Pseudoprogression During Enfortumab Vedotin Plus Pembrolizumab Therapy in Muscle‐Invasive Bladder Cancer Achieving Pathological Complete Response: A Case Report

ABSTRACT

Introduction

Enfortumab vedotin plus pembrolizumab has emerged as a standard first‐line therapy for advanced urothelial carcinoma (UC). However, pseudoprogression during this combination remains poorly characterized.

Case Presentation

A 71‐year‐old man with muscle‐invasive bladder cancer and lymph node metastasis received enfortumab vedotin plus pembrolizumab. During treatment, imaging suggested tumor progression with new hydronephrosis. Repeat transurethral resection revealed no viable tumor. Because of persistent symptoms, robot‐assisted radical cystectomy was performed. Histopathological examination demonstrated no residual tumor cells, indicating pathological complete response (ypT0N0), with prominent CD8‐ and CD4‐positive T‐cell infiltration and minimal CD20‐positive B‐cell infiltration.

Conclusion

This case suggests that pseudoprogression may occur during enfortumab vedotin plus pembrolizumab therapy. Careful interpretation of radiological findings is essential to avoid premature treatment discontinuation.

Keynote Message

Enfortumab vedotin plus pembrolizumab may induce radiological changes that do not necessarily reflect viable tumor burden. In our case, enlarged pelvic lymph nodes suggested disease progression, whereas pathological examination demonstrated a complete response. This discrepancy may represent pseudoprogression associated with immune activation. Clinicians should consider this possibility when evaluating treatment response and planning surgery after immunotherapy‐based treatment.

1. Introduction

Locally advanced and metastatic urothelial carcinoma (UC) has a poor prognosis. Enfortumab vedotin, an antibody–drug conjugate targeting Nectin‐4, combined with pembrolizumab has demonstrated high response rates and durable efficacy and is now a standard first‐line treatment for advanced UC [1, 2]. A recent Phase III trial of perioperative enfortumab vedotin plus pembrolizumab also demonstrated improved pathological response and survival outcomes [3].

Pseudoprogression, a transient increase in tumor burden due to immune‐mediated inflammation, has been reported during immune checkpoint inhibitor (ICI) therapy [4, 5]. Although recognized during ICI monotherapy [5, 6, 7], its incidence and pathological characteristics during enfortumab vedotin plus pembrolizumab remain unclear. We report a case of muscle‐invasive bladder cancer showing apparent radiological progression during treatment but pathological complete response (pCR) after cystectomy.

2. Case Presentation

A 71‐year‐old man was referred after urine cytology revealed Class V findings following microscopic hematuria (Figure 1). Cystoscopy demonstrated multiple non‐papillary tumors (Figure 2a). Magnetic resonance imaging (MRI) suggested muscle‐invasive bladder cancer with left obturator lymph node enlargement (Figure 2b,c), corresponding to cT2N1M0. PET‐CT and histological confirmation of the lymph node were not performed. The enlarged obturator lymph node was clinically considered metastatic based on imaging findings in the context of muscle‐invasive bladder cancer.

FIGURE 1.

Timeline of the clinical course. † Enfortumab vedotin (1.25 mg/kg on days 1 and 8) plus pembrolizumab (200 mg on day 1) was administered every 3 weeks for five cycles. CT after cycle 2 showed no significant change. Decreased appetite and fatigue developed from cycle 4. Subsequently, hematuria and dysuria developed, and CT demonstrated progressive disease (PD). Other adverse events included Grade 2 proteinuria and Grade 1 eczema and anemia.

FIGURE 2.

Cystoscopic and MRI findings before (a–c) and after five cycles of enfortumab vedotin plus pembrolizumab (d–f). (a) Cystoscopy showing multiple non‐papillary bladder tumors. (b) T2‐weighted MRI showing a muscle‐invasive bladder tumor and left obturator lymph node enlargement (arrow). (c) DWI showing high signal intensity in the bladder tumor and left obturator lymph node. (d) Cystoscopy showing non‐papillary lesions suspicious for recurrence. (e) T2‐weighted MRI showing bladder wall thickening and bilateral obturator and external iliac lymph node enlargement (arrows), suggestive of disease progression. (f) DWI showing high signal intensity in the bladder wall lesion and bilateral obturator and external iliac lymph nodes.

Transurethral resection of bladder tumor (TURBT) revealed urothelial carcinoma with squamous differentiation (G3 > G2), at least pT1. Although radical cystectomy was potentially curative, the patient strongly wished to avoid surgery. Given the clinically suspected nodal metastasis and his preference, systemic therapy with enfortumab vedotin plus pembrolizumab was selected after multidisciplinary discussion.

After two cycles, contrast‐enhanced computed tomography (CT) showed no significant change in the lymph node and circumferential bladder wall thickening without progression. During cycle 4, Grade 2 decreased appetite and proteinuria and Grade 1 fatigue, eczema, and anemia developed. During cycle 5, hematuria and voiding difficulty developed, and CT revealed right hydronephrosis. Cystoscopy showed non‐papillary tumors extending from the right lateral to posterior wall (Figure 2d). MRI demonstrated irregular circumferential bladder wall thickening with suspected muscle invasion, along with bilateral obturator and external iliac lymph node enlargement (Figure 2e,f). Recurrent disease was suspected, and repeat TURBT was performed.

