FGFR mutations. This integrated device treatment can provide better local control for patients, but there is still a certain risk of progression and metastasis for this patient population. Currently, immunotherapy has achieved certain success in the field of bladder cancer, such as the KEYNOTE-057 study, which led to the FDA approval of pembrolizumab for the treatment of high-risk NMIBC patients who do not respond to BCG, with or without papillary tumors, and with or without carcinoma in situ (CIS) who are not suitable for or do not undergo cystectomy.
In the future, exploration is still needed for localized enhanced treatment, systemic immunotherapy for dormant metastatic foci and advanced stages, as well as combination strategies involving multiple drugs. With technological advancements, it is believed that there will be more localized enhanced treatments and systemic treatment options for NMIBC patients, especially those who have failed BCG, to delay tumor progression.
References :
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Professor Wei Yu
Department of Urology, Peking University First Hospital
Chief Physician, Professor, Doctoral Supervisor
Standing Committee Member, Urinary Tract Epithelial Cancer Committee, Chinese Society of Clinical Oncology
Member, Basic Science Group, Chinese Urological Association (CUA)
Member, CUA Youth Physician Alliance for Urinary Control
Member, Tumor Group, Committee on Urology, Traditional Chinese Medicine and Western Medicine Integration, Chinese Association of Integrative Medicine
Standing Committee Member, Urology Committee, Beijing Cancer Prevention and Treatment Society
Member, Youth Committee, Tumor Branch, Beijing Medical Association
Specialization: Minimally Invasive and Comprehensive Treatment of Genitourinary System Tumors
