Neoadjuvant Therapy in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Recent Progress, Challenges, and Future Directions in the Era of TAR-200 and Enfortumab Vedotin Plus Pembrolizumab.
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| Titel: | Neoadjuvant Therapy in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Recent Progress, Challenges, and Future Directions in the Era of TAR-200 and Enfortumab Vedotin Plus Pembrolizumab. |
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| Autoren: | Di Lorenzo G; Oncology Unit, 'Andrea Tortora' Hospital, ASL Salerno, Pagani, Italy. g.dilorenzo@aslsalerno.it.; Associazione O.R.A. ETS-Oncology Research Assistance, Salerno, Italy. g.dilorenzo@aslsalerno.it.; UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy. g.dilorenzo@aslsalerno.it., Di Maio M; Department of Oncology, University of Turin, Medical Oncology 1U, AOU Città Della Salute E Della Scienza Di Torino, Turin, Italy., Buonerba C; Oncology Unit, 'Andrea Tortora' Hospital, ASL Salerno, Pagani, Italy.; Associazione O.R.A. ETS-Oncology Research Assistance, Salerno, Italy. |
| Quelle: | Oncology and therapy [Oncol Ther] 2026 Feb 21. Date of Electronic Publication: 2026 Feb 21. |
| Publication Model: | Ahead of Print |
| Publikationsart: | Journal Article; Review |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: Adis Country of Publication: New Zealand NLM ID: 101677510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2366-1089 (Electronic) Linking ISSN: 23661089 NLM ISO Abbreviation: Oncol Ther |
| Imprint Name(s): | Publication: 2016- : [Auckland, New Zealand] : Adis Original Publication: Cham, Switzerland : Springer International Publishing AG, [2016]- |
| Abstract: | Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy remains the standard of care for patients with nonmetastatic muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin. However, many patients cannot receive cisplatin because of renal dysfunction, frailty, neuropathy, ototoxicity, or comorbidities, leaving an unmet need for effective cisplatin-free perioperative options. Single-arm phase 2 studies of neoadjuvant immune checkpoint inhibitors (ICIs) have shown encouraging pathologic complete response (pCR) rates in patients who are ineligible for cisplatin or who decline it, and randomized survival evidence has only recently begun to mature. Two conceptually distinct cisplatin-free paradigms are now shaping the field: (1) systemic intensification with perioperative enfortumab vedotin plus pembrolizumab, an antibody-drug conjugate (ADC) plus programmed death 1 (PD-1) inhibitor regimen supported by phase 3 data; and (2) bladder-centered intensification with TAR-200 (intravesical sustained-release gemcitabine) combined with systemic PD-1 blockade, which has demonstrated promising pathologic activity in early-phase studies but remains investigational in MIBC. This narrative review summarizes the evolving perioperative evidence base across traditional NAC, neoadjuvant ICI monotherapy, ADC-ICI combinations, and locoregional drug delivery approaches; highlights key interpretive challenges including heterogeneous trial populations and endpoints and the limitations of cross-trial comparisons; and discusses future directions such as response-adapted escalation and de-escalation strategies using circulating tumor DNA and urinary tumor DNA. We present a conceptual framework for future prospective trials evaluating how systemic and bladder-centered strategies might be selected and sequenced, rather than definitive guidance for routine clinical practice. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Conflict of Interest: Giuseppe Di Lorenzo is an Editorial Board member of Oncology and Therapy. Giuseppe Di Lorenzo was not involved in the selection of peer reviewers for this manuscript nor in any of the subsequent editorial decisions. Carlo Buonerba reports consulting/speaker fees from Ipsen and Bayer and institutional funding by Astrazeneca. Massimo Di Maio reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, GlaxoSmithKline, Viatris, Resilience, Daiichi Sankyo for consultancy or participation to advisory boards and institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. |
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| Contributed Indexing: | Keywords: Cetrelimab; Circulating tumor DNA; Cisplatin ineligibility; Enfortumab vedotin; Muscle-invasive bladder cancer; Neoadjuvant therapy; Pembrolizumab; TAR-200 Local Abstract: [plain-language-summary] Muscle-invasive bladder cancer is often treated with removal of the bladder. In people whose cancer has not spread, giving chemotherapy before surgery can improve cure rates. The most effective chemotherapy uses cisplatin, but many people cannot receive cisplatin because of kidney problems, hearing loss, nerve damage, heart disease, or other illnesses. This review summarizes new cisplatin-free options being studied before and after surgery. One option combines enfortumab vedotin with pembrolizumab, two medicines that travel through the bloodstream and target cancer in the body. In a large clinical trial, this combination improved outcomes compared with surgery alone in people who could not receive cisplatin. Another option aims to treat the tumor mainly inside the bladder. It uses TAR-200, a small device placed in the bladder that slowly releases the chemotherapy drug gemcitabine, together with an immunotherapy medicine. Early results show promising tumor responses, but this approach is still experimental for muscle-invasive disease. We also discuss “liquid biopsies”, which measure tumor DNA in blood or urine. These tests may help identify who needs more treatment after surgery and who can safely avoid extra side effects. Future studies must compare these strategies and confirm the best way to choose and sequence treatments. |
| Entry Date(s): | Date Created: 20260221 Latest Revision: 20260221 |
| Update Code: | 20260221 |
| DOI: | 10.1007/s40487-026-00417-y |
| PMID: | 41722015 |
| Datenbank: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy remains the standard of care for patients with nonmetastatic muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin. However, many patients cannot receive cisplatin because of renal dysfunction, frailty, neuropathy, ototoxicity, or comorbidities, leaving an unmet need for effective cisplatin-free perioperative options. Single-arm phase 2 studies of neoadjuvant immune checkpoint inhibitors (ICIs) have shown encouraging pathologic complete response (pCR) rates in patients who are ineligible for cisplatin or who decline it, and randomized survival evidence has only recently begun to mature. Two conceptually distinct cisplatin-free paradigms are now shaping the field: (1) systemic intensification with perioperative enfortumab vedotin plus pembrolizumab, an antibody-drug conjugate (ADC) plus programmed death 1 (PD-1) inhibitor regimen supported by phase 3 data; and (2) bladder-centered intensification with TAR-200 (intravesical sustained-release gemcitabine) combined with systemic PD-1 blockade, which has demonstrated promising pathologic activity in early-phase studies but remains investigational in MIBC. This narrative review summarizes the evolving perioperative evidence base across traditional NAC, neoadjuvant ICI monotherapy, ADC-ICI combinations, and locoregional drug delivery approaches; highlights key interpretive challenges including heterogeneous trial populations and endpoints and the limitations of cross-trial comparisons; and discusses future directions such as response-adapted escalation and de-escalation strategies using circulating tumor DNA and urinary tumor DNA. We present a conceptual framework for future prospective trials evaluating how systemic and bladder-centered strategies might be selected and sequenced, rather than definitive guidance for routine clinical practice.<br /> (© 2026. The Author(s).) |
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| ISSN: | 2366-1089 |
| DOI: | 10.1007/s40487-026-00417-y |