The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) did not meet the dual primary end points of overall survival (OS) in patients with previously untreated unresectable or metastatic urothelial cancer in the cisplatin-ineligible population and the population of patients with a PD-L1 expression of at least 1% during the phase 3 CheckMate 901 trial (NCT03036098), demonstrating that this regimen will not affect the standard of care, according to Guru P. Sonpavde, MD, who added that additional work may help parse out which subsets of patients could benefit from this regimen.1
The study evaluated ipilimumab/nivolumab compared with gemcitabine plus cisplatin or carboplatin. Findings presented at the 2025 ASCO Annual Meeting showed that in cisplatin-ineligible patients, the median OS was 19.1 months (95% CI, 13.5-22.6) for nivolumab plus ipilimumab (n = 221) vs 13.2 months (95% CI, 11.6-15.2) for gemcitabine plus carboplatin (HR, 0.79; 98.27% CI, 0.61-1.01; P = .0245).
In the population of patients with a PD-L1 expression of at least 1%, the median OS was 17.2 months for nivolumab plus ipilimumab (n = 123) vs 15.2 months (95% CI, 19.9-18.4) for gemcitabine plus platinum-based chemotherapy (n = 127; HR, 0.87; 97.48% CI, 0.61-1.23; P = .364).
“This is disappointing; however, one of the silver linings here is that there were [patients who had] durable responses, [including] durable complete responders, with ipilimumab/nivolumab,” Sonpavde said during an interview with OncLive®. “Perhaps more work can be done looking at biomarkers to select these patients so that we give them yet another option in the first-line [setting]. Nevertheless, as it stands, [this portion of CheckMate 901] is a negative trial and does not, unfortunately, change or add to the standard of care in the first-line disease space.”
In the interview, Sonpavde discussed the background and rationale for the CheckMate 901 trial, the efficacy data, and the role of ipilimumab plus nivolumab following the negative trial results.
Sonpavde is the medical director of Genitourinary Oncology, assistant director of the Clinical Research Unit, and Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.
OncLive: What was the background and rationale for the CheckMate 901 trial?
Sonpavde: CheckMate 901 was a phase 3 trial, which previously had several comparisons. The sub-study that compared gemcitabine/cisplatin vs gemcitabine/cisplatin [plus] nivolumab was presented a couple years ago now, and that was a positive trial that led to approval of gemcitabine/cisplatin plus nivolumab for cisplatin-eligible patients as first-line therapy.
In the same study, there was also a comparison of ipilimumab plus nivolumab vs gemcitabine/platinum, [where] the platinum could be cisplatin or carboplatin [and patients were stratified by] PD-L1 status. There was also a cisplatin-ineligible cohort, where [patients were treated with] gemcitabine/carboplatin vs ipilimumab/nivolumab, and that was regardless of PD-L1 status with that comparison.
What we presented at ASCO 2025 were those comparisons of gemcitabine/carboplatin vs ipilimumab/nivolumab. We also presented gemcitabine/platinum vs ipilimumab/nivolumab in the PD-L1–high [population]. [OS] was the primary end point.
What were the efficacy data?
The [OS end point] was not met, unfortunately. The median survival was 13.2 months with gemcitabine/carboplatin and 19.1 months for ipilimumab/nivolumab. The P value was .0245; this did not meet the statistical bar for superiority. There were some very interesting signals for efficacy, though. The objective response rate [ORR] was 35.3% for ipilimumab/nivolumab and similar for gemcitabine/carboplatin [at 38.8%]. However, the duration of response [DOR] was very prolonged. With ipilimumab/nivolumab, the median DOR was [25.0 months] vs [7.4 months] for gemcitabine/carboplatin, as you might expect.
Of the 35.3% ORR, [14.9%] were complete responses [CR], and the duration of complete response has not yet reached the median. We expect, with hopefully longer follow-up, we will see an even more durable CRs. The progression-free survival [PFS] was a secondary end point, and that was not significantly different.
The other comparison in this study was gemcitabine/platinum, where the platinum could be cisplatin or carboplatin, vs ipilimumab/nivolumab. The OS difference was more modest than the cisplatin-ineligible comparison. [Specifically,] it was 15.2 months for the gemcitabine/platinum group vs 17.2 months for ipilimumab/nivolumab, and the hazard ratio was 0.87. [Ultimately,] ipilimumab/nivolumab could not attain superiority in both the cisplatin-ineligible cohort and the PD-L1–high cohort as first-line therapy in advanced urothelial carcinoma.
Although the results were not practice-changing, are these data relevant to your practice?
The short answer to that is no, at this point, given that the phase 3 trial is negative, and the only component of this phase 3 trial that’s positive, of course, is gemcitabine/cisplatin plus nivolumab, which is already [FDA-]approved.
However, ipilimumab/nivolumab, as it stands, is clearly active, with durable responders, and a 35.3% ORR. It needs more work in terms of developing a biomarker. Remember that the combination of [enfortumab vedotin-ejfv (Padcev)] plus pembrolizumab [Keytruda] is established as the preferred first-line standard of care, and that has set a very high bar. [It has shown an] ORR of 67.7% and the [median] DOR [has not been reached].2 That’s the bar we have to look at when we are also looking at what the value of ipilimumab/nivolumab will be.
The ipilimumab/nivolumab quality of response has to look across different trials, [and has to be] at least as good, if not better than enfortumab vedotin/pembrolizumab. We need to wait and see—after further maturity—what the duration of CRs will be. Are we curing some patients who have the CRs? The question [about a cure] lingers over the top of all these regimens, including enfortumab vedotin/pembrolizumab, gemcitabine/cisplatin plus nivolumab, and ipilimumab/nivolumab, which, of course, is not approved. However, what is the quality of CR? Are we curing more patients? The money may lie in whether we can identify a biomarker for patients who have these very durable CRs who we might be curing.
Is there still a role for ipilimumab/nivolumab, and are there future directions for this regimen?
Yet another point I want to highlight is that there was a treatment-free interval in a small subgroup of patients, which suggested that patients with CRs may continue to be in CR even after completing all therapy. That would be very interesting to tease out. These regimens, enfortumab vedotin/pembrolizumab, gemcitabine/cisplatin plus nivolumab, and ipilimumab/nivolumab, could [potentially] cure some patients, but we don’t know who those patients are.
References
- Van Der Heijden MS, Galsky MD, Powles T, et al. Nivolumab plus ipilimumab (nivo+ipi) vs gemcitabine-carboplatin (gem-carbo) chemotherapy for previously untreated unresectable or metastatic urothelial carcinoma (mUC): final results for cisplatin-ineligible patients from the CheckMate 901 trial. J Clin Oncol. 2025;43(suppl 16):4500. doi:10.1200/JCO.2025.43.16_suppl.4500
- Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117