Nivolumab plus chemotherapy approved in EU for urothelial carcinoma

The European Commission (EC) has approved the combination of nivolumab (Opdivo) with cisplatin and gemcitabine for the front-line treatment of adult patients with unresectable or metastatic urothelial carcinoma.¹

Nivolumab was also granted FDA approval in March 2024 for use in combination with cisplatin/gemcitabine in the treatment of patients with unresectable or metastatic urothelial carcinoma.

According to a news release from Bristol Myers Squibb,1 this approval marks the first concurrent immunotherapy-chemotherapy regimen approved in the European Union (EU) for this patient population. The approval is valid in all 27 members states of the EU, as well as Iceland, Liechtenstein, and Norway.

“With today’s approval by the EC, we’re pleased to be able to offer Opdivo concurrently with chemotherapy to eligible patients with unresectable or metastatic UC. This is a major step forward for this patient population and reinforces our goal of advancing and delivering new options to patients with difficult-to-treat cancers. We extend our sincerest gratitude to the patients, their families, investigators, and staff who contributed to this important research,” said Dana Walker, MD, MSCE, vice president and global program lead of gastrointestinal and genitourinary cancers at Bristol Myers Squibb, in the news release.¹

The approval of the nivolumab/chemotherapy regimen follows a positive opinion from the European Medical Agency’s Committee for Medicinal Products for Human Use recommending approval for the regimen in April 2024.² Nivolumab was also granted FDA approval in March 2024 for use in combination with cisplatin/gemcitabine in the treatment of patients with unresectable or metastatic urothelial carcinoma.³

Both the EC and FDA approvals were supported by findings from the phase 3 CheckMate-901 study (NCT03036098), which demonstrated that nivolumab plus cisplatin/gemcitabine followed by nivolumab monotherapy prolonged overall survival (OS) and progression-free survival (PFS) in patients with unresectable or metastatic urothelial carcinoma vs cisplatin/gemcitabine alone. Findings from the study were presented at the 2023 European Society of Medical Oncology Congress in Madrid, Spain and published in the New England Journal of Medicine.⁴

At a median follow-up of approximately 33 months, patients who received the nivolumab regimen demonstrated a median OS of 21.7 months, compared with 18.9 months among those receiving chemotherapy alone (HR, 0.78; 95% CI, 0.63, 0.96; P = .0171). At the 24-month landmark analysis, the OS rate was 46.9% in the nivolumab arm, compared with 40.7% in the chemotherapy arm.

Further, treatment with nivolumab reduced the rate of progression or death by 28%, with a median PFS of 7.9 months vs 7.6 months with chemotherapy alone (HR, 0.72; 95% CI. 0.59, 0.88; P = .0012). At the 24-month analysis, PFS was 23.5% in the nivolumab cohort compared with 9.6% in the chemotherapy alone cohort.

Further, the overall response rate (ORR) in the cohort receiving nivolumab plus chemotherapy was 57.6% (95% CI, 51.8-63.2), compared with 43.1% (95% CI, 37.5-48.9) in the cohort receiving chemotherapy alone. The complete and partial response rates in the nivolumab regimen cohort were 22% (n = 66) and 36% (n = 109), respectively, vs 12% (n = 36) and 31% (n = 95) in the chemotherapy alone cohort.

Regarding safety, 48% of patients receiving nivolumab plus chemotherapy experienced a serious adverse event (SAE). The most common SAEs (reported in 2% or more of patients) were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and a decrease in platelet count (2.3%). Fatal adverse events occurred in 3.6% of patients who received the nivolumab regimen, which included sepsis in 1% of patients. Among all patients who received nivolumab plus chemotherapy, 30% of patients discontinued treatment due to AEs and 67% of patients delayed treatment due to an AE.

Lead author Michiel Van der Heijden, MD, PhD, stated in the news release,¹ “In the CheckMate -901 trial, the combination of Opdivo with cisplatin and gemcitabine improved overall survival, reduced the risk of disease progression or death by 28% versus chemo alone, and demonstrated deep and durable responses versus chemo alone. These findings are significant and reinforce that concurrent Opdivo and chemotherapy should be considered as a new standard of care for the first line treatment of eligible patients with this difficult-to-treat cancer.”

In total, the sub-study of the phase 3 CheckMate-901 trial included 608 adult patients with unresectable or metastatic urothelial carcinoma. Patients were randomly assigned to receive 360 mg nivolumab in combination with cisplatin/gemcitabine every 3 weeks for up to 6 cycles followed by 480 mg nivolumab monotherapy every 4 weeks for up to 2 years or until disease progression or death, or to cisplatin/gemcitabine alone every 3 weeks for up to 6 cycles.

The primary end points for the trial were OS and PFS. Secondary end points included ORR and complete and partial response rates.

The primary open-label, phase 3 CheckMate-901 study sought to evaluate nivolumab in combination with ipilimumab (Yervoy) or nivolumab in combination with cisplatin/gemcitabine following by nivolumab monotherapy vs cisplatin/gemcitabine alone in patients with previously untreated unresectable or metastatic urothelial carcinoma.

The primary CheckMate-901 study remains ongoing to assess nivolumab plus ipilimumab vs standard-of-care chemotherapy.

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. News release. Bristol Myers Squibb. Published online and accessed May 29, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-in-Combination-with-Cisplatin-and-Gemcitabine-for-the-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx

2. CHMP adopts positive opinion recommending approval of Bristol Myers Squibb’s Opdivo (nivolumab) in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. News release. Bristol Myers Squibb. April 26, 2024. Accessed May 29, 2024. https://news.bms.com/news/corporate-financial/2024/CHMP-Adopts-Positive-Opinion-Recommending-Approval-of-Bristol-Myers-Squibbs-Opdivo-nivolumab-in-Combination-with-Cisplatin-and-Gemcitabine-for-the-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx

3. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. News release. US Food and Drug Administration. March 6, 2024. Accessed May 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial

4. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine–cisplatin in advanced urothelial carcinoma. N Eng J Med. 2023;389(19):1778-1789. doi:10.1056/NEJMoa2309863