SUMMARY: The FDA on March 6, 2024, approved Nivolumab (OPDIVO®) in combination with Cisplatin and Gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of all urothelial cancers, and the latter can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.
Platinum-based chemotherapy remains the standard of care for the first line treatment of unresectable or metastatic urothelial carcinoma. Cisplatin-based chemotherapy is preferred over Carboplatin-based chemotherapy for eligible patients and has a response rate of over 40%, with a median Overall Survival (OS) of approximately 15 months. These responses, however, are not durable. To date, no novel agent has improved Overall Survival when added to platinum-based chemotherapy, for first-line treatment of metastatic urothelial carcinoma. There is an unmet need for more effective treatment.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Nivolumab presently is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma after previous platinum-based chemotherapy, as well as for adjuvant treatment of high-risk muscle-invasive urothelial carcinoma after radical resection.
Based on the data from Phase II studies, CheckMate 901 clinical trial was conducted to evaluate the benefit of a combination of Nivolumab plus Gemcitabine and Cisplatin, as compared with Gemcitabine and Cisplatin alone, in patients with previously untreated advanced urothelial carcinoma. CheckMate 901 is an international, open-label, randomized, Phase III trial, consisting of 2 parts. In the first part which is summarized below, Nivolumab plus Gemcitabine and Cisplatin was compared with Gemcitabine and Cisplatin alone, in patients with previously untreated, unresectable or metastatic urothelial carcinoma. In the second part of this study, which is ongoing, patients were assigned to receive either Nivolumab plus Ipilimumab or platinum-based chemotherapy.
In the current trial, 608 patients (N=608) with previously untreated unresectable or metastatic urothelial carcinoma were randomized assigned 1:1 to receive either Nivolumab 360 mg IV in combination with Cisplatin and Gemcitabine every 3 weeks for up to six cycles, followed by Nivolumab 480 mg IV every 4 weeks until disease progression, unacceptable toxic effects, or up to a maximum of 2 years, or Gemcitabine and Cisplatin alone every 3 weeks for up to six cycles. Patients who discontinued Cisplatin alone could be switched to Gemcitabine and Carboplatin for the remainder of the platinum-doublet cycles up to six cycles in total. Randomization was stratified by tumor PD-L1 expression and presence of liver metastasis. Patient characteristics were well-balanced between the two study groups. The median patient age was 65 years. The primary tumor site was the bladder in 75% of patients. 37% of patients had a high tumor PD-L1 expression (1% or more) and 21% of patients had evidence of liver metastases. The dual Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Objective response rate (ORR) per BICR was an exploratory endpoint.
At a median follow up of 33.6 months, there was a statistically significant improvement in both Overall Survival and Progression Free Survival for Nivolumab in combination with Cisplatin and Gemcitabine followed by Nivolumab, compared to Cisplatin and Gemcitabine alone. The median OS was 21.7 months for patients who received Nivolumab in combination with Cisplatin and Gemcitabine and 18.9 months for those who received Cisplatin and Gemcitabine alone, (HR=0.78; P=0.02). Overall survival was 70.2% and 62.7%, respectively, at 12 months and 46.9% and 40.7%, respectively, at 24 months. The median PFS was 7.9 months and 7.6 months, respectively (HR=0.72; P=0.0012). The PFS was 34.2% and 21.8%, respectively, at 12 months and 23.5% and 9.6%, respectively, at 24 months.
The Objective Response Rate and Complete Response Rates were 57.6% and 21.7% respectively with Nivolumab combination therapy, versus 43.1% and 11.8% with Gemcitabine and Cisplatin alone. The median duration of Complete Response was 37.1 months with Nivolumab combination therapy and 13.2 months with Gemcitabine and Cisplatin alone. The most common treatment-related Adverse Events with the Nivolumab combination were anemia, nausea, and neutropenia.
It was concluded that a combination of Nivolumab with Gemcitabine and Cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma, compared to Gemcitabine and Cisplatin alone. The researchers added that this study provides evidence of the benefit of concurrent administration of an immune checkpoint inhibitor and chemotherapy in improving Overall Survival in this patient population.
Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. van der Heijden MS, Sonpavde G, Powles T, et al., for the CheckMate 901 Trial Investigators. N Engl J Med 2023; 389:1778-1789.
