Adding Nivolumab to Chemotherapy Improves Survival Rates in Metastatic Urothelial Carcinoma


Nivolumab plus gemcitabine-cisplatin improved overall and progression-free survival in unresectable or metastatic urothelial carcinoma.

Findings from the phase 3 CheckMate 901 trial (NCT03036098) demonstrated that frontline nivolumab (Opdivo), in addition to gemcitabine-cisplatin (GC), improved overall (OS) and progression-free survival (PFS), compared with chemotherapy alone in patients with unresectable or metastatic urothelial carcinoma.

Data were presented at the 2023 European Society Medical Oncology Congress.

“Nivolumab plus gemcitabine is the first frontline concurrent checkpoint inhibitor plus chemotherapy combination to improve OS in this setting, with results supporting nivolumab plus cisplatin-based chemotherapy as a new standard of care for patients with unresectable or metastatic urothelial cancer,” Michiel S. Van der Heijden, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands, said during a presentation of the data.

OS and PFS in CheckMate 901

Median OS with nivolumab plus GS was 21.7 months (95% CI, 18.6-26.4), compared with 18.9 months (95% CI, 14.7-22.4) with GC alone, reducing the risk of death by 22% (HR, 0.78; 95% CI, 0.63-0.96; P = .0171), meeting the primary end point of the study. The 12- and 24-month OS rates with the nivolumab combination were 70.2% and 46.9%, vs 62.7% and 40.7%, respectively, with GC alone.

OS benefit with the addition of nivolumab was also seen across the subgroup analysis, including age, sex, race, region, ECOG performance status, PD-L1 expression, liver metastases, and previous systemic anticancer therapy.

PFS by blind independent central review (BICR) was also met in the trial, with a median PFS of 7.9 months (95% CI, 7.6-9.5) with nivolumab plus GC, compared with 7.6 months (95% CI, 6.1-7.8) with GC alone, reducing the risk for progression by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .0012). The 12- and 24- months PFS rates with the addition of nivolumab were 34.2% and 23.5%, compared with 21.8% and 9.6%, respectively, in the GC-alone arm.

“Although the median progression-free survival was similar in both arms, the curves started to separate after 6 months,” Van der Heijden said, adding that this benefit was also consistent across the subgroup analysis.

He noted that, for the primary analysis of PFS, patients who went on to receive subsequent anticancer therapy before disease progression were censored (nivolumab combination arm, 8% vs GC-alone arm, 24%). Immunotherapies were the most commonly used in the GC-alone arm. Therefore, since this may have impacted the primary analysis, the investigators conducted a sensitivity analysis and uncensored this patient population, finding that the median PFS with nivolumab plus GC was 7.9 months (95% CI, 7.6-9.5), compared with 7.5 months (95% CI, 6.1-7.8) in the GC-alone arm (HR, 0.74; 95% CI, 0.62-0.89).

Secondary end points

The objective response rate (ORR) in the nivolumab combination arm was 57.6% (95% CI, 51.8%-63.2%), including a complete response (CR) rate of 21.7%, partial response (PR) rate of 35.9%, stable disease (SD) rate of 25.3%, and progressive disease (PD) rate of 7.6%. The ORR in the GC-alone arm was 43.1% (95% CI, 37.5%-48.9%), including a CR rate of 11.8%, PR rate of 31.3%, SD rate of 28.3%, and PD rate of 15.8%.

When evaluating any objective response, median time to response (TTR) with nivolumab plus GC was 2.1 months (95% CI, 2.0-2.3) vs 2.1 months (2.0-2.2) with GC alone, while median duration of response (DOR) was 9.5 months (95% CI, 7.6-15.1) and 7.3 months (95% CI, 5.7-8.9), respectively. Among those who experience a CR, median TTR was 2.1 months in both arms ([95% CI, 1.9-2.2] vs [95% CI, 1.9-2.2], respectively) and median DOR was 37.1 months (95% CI, 18.1-not evaluable) and 13.2 months (95% CI, 7.3-18.4).

Exploratory end points

Median DOR by BICR with the addition of nivolumab was 9.5 months (95% CI, 7.6-15.1), compared with 7.3 months (95% CI, 5.7-8.9) with GC alone. The 12- and 24-month DOR rates with nivolumab combination therapy were 46.2% and 35.0%, compared with 29.2% and 12.6%, respectively, with GC alone.