Histopathological examination revealed predominantly necrotic material with scattered calcifications, focal granulation tissue, exudates, and inflammatory cell aggregates of neutrophils, lymphocytes, and histiocytes, without viable tumor cells. Lymph node biopsy was considered but not performed because the result would not have altered management. Despite negative repeat TURBT, the patient had persistent hematuria and voiding difficulty, bladder abnormalities with hydronephrosis, and difficulty continuing therapy because of adverse events. Therefore, robot‐assisted radical cystectomy with pelvic lymph node dissection and intracorporeal ileal conduit urinary diversion was performed for local disease and symptom control.

Intraoperatively, ascites was observed, but cytology was negative. Severe adhesions around the bladder were noted. Operative time was 7 h 26 min, console time 6 h 31 min, and estimated blood loss 402 mL. The postoperative course was uneventful, and no adjuvant therapy was administered. At 16 months after surgery, the patient remained recurrence‐free.

Gross examination showed a 70 × 40 mm ulcerative lesion with posterior‐wall induration (Figure 3). Histopathology revealed necrotic material, scar tissue, and inflammatory granulation tissue without viable tumor cells in the bladder or lymph nodes (0/28), indicating pCR (ypT0N0) (Figure 4a,b). Extensive CD3‐positive T‐cell infiltration was observed (Figure 4c), predominantly CD8‐positive cytotoxic T cells (Figure 4d) and CD4‐positive T cells (Figure 4e), whereas CD20‐positive B‐cell infiltration was minimal (Figure 4f). These findings suggested a T cell–dominant immune response consistent with pseudoprogression.

FIGURE 3.

Gross pathological findings of the cystectomy specimen showing a 70 × 40 mm ulcerated induration centered on the posterior wall of the bladder (arrow).

FIGURE 4.

Histopathological findings of the cystectomy specimen. (a) Hematoxylin–eosin staining showing necrotic tissue and inflammatory granulation without viable tumor cells (original magnification × 100). (b) Higher magnification view demonstrating inflammatory granulation tissue with multinucleated giant cells (arrow) (hematoxylin–eosin stain, original magnification × 200). (c) Immunohistochemical staining demonstrating infiltration of CD3‐positive T cells (original magnification × 100). (d) CD8 immunostaining showing cytotoxic T lymphocytes (original magnification × 100). (e) CD4 immunostaining demonstrating helper T cells (original magnification × 100). (f) CD20 immunostaining showing limited B‐cell infiltration (original magnification × 100).

3. Discussion

This case demonstrated pCR despite radiological findings suggesting disease progression during enfortumab vedotin plus pembrolizumab. Pseudoprogression is transient tumor enlargement caused by immune cell infiltration, necrosis, and edema [4, 5]. Reported histopathological findings include tumor necrosis, fibrotic and inflammatory changes, macrophage or histiocyte infiltration, and T‐cell–predominant lymphocytic infiltration [8, 9, 10, 11, 12, 13]. In our case, repeat TURBT and the cystectomy specimen showed necrotic material, granulation tissue, and inflammatory cell infiltration. Immunohistochemistry demonstrated predominant T‐cell infiltration with minimal B‐cell involvement, consistent with reported patterns. To our knowledge, pseudoprogression during enfortumab vedotin plus pembrolizumab has not previously been pathologically confirmed.

Pseudoprogression occurs in approximately 6% of patients treated with immune checkpoint inhibitors [14]. Pseudoprogression is classified as early when occurring within 12 weeks after treatment initiation and delayed when occurring after 12 weeks [4]. New lesions may also appear, leading to misclassification as progressive disease under conventional RECIST criteria [4, 15]. In this case, radiological progression at 13 weeks was consistent with delayed pseudoprogression.

The mechanism of pseudoprogression during enfortumab vedotin plus pembrolizumab remains unclear. It may involve EV‐induced tumor cell death and pembrolizumab‐mediated immune activation, producing an inflammatory response characterized by lymphocytic infiltration, edema, and tumor necrosis that mimics progression.

Accurate differentiation between true progression and pseudoprogression is essential. Under iRECIST, initial progression is classified as unconfirmed progressive disease (iUPD), with reassessment after 4–8 weeks recommended [15]. When clinically feasible, treatment should not be discontinued solely on radiological progression [4, 15].

In this case, surgery was performed for symptom relief and because adverse events made continued systemic therapy difficult. Eczema and decreased appetite may have been related to enfortumab vedotin rather than immune‐related toxicity. Complete tumor regression was unexpectedly confirmed in the surgical specimen, highlighting the limitations of imaging alone and the importance of integrating clinical, imaging, and pathological findings. The KEYNOTE‐905/EV‐303 trial demonstrated a pCR rate of 57.1% with perioperative enfortumab vedotin plus pembrolizumab [3]; however, pseudoprogression may complicate radiological response assessment.

In conclusion, pseudoprogression can occur during enfortumab vedotin plus pembrolizumab therapy. As use of this combination increases, recognizing immune‐related response patterns will be important for appropriate treatment decisions.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.