FDA Approves Frontline Nivolumab Plus Chemo for Unresectable or Metastatic Urothelial Carcinoma


The FDA has approved nivolumab plus cisplatin and gemcitabine for first-line use in adult patients with unresectable or metastatic urothelial carcinoma.



The FDA has approved nivolumab (Opdivo) plus cisplatin and gemcitabine for the frontline treatment of adult patients with unresectable or metastatic urothelial carcinoma.1,2

The regulatory decision is supported by findings from the phase 3 CheckMate 901 study (NCT03036098), which showed that the nivolumab combination significantly improved overall survival (OS) and progression-free survival (PFS) vs cisplatin/gemcitabine alone.

Specifically, the median OS with nivolumab plus chemotherapy (n = 304) was 21.7 months (95% CI, 18.6-26.4) vs 18.9 months (95% CI, 14.7-22.4) with chemotherapy alone (n = 304), translating to a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.63-0.96; 2-sided P = .0171). The median PFS with nivolumab/chemotherapy was 7.9 months (95% CI, 7.6-9.5) vs 7.6 months (95% CI, 6.0-7.8) with chemotherapy alone, translating to a 28% reduction in the risk of disease progression or death (HR, 0.72; 95% CI, 0.59-0.88; 2-sided P = .0012).

Moreover, the objective response rate (ORR) achieved with nivolumab plus chemotherapy was higher than that experienced with chemotherapy alone, at 57.6% (95% CI, 51.8%-63.2%) and 43.1% (95% CI, 37.5%-48.9%), respectively. In the chemoimmunotherapy arm, the complete response (CR) and partial response (PR) rates were 22% and 36%, respectively; in the chemotherapy-alone arm, these respective rates were 12% and 31%. The median duration of response with nivolumab/chemotherapy was 9.5 months (95% CI, 7.6-15.1) vs 7.3 months (95% CI, 5.7-8.9) with chemotherapy alone.

About CheckMate 901: Eligibility, Treatment, Objectives

The open-label, randomized, phase 3 study enrolled patients with previously untreated unresectable or metastatic urothelial carcinoma. Notably, previous neoadjuvant or adjuvant chemotherapy was allowed if patients experienced disease recurrence 12 months or more from completion of the treatment. Those who were not candidates to receive cisplatin or who had active central nervous system metastases were not permitted.

Study participants were randomly assigned 1:1 to nivolumab/chemotherapy or chemotherapy alone. Those in the investigative arm received 360 mg of nivolumab plus 70 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of gemcitabine on days 1 and 8 of 21-day treatment cycles for up to 6 cycles followed by 480 mg of nivolumab monotherapy every 4 weeks until disease progression or intolerable toxicity. Nivolumab was continued for no longer than 2 years from the first dose. Those in the control arm received the same chemotherapy dose and schedule until progression or intolerable toxicity. Those who discontinued cisplatin alone were allowed to switch to carboplatin.

OS and PFS by blinded independent central review (BICR) and RECIST v1.1 criteria served as the trial's primary efficacy outcome measures. Another key outcome measure BICR-assessed ORR.

The median patient age was 65 years (range, 32-86), and approximately half (51%) were 65 years of age or older. Most patients were White (72%) and male (77%). Regarding ECOG performance status, 53% had a status of 0, and 46% had a status of 1. Moreover, 87% of patients had metastatic disease and 20% of those patients had liver metastases; 11% of patients had locally advanced disease. Approximately half (51%) had histologic variants.


The median duration of exposure to nivolumab was 7.4 months (range, 0.03-47.9). Forty-eight percent of patients who received nivolumab combined with chemotherapy experienced serious toxicities and 3.6% experienced fatal events, including sepsis (1%). Moreover, 67% of patients experienced an adverse effect (AE) that required treatment delay with nivolumab and/or chemotherapy and 30% experienced an AE that led to discontinuation.

The most common AEs experienced by at least 10% of patients treated with nivolumab/chemotherapy on CheckMate 901 were nausea (all grade, 52%; grade 3/4, 0.3%), constipation (30%; 0%), vomiting (23%; 1.3%), diarrhea (19%; 2%), abdominal pain (14%; 0.3%), fatigue (48%; 3.9%), edema (18%; 0%), pyrexia (14%; 1%), musculoskeletal pain (33%; 3%), reduced appetite (30%; 1.6%), rash (25%; 2.3%), pruritus (17%; 0.7%), peripheral neuropathy (20%; 0.7%), headache (11%; 0%), urinary tract infections (19%; 8%), hypothyroidism (17%; 0%), renal dysfunction (14%; 6%), hematuria (11%; 1%), and decreased weight (11%; 0.3%).

The most common laboratory abnormalities that worsened from baseline and occurred in at least 20% of patients who received the chemoimmunotherapy regimen on the trial included anemia (grade 1-4, 88%; grade 3/4, 21%), neutropenia (82%; 35%), lymphopenia (71%; 17%), thrombocytopenia (60%; 13%), increased creatinine (53%; 2.4%), hypomagnesemia (48%; 3.8%), hyponatremia (43%; 13%), hyperglycemia (41%; 3.9%), hypocalcemia (36%; 2.1%), hyperkalemia (33%; 3.0%), increased amylase (32%; 4.2%), increased aspartate aminotransferase (31%; 2.4%), and increased alanine aminotransferase (29%; 2.4%).


  1. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed March 7, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial
  2. Opdivo. Prescribing information. Bristol-Myers Squibb; 2024. Accessed March 7, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125554s125lbl.pdf
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