Enfortumab vedotin plus pembrolizumab has transformed the first-line treatment of locally advanced or metastatic urothelial cancer. However, the optimal treatment strategy after disease progression remains uncertain, as clinical data evaluating subsequent therapies are limited.
Platinum chemotherapy is frequently used in this setting. In the phase 3 EV-302 trial, it was administered to most patients who received subsequent systemic therapy after enfortumab vedotin plus pembrolizumab, but treatment-specific outcomes were not reported. A new real-world analysis now provides one of the first reported outcomes datasets for platinum chemotherapy following this combination.
The article, titled “Platinum-based chemotherapy after enfortumab vedotin and pembrolizumab in metastatic urothelial carcinoma: a real-world study,” was published in the August 2026 issue of ESMO Open.
Authors: M. Sternschuss, K. Whiting, A. Arbuiso, A. Gupta, E. Bent, N. Alvarez, A. Regazzi, S. Liang, F. Ahmed, O. Akin, V. Beylergil, S. Niglio, D. Lage, S.A. Funt, D. Bajorin, G. Iyer, D. Aggen, I. Ostrovnaya, and J.E. Rosenberg.
Study Design
Investigators retrospectively reviewed the Enfortumab vedotin and Pembrolizumab In Real-world Experience, or EMPIRE, database at Memorial Sloan Kettering Cancer Center. The database included 236 consecutive patients with metastatic urothelial carcinoma who initiated first-line enfortumab vedotin plus pembrolizumab between October 2018 and December 2024.
Among 62 patients who received subsequent systemic therapy, 46, or 74%, were treated with platinum-based chemotherapy. Carboplatin was administered to 34 patients and cisplatin to 12 patients. Nine patients subsequently received maintenance avelumab.
Tumor responses were assessed by investigators. Progression-free survival and overall survival were calculated from the initiation of platinum chemotherapy, while duration of response was measured from the first documented complete or partial response to disease progression or death.
Patient Characteristics
The median age at the start of platinum chemotherapy was 73 years, and 65% of patients were male. Upper-tract primary tumors were present in 30%, while 43% had divergent differentiation or another histologic subtype. Bone metastases were reported in 39% of patients, lung metastases in 33%, and liver metastases in 30%. Fifteen percent had lymph node-only disease.
In the platinum-treated cohort, the objective response rate to first-line enfortumab vedotin plus pembrolizumab was 41%, and median progression-free survival was 4.4 months. In this cohort, enfortumab vedotin plus pembrolizumab was discontinued because of disease progression in 85% of patients and toxicity in 15%.
Among the 34 patients who received carboplatin, the most common reason for cisplatin ineligibility was peripheral neuropathy, reported in 53%. Other reasons included renal insufficiency, poor performance status, and hearing impairment. Patients treated with carboplatin were older than those receiving cisplatin and more frequently had higher Bellmunt prognostic scores.
Efficacy of Platinum-Based Chemotherapy
Among 45 response-evaluable patients, the objective response rate to platinum-based chemotherapy was 49%, with a 95% confidence interval of 34% to 64%.
Two patients achieved a complete response and 20 achieved a partial response. Stable disease was reported in nine patients, while 14 had progressive disease as their best response. The objective response rate was 47% with carboplatin and 55% with cisplatin. The difference was not statistically significant.
After a median follow-up of 11 months from the initiation of platinum-based chemotherapy, median duration of response was 5.2 months. Median progression-free survival was 5.0 months, and median overall survival was 12 months. No statistically significant differences between carboplatin and cisplatin were observed for progression-free survival, overall survival, or duration of response.
Treatment Delivery and Safety
Patients received a median of five cycles of platinum-based chemotherapy. At the data cut-off, four patients remained on platinum-based chemotherapy. Among patients who had discontinued treatment, 50% completed chemotherapy as planned, while 38% discontinued because of disease progression. Among patients who had discontinued treatment, 7% discontinued because of toxicity and 5% according to patient preference.
Among 45 patients with available data, treatment-related adverse events led to dose reductions or other treatment modifications in 67%, most frequently because of hematologic toxicity. Among 44 patients with available hematologic toxicity data, grade 3 or higher anemia occurred in 61%, grade 3 or higher neutropenia in 41%, and grade 3 or higher thrombocytopenia in 32%. Granulocyte colony-stimulating factor was administered to 68% of patients.
Peripheral neuropathy was present in 65% of patients before platinum chemotherapy was initiated. New or worsening neuropathy occurred in five patients, or 11%, but did not lead to treatment discontinuation. No treatment-related deaths were reported.
Maintenance Avelumab
Nine patients received maintenance avelumab following platinum chemotherapy, with a median of seven cycles administered. Among seven patients who had achieved stable disease or a partial response with chemotherapy, no further changes in tumor size were observed after avelumab was initiated.
At the data cut-off, two patients remained on maintenance treatment. The other seven patients had discontinued avelumab because of disease progression.
The investigators noted that the role of maintenance immune checkpoint inhibition after second-line platinum chemotherapy remains unclear in patients previously treated with enfortumab vedotin plus pembrolizumab. Interpretation was limited by the small number of patients and potential selection bias.
Clinical Interpretation
The objective response rate of 49% indicates that platinum-based chemotherapy retains substantial antitumor activity after enfortumab vedotin plus pembrolizumab.
The response rate appeared comparable to that historically reported with platinum chemotherapy in the first-line setting. However, median duration of response was 5.2 months and median progression-free survival was 5.0 months, indicating modest durability.
The absence of a significant difference between carboplatin and cisplatin may also be clinically relevant. In this cohort, many patients had peripheral neuropathy, renal impairment, poor performance status, or hearing impairment that limited cisplatin eligibility.
However, the small cohort, particularly the 12-patient cisplatin subgroup, prevents definitive conclusions regarding comparative efficacy.
Study Limitations
The study was limited by its retrospective, nonrandomized design and relatively small sample size. Treatment was delivered at a single academic referral center, and treatment selection was based on the clinical judgment of the treating physician.
Responses were investigator-assessed from radiological reports, and response assessment was not standardized. The retrospective collection of safety data may also have underestimated nonlaboratory toxicities such as peripheral neuropathy.
The cohort was also enriched for patients with primary or early acquired resistance to enfortumab vedotin plus pembrolizumab. Patients who experienced disease progression after a prolonged initial response were underrepresented because of the limited time since enfortumab vedotin plus pembrolizumab was approved.
Takeaway
In this real-world analysis, platinum-based chemotherapy demonstrated clinically meaningful activity after enfortumab vedotin plus pembrolizumab in patients with metastatic urothelial carcinoma, producing an objective response in approximately half of response-evaluable patients. However, median progression-free survival and duration of response remained modest.
These findings provide one of the first reported outcomes datasets for platinum chemotherapy in the post-enfortumab vedotin plus pembrolizumab setting and may help inform clinical decision-making and the design of prospective trials evaluating subsequent treatment strategies.
The full article is available in ESMO Open.