Editor's Note: Bladder cancer is one of the common malignant tumors among residents in China, with 75% of bladder cancers being non-muscle-invasive bladder cancer (NMIBC) with a high postoperative recurrence rate. Intravesical instillation therapy involves injecting cytotoxic drugs directly into the bladder to kill tumor cells or injecting immunotherapeutic agents like BCG to induce a local immune response, thereby reducing the risk of tumor recurrence and progression. The 2024 ASCO Annual Meeting was held in Chicago, USA, from May 31 to June 4, showcasing multiple latest research advances in urologic oncology. Among them was a study on intravesical camrelizumab from Fudan University Cancer Hospital, which was selected for poster presentation (Abstract No. 4594). "Oncology Frontier" invited Professor Yijun Shen from Fudan University Cancer Hospital to share and interpret the findings.Oncology Frontier: What are the unmet treatment needs for high-risk NMIBC patients?
Professor Yijun Shen: NMIBC has always been a focus and challenge in bladder cancer diagnosis and treatment. These patients have a high clinical recurrence rate, and although BCG intravesical instillation is the standard treatment, the recurrence rate within five years is nearly 50%, posing a significant treatment challenge. Currently, for high-risk NMIBC patients who do not respond to or fail BCG treatment, the recommended option is radical cystectomy. However, these patients often have a strong desire to preserve their bladder to maintain a high quality of life, making this an unmet treatment need and a focus of high-risk NMIBC treatment.
Oncology Frontier: You presented the latest research results on PD-1 antibody therapy for high-risk NMIBC patients (intravesical camrelizumab phase II study) at this year’s ASCO meeting. What are the efficacy and safety outcomes?
Professor Yijun Shen: Our team presented phase II study results at this year’s ASCO meeting, where we treated high-risk NMIBC patients who did not respond to or failed BCG treatment with intravesical camrelizumab. The idea originated four years ago when many patients who failed BCG treatment needed to undergo radical cystectomy. The advent of immunotherapy brought significant progress for advanced urothelial carcinoma. The US FDA approved pembrolizumab (Keytruda) for high-risk NMIBC patients who did not respond to BCG and were not suitable for or declined cystectomy based on the KEYNOTE-057 trial.
Pembrolizumab is typically administered systemically via intravenous injection, but systemic therapy can still lead to a certain proportion of adverse reactions. Although the incidence of severe adverse reactions (grade 3/4) is not high, the clinical challenge lies in the inability to predict which patients might experience severe immune-related adverse reactions. These severe reactions, such as immune myocarditis, pneumonitis, and colitis, can cause organ damage. Therefore, we considered whether localized immune therapy could be applied to localized bladder cancer to address treatment challenges while significantly reducing treatment-related adverse reactions.
BCG treatment failure patients are relatively uncommon in clinical practice, and some high-risk patients are unwilling to undergo BCG treatment, making patient enrollment difficult. Ultimately, 14 patients were enrolled for localized camrelizumab treatment, and the phase II study’s initial efficacy analysis was presented at this year’s ASCO meeting. In a previous exploratory analysis of six patients treated with localized camrelizumab presented at the EAU meeting two years ago, we found good safety and tolerability with no grade 3 or higher immune-related adverse reactions. Moreover, cystoscopy after three months of treatment showed no tumor recurrence or residual in nearly 67% of patients, strengthening our confidence for the phase II exploration.
The phase II study’s results are exciting, with a median follow-up of 23.1 months and a median event-free survival (EFS) of 12.68 months. The 3-month, 6-month, and 12-month EFS rates were 92.3%, 75.5%, and 50.3%, respectively. The median recurrence-free survival (RFS) and progression-free survival (PFS) were both 12.68 months. Overall, the intravesical immune therapy met the expected research goals. Safety-wise, only 2 patients (14.3%) experienced grade 3 or higher treatment-emergent adverse events (TEAEs), including one case of urinary tract infection and one case of vertebrobasilar insufficiency. One patient (7.1%) experienced a serious TEAE. No deaths were reported. Interestingly, some patients responded remarkably well to PD-1 drug instillation, with two patients receiving camrelizumab treatment for up to two years without tumor recurrence during regular follow-ups.
Oncology Frontier: You also analyzed related biomarkers. What factors are associated with patient outcomes? Do patients with PD-L1 expression show better efficacy?
Professor Yijun Shen: Some patients showed significant efficacy, but not all 14 patients maintained long-term favorable outcomes. Therefore, we explored the correlation between drug mechanisms or immunotherapy itself and patient efficacy. It is known that patients with high tumor PD-L1 expression often have better outcomes with systemic immunotherapy. We first analyzed PD-L1 expression in 10 out of the 14 patients. Two patients with high PD-L1 expression maintained a tumor-free state throughout the treatment. Although the sample size was too small to draw definitive conclusions, we observed a trend of better efficacy with high PD-L1 expression. Additionally, through bioinformatics clustering, we found that better outcomes were possibly associated with immune-related pathway activation at the proteomic level.
Combining these two aspects of the study results, we believe that efficacy is related to the local immune activation response induced by the immunotherapy itself, particularly with better outcomes in PD-L1 high expression patients using localized PD-1 instillation. This deserves further basic research exploration. Future research could use drug screening or biomarker screening to further explore the mechanism underlying the relationship between localized immunotherapy and tumors.
Oncology Frontier: In recent years, several new intravesical drug delivery systems, such as TAR-200 and TAR-210, have emerged. What is your view on the efficacy of these delivery strategies for high-risk NMIBC patients?
Professor Yijun Shen: This is an excellent question. We have also noticed a significant need for bladder preservation in high-risk NMIBC, especially in patients treated with BCG. In recent years, many new drugs have been approved or are about to be approved internationally for high-risk NMIBC patients who failed BCG treatment, such as pembrolizumab for systemic therapy, gene therapy drugs, and the IL-15 immunostimulant combined with BCG. Additionally, drug-device combinations (like TAR-200, TAR-210) involve inserting a small device into the patient’s bladder through a cystoscope to slowly release gemcitabine intravesically.
Whether it is immune instillation in our study or localized treatment with drug-device combinations, both approaches treat NMIBC post-BCG treatment failure through local drug delivery. The primary goal of NMIBC treatment is long-term control. However, long-term systemic treatment (including immunotherapy, chemotherapy, ADC drugs) may cause adverse reactions that some patients find difficult to tolerate. Localized drug delivery, with fewer adverse reactions, has thus become a mainstream research strategy and future exploration direction for high-risk NMIBC globally.
