Pathologic Complete Response After Enfortumab Vedotin Plus Pembrolizumab in Node-positive Upper Tract Urothelial Carcinoma

Discussion

The present case highlights the potential clinical value of combining EVP with consolidative surgery in selected patients with node-positive UTUC. A major strength of this case is the achievement of pCR following systemic therapy, which enables a treatment-free strategy without compromising short-term oncological control.

The EV-302 trial established EVP as the preferred first-line regimen for la/mUC, demonstrating a significantly improved overall response rate, PFS, and OS compared with platinum-based chemotherapy (1). Several real-world studies have reported on the effectiveness and manageable safety of EVP in clinical practice (3-6). Furthermore, real-world data in elderly populations have demonstrated that EV-based therapy remains feasible and effective, although careful toxicity monitoring is essential (7, 8). Importantly, subgroup analyses showed that patients with lymph node–only metastases had particularly favorable responses, suggesting a high sensitivity of nodal disease to EVP. Furthermore, durable responses have been reported in patients who achieved a CR, supporting the idea that deep initial responses may translate into prolonged disease control. However, the optimal duration of EVP therapy for patients who achieve a CR remains unclear. In clinical trials, pembrolizumab administration is limited to a maximum of two years according to the protocol design, whereas EV is continued until disease progression or unacceptable toxicity. Prolonged exposure to EV is associated with cumulative toxicities, most notably peripheral neuropathy, which can significantly impair quality of life and may be irreversible (9, 10). Recent evidence suggests that maintaining an adequate relative dose intensity of EV is associated with improved oncological outcomes, although dose reduction may be necessary to balance toxicity and efficacy (11). However, there are no established criteria for discontinuing EV or EVP in patients who achieve radiographic CR. Moreover, outcomes after progression on EV remain heterogeneous, and optimal post-EV treatment strategies have not yet been established (12). Imaging alone cannot reliably exclude residual microscopic disease, creating uncertainty regarding the safety of treatment cessation. Consolidative surgery may serve both diagnostic and therapeutic purposes. Several recent case reports have described patients with urothelial carcinoma who achieved pCR after EVP followed by surgical resection, allowing the discontinuation of systemic therapy. Chan et al. reported that an 84-year-old woman with UTUC with regional lymph node metastases who underwent EVP achieved pCR after subsequent radical nephroureterectomy. This case suggests the potential role of combining EVP with surgery in selected patients with UTUC (13). Hara et al. reported that a 76-year-old man with node-positive urothelial carcinoma achieved a pCR after six cycles of EVP followed by robot-assisted nephroureterectomy with lymph node dissection (LND) (14). This case demonstrates the feasibility of surgical consolidation after an excellent systemic response in a patient initially considered unresectable because of bulky nodal disease. Although both reports achieved a pCR after EVP and subsequently adopted a treatment-free strategy, there was a significant difference between the two cases. In the report by Chan et al., treatment discontinuation was decided without LND, whereas in the report by Hara et al., LND was performed and the ypN0 status was pathologically confirmed before transitioning to treatment-free surveillance. While pathological confirmation of ypN0 may offer additional confidence in adopting a treatment-free strategy, the potential benefits should be balanced with the invasiveness of lymph node dissection. Wakamiya et al. reported a case of a 76-year-old woman with renal pelvic urothelial carcinoma who received multiple lines of systemic therapy, including platinum-based chemotherapy and pembrolizumab, followed by enfortumab vedotin. After prolonged enfortumab vedotin treatment, the metastatic lymph nodes remained radiologically stable, while isolated progression of the primary tumor was observed, prompting salvage nephroureterectomy. No additional systemic therapy was administered after salvage nephroureterectomy, and the patient remained recurrence-free for approximately one year postoperatively (15). The authors considered that LND was intentionally omitted because nodal disease appeared to be well-controlled radiographically, and there was limited evidence supporting the curative benefit of systematic lymphadenectomy in this setting.

Our patient had locally advanced lower ureteral carcinoma with clinically positive lymph node metastases and achieved a marked radiologic response after six cycles of EVP, including complete resolution of nodal disease. Radical nephroureterectomy was subsequently performed and pathological examination revealed a CR in the resected specimen. As LND was not performed, pathological confirmation of the nodal response was not available, and systemic therapy with EVP was resumed postoperatively. However, after one additional postoperative cycle, EVP was discontinued based on shared decision-making, considering the patient’s concerns regarding cumulative peripheral neuropathy. Six months after surgery, the patient remained recurrence-free without treatment-related adverse events, suggesting that a treatment-free strategy may be feasible even in initially node-positive disease when a strong response to EVP is achieved.

Study limitations. First, this is a single case report, and the findings cannot be generalized. Second, the follow-up duration was relatively short, and the long-term oncologic outcomes remain uncertain. In addition, lymph node dissection was not performed; therefore, pathological confirmation of the nodal response was not possible. Larger prospective studies are required to define the optimal treatment duration, identify candidates for consolidative surgery, and establish evidence-based strategies for treatment discontinuation in patients who achieve a complete response to EVP.