The impact of treatment sequencing in chemoimmunotherapy combinations for metastatic urothelial cancer remains uncertain. While these approaches have largely been studied as concurrent treatment or switch maintenance strategies, a randomized phase II study investigated two alternative schedules: chemotherapy lead-in followed by chemoimmunotherapy, or atezolizumab lead-in followed by chemoimmunotherapy.
The study was published in the August 2026 issue of Clinical Genitourinary Cancer.
The original study was titled “Atezolizumab in Combination With Gemcitabine and Cisplatin as First-Line Treatment in Metastatic Urothelial Cancer: A Randomized Phase II Study of Two Alternative Dosing Schedules.”
Authors: Michal Sternschuss, Charlie White, Colleen Quinlan, Ashley Regazzi, Marwah Jihad, Jiawen Chen, Asia McCoy, William Rafelson, Andrew Laccetti, Michelle Makris, Hikmat Al-Ahmadie, Min Y. Teo, Han Xiao, Gopa Iyer, Dean F. Bajorin, Joshua L. Chaim, Irina Ostrovnaya, Jonathan E. Rosenberg, Peter H. O’Donnell, Amir Mortazavi, and Samuel A. Funt.
Study Design
This randomized, multicenter, open-label phase II study, NCT03093922, enrolled adults with previously untreated locally advanced or metastatic urothelial carcinoma who had measurable disease and were eligible to receive cisplatin. Patients were required to have an ECOG performance status of 0–1 and an estimated glomerular filtration rate of at least 50 mL/min/1.73 m².
Patients were randomized 1:1 to two sequencing strategies. In the chemo-first arm, patients received two 21-day cycles of gemcitabine plus cisplatin, followed by four cycles of gemcitabine/cisplatin plus atezolizumab and subsequent atezolizumab maintenance.
In the CPI-first arm, patients initially received two cycles of atezolizumab alone before six cycles of gemcitabine/cisplatin plus atezolizumab, followed by atezolizumab maintenance. Following an FDA alert and subsequent label restriction concerning atezolizumab and pembrolizumab monotherapy in metastatic urothelial carcinoma, the protocol was amended in May 2018 to shorten the atezolizumab lead-in from two cycles to one.
The primary endpoint was confirmed overall response rate according to RECIST v1.1. Progression-free survival, overall survival, and safety were secondary endpoints. The study used separate Simon two-stage phase II designs for each treatment schedule and was not designed to definitively compare the two strategies.
Patient Population
Between September 2017 and February 2021, 31 patients were enrolled across three institutions. Fifteen were assigned to the chemo-first strategy and 16 to CPI-first treatment.
Twelve patients were enrolled before the protocol amendment, including six in each treatment arm. Following the amendment, 19 patients were enrolled: nine in the chemo-first arm and 10 in the amended CPI-first arm. These 19 patients constituted the per-protocol population evaluable for the primary endpoint.
The median age was 63 years, 68% of patients were male, 29% had an upper urinary tract primary tumor, and 68% had visceral metastases involving the lung, liver, or bone.
Response and Survival
Among the 19 patients evaluable for the primary endpoint, the confirmed objective response rate was 44% in the chemo-first group, with four partial responses among nine patients. In the amended CPI-first group, the objective response rate was 40%, with four responses among 10 patients, including one complete response and three partial responses.
At the time of early study closure, neither schedule had met the prespecified efficacy threshold; however, the chemo-first arm had not completed its planned first-stage enrollment. Importantly, enrollment was stopped early as the treatment landscape for metastatic urothelial carcinoma changed, and the chemo-first arm had not completed its planned first-stage enrollment when the trial was discontinued.
After a median follow-up of 60 months, median progression-free survival across the entire cohort was 5.5 months, while median overall survival was 15 months.
By treatment schedule, median PFS was:
- 1.3 months with the original two-cycle CPI-first schedule
- 7.6 months with the amended one-cycle CPI-first schedule
- 6.1 months with the chemo-first schedule
Median OS was:
- 12 months with the original CPI-first schedule
- 26 months with the amended CPI-first schedule
- 15 months with the chemo-first schedule
These survival estimates were exploratory and should not be interpreted as demonstrating superiority of one sequencing strategy over another. Two patients achieved confirmed complete responses across the full study population: one receiving the amended CPI-first schedule and one receiving chemo-first treatment before the protocol amendment. Both completed protocol treatment without documented progression.
Safety
All 31 patients experienced at least one treatment-related adverse event, while grade 3 or higher treatment-related adverse events occurred in 87%. The most common treatment-related adverse events of any grade were anemia and nausea, each reported in 77% of patients, followed by fatigue in 65%. The most frequent grade 3–4 events were neutropenia in 42% and anemia in 35%.
Six patients experienced treatment-related thromboembolic events. Rash was the most common immune-related adverse event, occurring in 29% of patients. Treatment-related adverse events led to treatment discontinuation in two patients: one because of grade 4 acute kidney injury and another because of grade 4 reversible posterior leukoencephalopathy syndrome. No treatment-related deaths occurred.
Why Lead-In Duration Matters
The duration of the atezolizumab lead-in emerged as an important exploratory observation. Among the six patients treated with the original two-cycle, six-week CPI lead-in, no objective responses were observed and median PFS was 1.3 months. After the protocol amendment shortened the atezolizumab lead-in to one three-week cycle, the objective response rate was 40% and median PFS was 7.6 months.
The investigators emphasized that the original and amended CPI-first schedules could not be formally compared. Baseline imbalances, off-protocol consolidative therapy, treatment beyond progression, and early study closure also complicated interpretation of the survival findings.
The numerically longer median OS of 26 months observed with the amended CPI-first schedule was considered exploratory, as other factors, including off-protocol consolidation therapy, may have influenced long-term outcomes.
Takeaway
This randomized phase II study evaluated two alternative sequencing strategies of cisplatin-based chemotherapy and atezolizumab in previously untreated, cisplatin-eligible metastatic urothelial carcinoma.
Neither sequencing strategy met the study’s predefined efficacy threshold, and the trial was limited by its small sample size and early discontinuation. Exploratory observations suggested that the duration of the checkpoint inhibitor lead-in phase may warrant consideration in future trial design. The findings remain exploratory and do not establish the relative efficacy or superiority of either sequencing strategy.
The full article is available in Clinical Genitourinary Cancer.
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