EMA Validates Application for Frontline Nivolumab Plus Chemo in Advanced Urothelial Cancer

Dana Walker, MD, MSCE

The European Medicines Agency (EMA) has validated a type II variation application for the first-line combination of nivolumab (Opdivo) and cisplatin-based chemotherapy for adult patients with unresectable or metastatic urothelial carcinoma.¹

If approved, nivolumab plus cisplatin-based chemotherapy would represent the first frontline chemoimmunotherapy combination for patients with metastatic or unresectable urothelial carcinoma in the European Union, according to Bristol Myers Squibb, the developer of nivolumab.

The application is supported by findings from the phase 3 CheckMate901 trial (NCT03036098), which were presented at the 2023 ESMO Congress and published in the New England Journal of Medicine.^2,3 In this trial, nivolumab plus cisplatin and gemcitabine elicited a median overall survival (OS) of 21.7 months (95% CI, 18.6-26.4) vs 18.9 months (95% CI, 14.7-22.4) with gemcitabine/cisplatin alone (HR, 0.78; 95% CI, 0.63-0.96; P = .02).² Additionally, the median progression-free survival (PFS) was 7.9 months (95% CI, 7.6-9.5) in the nivolumab arm vs 7.6 months (95% CI, 6.1-7.8) in the gemcitabine/cisplatin alone arm (HR, 0.72; 95% CI, 0.59-0.88; P= .001). The 12-month PFS rates were 34.2% and 21.8% in the nivolumab and gemcitabine/cisplatin alone arms, respectively.

“We know that approximately 20% to 25% of patients diagnosed with urothelial carcinoma will experience disease metastasis, and an additional 5% of patients present de novo with metastatic disease. As a result, first-line treatment options that may offer these patients a chance for durable responses and improved survival outcomes are needed,” Dana Walker, MD, MSCE, vice president and global program lead of genitourinary cancers at Bristol Myers Squibb, stated in a press release.¹ “We are pleased that the CheckMate901 trial has displayed potential for [nivolumab] in combination with cisplatin-based chemotherapy to help address this unmet need and provide hope for patients and their loved ones.”

The open-label, randomized CheckMate901 trial enrolled patients at least 18 years of age with histological or cytological evidence of metastatic or surgically inoperable urothelial carcinoma involving the ureter, renal pelvis, urethra, or bladder who had a ECOG performance status of 0 or 1.⁴ Patients were excluded if they had disease suitable for local therapy with curative intent; any uncontrolled or serious medical disorder that may increase the risk associated with trial participation or study drug administration or interfere with the interpretation of the trial results, as determined by the investigator; or prior treatment with a PD-1, PD-L1, PD-L2, CD137, or CTLA-4 inhibitor, or any other drug or antibody targeting checkpoint pathways or T-cell costimulation.

Patients were randomly assigned to receive intravenous nivolumab at 360 mg plus gemcitabine/cisplatin every 3 weeks for a maximum of 6 cycles, followed by 480 mg of nivolumab every 4 weeks for up to 2 years, or gemcitabine/cisplatin every 3 weeks for a maximum of 6 cycles.²

OS and PFS served as the co-primary end points of this trial. Secondary end points included EORTC Global Health Status score, PFS by blinded independent central review (BICR) in patients with PD-L1 expression of at least 1% by immunohistochemistry (IHC), and OS by BICR in patients with PD-L1 expression of at least 1% by IHC.⁴ Overall response rate (ORR) and safety served as exploratory outcomes.²

The ORR was 57.6% (95% CI, 51.8%-63.2%) in the nivolumab arm and 43.1% (95% CI, 37.5%-48.9%) in the gemcitabine/cisplatin alone arm, and the complete response rates were 21.7% and 11.8%, respectively.² Furthermore, the median durations of response were 31.7 months and 13.2 months in the nivolumab and gemcitabine/cisplatin alone arms, respectively.

Grade 3 or higher adverse effects were observed in 61.8% of patients in the nivolumab arm and 51.7% of those in the gemcitabine/cisplatin alone arm.

“We are eager to continue working with the EMA to discuss how we may bring this first-line regimen to appropriate patients across Europe,” Walker concluded in the press release.¹

References

1. European Medicines Agency validates Bristol Myers Squibb’s application for Opdivo (nivolumab) in combination with cisplatin-based chemotherapy for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. News Release. Bristol Myers Squibb. October 30, 2023. Accessed October 30, 2023. https://news.bms.com/news/corporate-financial/2023/European-Medicines-Agency-Validates-Bristol-Myers-Squibbs-Application-for-Opdivo-nivolumab-in-Combination-with-Cisplatin-Based-Chemotherapy-for-the-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx
2. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. New Engl J Med. Published online October 22, 2023. doi:10.1056/NEJMoa2309863
3. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial. Ann Oncol. 2023;34(suppl 2):S1341. doi:10.1016/j.annonc.2023.10.107
4. Study of nivolumab in combination with ipilimumab or standard of care chemotherapy compared to the standard of care chemotherapy alone in treatment of participants with untreated inoperable or metastatic urothelial cancer (CheckMate901). ClinicalTrials.gov. Updated October 23, 2023. Accessed October 30, 2023. https://clinicaltrials.gov/study/NCT03036098