A large phase 3 clinical trial has found that adding the immunotherapy drug nivolumab to standard chemotherapy significantly improves survival outcomes for patients with advanced urothelial cancer. The international, randomized, open-label study, known as CheckMate 901, was funded by Bristol Myers Squibb in collaboration with Ono Pharmaceutical and published in the New England Journal of Medicine on November 9, 2023.
The trial aimed to evaluate whether combining nivolumab with gemcitabine-cisplatin chemotherapy could improve outcomes compared to chemotherapy alone as first-line treatment for patients with previously untreated unresectable or metastatic urothelial carcinoma. Urothelial carcinoma is the most common type of bladder cancer, and advanced cases have historically had poor prognoses with standard chemotherapy regimens.
A total of 608 patients were enrolled in the study between January 2018 and September 2022 across 135 sites in 30 countries. Eligible patients had histologically confirmed unresectable or metastatic urothelial carcinoma involving the renal pelvis, ureter, bladder, or urethra. They were required to have measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Importantly, all patients had to be eligible to receive cisplatin-based therapy, which included having adequate renal function with a glomerular filtration rate of at least 60 mL/min.
Patients were randomly assigned in a 1:1 ratio to receive either nivolumab (360 mg intravenously) plus gemcitabine-cisplatin chemotherapy every 3 weeks for up to 6 cycles, followed by nivolumab maintenance therapy (480 mg every 4 weeks) for up to 2 years, or gemcitabine-cisplatin chemotherapy alone every 3 weeks for up to 6 cycles. Randomization was stratified by tumor PD-L1 expression level and presence or absence of liver metastases.
The study population was representative of the typical advanced urothelial cancer patient population. The median age was 65 years in both groups, with about half of patients aged 65 or older. Approximately 77% of patients were male. The majority of patients (85-88%) had metastatic disease, while 11-13% had locally unresectable, non-metastatic disease. About 36% of patients in each group had tumors with PD-L1 expression ≥1%, and 21% had liver metastases.
The two primary endpoints of the trial were overall survival and progression-free survival as assessed by blinded independent central review. At a median follow-up of 33.6 months, both endpoints showed statistically significant improvements with the addition of nivolumab.
Median overall survival was 21.7 months in the nivolumab combination group compared to 18.9 months with chemotherapy alone (hazard ratio [HR] 0.78, 95% CI 0.63-0.96, p=0.02). The 12-month overall survival rate was 70.2% vs 62.7%, and the 24-month rate was 46.9% vs 40.7%, favoring the nivolumab combination.
Progression-free survival was also significantly longer in the nivolumab group, with a median of 7.9 months vs 7.6 months (HR 0.72, 95% CI 0.59-0.88, p=0.001). The 12-month progression-free survival rate was 34.2% with nivolumab vs 21.8% with chemotherapy alone.
Importantly, the nivolumab combination nearly doubled the complete response rate compared to chemotherapy alone (21.7% vs 11.8%). The overall objective response rate was also higher at 57.6% vs 43.1%. Responses appeared to be more durable with nivolumab as well, with a median duration of complete response of 37.1 months vs 13.2 months.
The safety profile of nivolumab plus chemotherapy was consistent with the known effects of these agents. Treatment-related adverse events of any grade occurred in 97.4% of patients receiving nivolumab combination therapy compared to 92.7% with chemotherapy alone. Grade 3 or higher treatment-related adverse events were seen in 61.8% vs 51.7% of patients, respectively. The most common high-grade adverse events in the nivolumab group were anemia (22.0%), neutropenia (18.8%), and decreased neutrophil count (14.5%).
Treatment-related adverse events leading to discontinuation occurred in 21.1% of nivolumab-treated patients vs 17.4% of those receiving chemotherapy alone. One treatment-related death (due to sepsis) was reported in the nivolumab group, and one (due to acute kidney injury) in the chemotherapy group.
The study authors concluded that the addition of nivolumab to gemcitabine-cisplatin chemotherapy resulted in significantly better outcomes for patients with previously untreated advanced urothelial carcinoma compared to chemotherapy alone. They noted that the combination therapy showed early antitumor activity, with a median time to response of about 2 months, similar to chemotherapy alone. However, the responses appeared deeper and more durable with nivolumab.
Some limitations of the study should be noted. This was an open-label trial, which could potentially introduce bias in the assessment of progression-free survival and adverse events. However, the use of blinded independent central review for the primary efficacy endpoints helps mitigate this concern. Additionally, the trial only included patients eligible for cisplatin-based therapy, so the results may not be generalizable to cisplatin-ineligible patients who often receive carboplatin-based regimens.
The findings of CheckMate 901 have potentially important clinical implications for the first-line treatment of advanced urothelial cancer. To date, no new agent had demonstrated an overall survival benefit when added to standard cisplatin-based chemotherapy in this setting. Previous phase 3 trials combining immune checkpoint inhibitors with platinum-based chemotherapy, such as KEYNOTE-361 with pembrolizumab and IMvigor130 with atezolizumab, failed to show significant improvements in both overall survival and progression-free survival in the overall study populations.
The positive results seen with nivolumab may be partly explained by the trial's focus on combining immunotherapy specifically with cisplatin-based chemotherapy, rather than including carboplatin-based regimens. Some evidence suggests cisplatin may have greater immunomodulatory effects than carboplatin, potentially enhancing the efficacy of checkpoint inhibition. The CheckMate 901 results support the hypothesis that cisplatin-based chemotherapy may combine more favorably with immunotherapy in urothelial cancer.
If approved by regulatory agencies, the nivolumab-chemotherapy combination could become a new standard of care for first-line treatment of cisplatin-eligible patients with advanced urothelial carcinoma. The significant improvements in overall survival, progression-free survival, and complete response rate offer meaningful clinical benefits. The nearly three-fold increase in duration of complete response is particularly noteworthy, as it suggests the potential for long-term disease control in a subset of patients.
However, the increased rates of adverse events with the combination therapy will need to be weighed against the survival benefits. Careful patient selection and management of immune-related toxicities will be important considerations for clinical implementation. Future biomarker analyses may help identify which patients are most likely to benefit from the addition of nivolumab.
It's also worth noting that during the course of this trial, maintenance avelumab immunotherapy after initial platinum-based chemotherapy became a standard approach based on the JAVELIN Bladder 100 trial. Some patients in the control arm of CheckMate 901 received maintenance checkpoint inhibitors, though cross-trial comparisons are not appropriate given differences in study populations. The concurrent chemoimmunotherapy approach in CheckMate 901 appears to offer advantages over sequential therapy, at least for cisplatin-eligible patients, but further studies may be needed to optimize treatment sequencing.
In conclusion, the CheckMate 901 trial represents an important advance in the first-line treatment of advanced urothelial carcinoma. By demonstrating significant improvements in overall survival and other key endpoints, the addition of nivolumab to standard cisplatin-based chemotherapy has the potential to change practice and improve outcomes for patients with this aggressive malignancy. As with any new treatment approach, long-term follow-up and real-world data will be valuable to further characterize the benefits and risks of this combination therapy.
References
van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023;389(19):1778-1789. doi:10.1056/NEJMoa2309863