“Complete responses were also achieved rapidly, and median duration of complete remission had a notable, substantial improvement in duration over [GC] alone, indicating that nivolumab plus [GC] is associated with rapid, deep, and durable responses,” Van der Heijden highlighted.

More patients in the GC-alone arm went on to receive subsequent immunotherapy (60 vs 8), compared with the nivolumab arm. Van der Heijden noted that the proportion of patients receiving non-immunotherapy subsequent therapy, including surgery, radiotherapy, and/or platinum-based chemotherapy, was similar in both arms.

Any-grade treatment-related adverse events (TRAEs) occurred in 97% of the nivolumab combination arm, compared with 93% of the GC-alone arm, with 62% and 52%, respectively, being grade 3 or higher. The most common grade 3 or higher TRAEs in the nivolumab combination and GC-alone arms included anemia (22% vs 18%, respectively), neutropenia (19% vs 15%), decreased neutrophil count (14% vs 11%), decreased platelet count (8% vs 5%), decreased white blood cell count (10% vs 4%), thrombocytopenia (7% vs 5%), and leukopenia (2% each).

Lastly, health-related quality of life (HRQoL) was stable in both arms on the study.

Treatment exposure

The median duration of study therapy was 7.4 months (range, 0.0-47.9) in the nivolumab combination arm, compared with 3.7 months (range, 0.0-14.3) with GC alone. In total, 74% of patients treated with nivolumab and 55% of those treated with GC alone completed 6 cycles of treatment per the study protocol. Treatment discontinuation occurred as a result of disease progression (7% vs 17%, respectively) and study drug toxicity (8% each).

Of those treated with nivolumab plus GC in the combination phase, 244 went on to receive nivolumab monotherapy maintenance therapy, with 20 (8%) completing treatment and 23 (9%)still on therapy at data cutoff.

Addressing an unmet need

“For decades, cisplatin-based chemotherapy is the first-line standard of care for eligible patients with advanced urothelial cancer in first the line. No new agents have improved OS when added concurrently to chemotherapy in the first-line treatment of advanced urothelial cancer,” Van der Heijden explained, however, adding that avelumab (Bavencio) has been approved in a maintenance setting for this patient population who have not progressed on or immediately after first-line platinum-based chemotherapy.

“Still an unmet need remains in first-line setting for treatments that improve patient outcomes,” he added.

Therefore, in the global, open-label, randomized phase 3 trial, patients were randomized 1:1 to receive either 360 mg nivolumab plus 1000 mg/m2 gemcitabine and 70 mg/m2 cisplatin every 3 weeks for up to 6 cycles (n = 304) or the gemcitabine/cisplatin regimen alone (n = 304). Patients treated with nivolumab in the combination phase then went on to receive 480 mg nivolumab every 4 weeks until disease progression, unacceptable toxicity, withdrawal, or up to a maximum of 24 months of maintenance therapy.

OS and PFS per BICR served as the primary end points, while the secondary end points included OS and PFS by PD-L1 of 1% or greater and HRQoL. The key exploratory end points were ORR per BICR and safety.

Patients were eligible for the trial if they were 18 years of age or older; had previously untreated, unresectable, or metastatic urothelial carcinoma involving the renal pelvis, ureter, bladder, or urethra; were cisplatin eligible; and had an ECOG performance status of 0 to 1.

The investigators stratified patients by tumor PD-L1 expression and liver metastases.

Median follow-up was 33.6 months (range, 7.4-62.4).

At baseline, patients in the nivolumab arm were a median age of 65 years (range, 32-86), while the majority were male (78%), White (69%), and had an ECOG performance status of 0 (53%). At initial diagnosis, 77% of patients had urinary bladder disease, 11% had renal pelvis disease, and 12% with other. In total, 37% of patients in this arm had PD-L1 expression of 1% or more vs 63% with less than 1%. Lastly, 21% of patients had liver metastases.


1. 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. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA7.

2. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. N Eng J Med. Published: October 22, 2023. doi:10.1056/NEJMoa2309863.

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