Frontline Nivolumab/Chemo Approved in Europe for Unresectable or Metastatic Urothelial Cancer

Michiel Van der Heijden, MD, PhD

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

The regulatory decision was supported by findings from the phase 3 CheckMate 901 study (NCT03036098) in which nivolumab plus chemotherapy followed by single-agent nivolumab (n = 304) significantly improved survival vs chemotherapy alone (n = 304).2 The median overall survival (OS) achieved with nivolumab/chemotherapy was 21.7 months (95% CI, 18.6-26.4) by blinded independent central review (BICR) vs 18.9 months (95% CI, 14.7-22.4) with chemotherapy alone (HR, 0.78; 95% CI, 0.63-0.96; P = .0171). The median progression-free survival (PFS) with nivolumab was 7.9 months (95% CI, 7.6-9.5) vs 7.6 months (95% CI, 6.1-7.8) without (HR, 0.72; 95% CI, 0.59-0.88; P = .0012).

“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,” Michiel Van der Heijden, MD, PhD, medical oncologist and research group leader at Netherlands Cancer Institute, stated in a news release.¹ “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.”

The phase 3 trial enrolled patients with treatment-naive unresectable or metastatic urothelial cancer involving the renal pelvis, ureter, bladder, or urethra.² They needed to be at least 18 years of age, be eligible to receive cisplatin, and have an ECOG performance status of 0 or 1.

Participants were randomized to receive gemcitabine at 1000 mg/m² on day 1 and day 8 plus cisplatin at 70 mg/m² on day 1 every 3 weeks for up to 6 cycles with or without nivolumab at 360 mg on day 1. Three weeks later, those who received the chemoimmunotherapy combination went on to receive nivolumab monotherapy at 480 mg every 4 weeks until disease progression, intolerable toxicity, withdrawal, or up to 24 months. Stratification factors included PD-L1 expression (≥1% vs <1%) and liver metastases (yes vs no).

OS and PFS by BICR served as the trial’s co-primary end points, and key secondary end points included OS and PFS in those with a PD-L1 expression of 1% or higher and health-related quality of life (HRQOL). Important exploratory end points included objective response rate by BICR and safety.

Final data from the study were reported during the 2023 ESMO Congress and had a median follow-up of 33.6 months (range, 7.4-62.4).

The patient median age in the nivolumab/chemotherapy and chemotherapy-alone arms was 65 years (range, 32-86). The majority of patients were male (78% vs 77%) and White (69% vs 74%) and just under half (44% vs 47%) were from Europe. Fifty-three percent of patients in both arms had an ECOG performance status of 0. Most patients’ tumor type at initial diagnosis was urinary bladder (77% vs 72%). Regarding PD-L1 expression, more than half of patients in both arms had expression less than 1% or indeterminate (63% vs 64%) and the remainder had a status of 1% or higher (37% vs 36%). Liver metastases were present in 21% of patients in both arms.

Additional efficacy data showed that the 12-month OS rates in the nivolumab/chemotherapy and chemotherapy-alone arms were 70.2% and 62.7%, respectively; the 24-month OS rates were 46.9% and 40.7%, respectively. Moreover, the respective 12-month PFS rates were 34.2% and 21.8% and the 24-month rates were 23.5% and 9.6%.

For the primary analysis of PFS in the study, those who subsequently received anticancer therapy prior to disease progression were censored; this was 8% of those in the nivolumab arm and 24% of those in the chemotherapy-alone arm. In the chemotherapy-alone arm, immunotherapy represented the most commonly received subsequent treatment prior to progression. Investigators conducted a sensitivity analysis in which these patients were not censored. The median PFS in the nivolumab/chemotherapy arm was 7.9 months (95% CI, 7.6-9.5) vs 7.5 months (95% CI, 6.1-7.8) in the chemotherapy-alone arm (HR, 0.74; 95% CI, 0.62-0.89).

The ORR achieved with the nivolumab regimen was 57.6% (95% CI, 51.8%-63.2%), which included a complete response (CR) rate of 21.7% and a partial response (PR) rate of 35.9%. The ORR reported with chemotherapy-alone was 43.1% (95% CI, 37.5%-48.9%), which comprised CR and PR rates of 11.8% and 31.3%, respectively. The median time to response in both arms was 2.1 months. The median duration of response (DOR) with nivolumab plus chemotherapy was 9.5 months (95% CI, 7.6-15.1) vs 7.3 months (95% CI, 5.7-8.9) with chemotherapy alone. The 24-month DOR rates in these respective arms were 35.0% and 12.6%.

HRQOL was maintained with the addition of nivolumab to chemotherapy.

Treatment-related adverse effects (TRAEs) of any grade occurred in 97% of those in the nivolumab arm vs 93% of those in the chemotherapy-alone arm; these effects were grade 3 or higher for 62% and 52% of patients, respectively. In the nivolumab/chemotherapy arm, any-grade TRAEs resulted in discontinuation for 21% of patients; 11% of patients experienced grade 3 or higher TRAEs that led to discontinuation. In the chemotherapy-alone arm, any-grade and grade 3 or higher TRAEs resulted in discontinuation for 17% and 8% of patients, respectively.

In the nivolumab/chemotherapy arm, the most common TRAEs included anemia (grade 1/2, 57%; grade ≥3, 22%), nausea (47%; <1%), neutropenia (31%; 19%), decreased neutrophil count (25%; 14%), fatigue (24%; 2%), decreased appetite (22%; 1%), decreased platelet count (22%; 8%), decreased white blood cell count (21%; 10%), vomiting (18%; 1%), asthenia (15%; 1%), thrombocytopenia (15%; 7%), pruritus (14%; 1%), constipation (14%; 0%), rash (13%; 1%), diarrhea (13%; 1%), hypothyroidism (13%; 0%), increased blood creatinine (13%; <1%), and leukopenia (13%; 2%).

Previously, in March 2024, the FDA approved nivolumab plus cisplatin and gemcitabine for frontline use in patients with unresectable or metastatic urothelial carcinoma based on CheckMate 901 data.³ In a recent interview with OncLive®, Matthew Galsky, MD, of The Tisch Cancer Institute of Mount Sinai, in New York, noted that this was the first phase 3 trial to elicit positive results with the addition of immunotherapy to cisplatin-based chemotherapy in this population.

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. May 29, 2024. Accessed May 29, 2024. https://news.bms.com/news/details/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. van der Heijden MS, Sonpavde GP, Powles TB, et al. LBA7 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
3. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. 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