Antibody-drug conjugates for urothelial carcinoma

Thomas, Joseph; Sun, Michael; Getz, Ted; Ho, Benedict; Nauseef, Jones T.; Tagawa, Scott T.

doi:10.1016/j.urolonc.2023.06.006

Cited by 8 publications

(6 citation statements)

References 44 publications

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“…These results suggest that oncological outcomes may improve when patients with mUC maintain good general health and receive third-line treatment with EV relatively early. Combination therapy of EV with various antitumor agents, such as pembrolizumab, cisplatin, or carboplatin, is currently being investigated [ 7 ]. If these trials demonstrate a therapeutic effect on mUC, EV could be administered earlier to patients with mUC, which may further improve oncologic outcomes.…”

Section: Discussionmentioning

confidence: 99%

Temporary Tumor Shrinkage Following Enfortumab Vedotin Therapy for Metastatic Urothelial Carcinoma After Radical Cystectomy With Neoadjuvant Chemotherapy: A Case Report

Namiki¹,

Kato²,

Iinuma³

et al. 2023

Cureus

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A 39-year-old Japanese male patient presented with a chief complaint of gross hematuria persistent for two months. However, no relevant findings in the patient’s medical and family history were observed. He was diagnosed with muscle-invasive bladder cancer, clinical stage T2bN0M0. After four courses of neoadjuvant chemotherapy with gemcitabine and cisplatin, the tumor size reduced by approximately 30%. The patient underwent robot-assisted radical cystectomy with standard lymph node dissection followed by intracorporeal ileal conduit reconstruction. Histologically, the tumor was diagnosed as a high-grade urothelial carcinoma invading the fatty tissue surrounding the bladder and metastasizing to the lymph nodes, with a pathological stage of ypT3aypN2M0. Four months after surgery, multiple metastases were detected, and treatment with pembrolizumab was initiated immediately. However, the patient did not respond to pembrolizumab. Therefore, a third-line treatment with enfortumab vedotin (EV) was initiated. Thereafter, the metastatic lesion shrank quickly, and the metastatic lesions almost disappeared after two courses of EV administration. Although new metastases were observed at other sites, there has been no regrowth to date. EV-related adverse events were not observed during follow-up. Eighteen months after the surgery, the patient remains alive with multiple metastases. Therefore, the sequence of treatment should be considered to maximize the therapeutic effect of EV, and, consequently, administering EV as early as possible may be important.

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Section: Discussionmentioning

confidence: 99%

Temporary Tumor Shrinkage Following Enfortumab Vedotin Therapy for Metastatic Urothelial Carcinoma After Radical Cystectomy With Neoadjuvant Chemotherapy: A Case Report

Namiki¹,

Kato²,

Iinuma³

et al. 2023

Cureus

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“…This ADC consists of an antibody targeting the transmembrane calcium signal transducer protein TROP-2, coupled with several molecules of SN-38, a topoisomerase-1 inhibitor. Several clinical trials are currently investigating the efficacy of using sacituzumab govitecan as a single agent or in combination with ICI [ 34 ]. Furthermore, a phase III trial to test the efficacy of sacituzumab govitecan as a single agent is ongoing [ 35 ].…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

“…Human epidermal growth factor 2 (HER2) is also overexpressed in a significant amount of MIBC patients [ 38 ]. Different ADCs targeting HER2 (disitamab vedotin, trastuzumab deruxtecan and trastuzumab emtasine) coupled with distinct cytotoxic compounds are also currently being investigated in clinical trials for their use in bladder cancer [ 34 ].…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Advances in preclinical assessment of therapeutic targets for bladder cancer precision medicine

Nössing,

Herek,

Shariat

et al. 2024

Current Opinion in Urology

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Purpose of review Bladder cancer incidence is on the rise, and until recently, there has been little to no change in treatment regimens over the last 40 years. Hence, it is imperative to work on strategies and approaches to untangle the complexity of intra and inter-tumour heterogeneity of bladder cancer with the aim of improving patient-specific care and treatment outcomes. The focus of this review is therefore to highlight novel targets, advances, and therapy approaches for bladder cancer patients. Recent findings The success of combining an antibody-drug conjugate (ADC) with immunotherapy has been recently hailed as a game changer in treating bladder cancer patients. Hence, interest in other ADCs as a treatment option is also rife. Furthermore, strategies to overcome chemoresistance to standard therapy have been described recently. In addition, other studies showed that targeting genomic alterations (e.g. mutations in FGFR3, DNA damage repair genes and loss of the Y chromosome) could also be helpful as prognostic and treatment stratification biomarkers. The use of single-cell RNA sequencing approaches has allowed better characterisation of the tumour microenvironment and subsequent identification of novel targets. Personalized functional precision medicine could be another avenue to improve and guide personalized treatment options. Summary Several novel preclinical targets and treatment options have been described recently. The validation of these advances will lead to the development and implementation of robust personalized treatment regimens for bladder cancer patients.

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“…Despite the satisfactory efficacy and tolerance of ADCs for advanced BCa, the high incidence of treatment‐related adverse events (TRAEs) (94–100%) caused by systemic administration cannot be ignored; the incidence of TRAEs of grade ≥3 is 54–58.1%. [ 13 ] Considering the promising efficacy of ADCs in the treatment of advanced BCa, the timing of ADCs treatment is expected to move forward, especially in the treatment of high‐risk NMIBC. For NMIBC, intravesical instillation could enable direct exposure of drugs to BCa cells with reduced systemic exposure and adverse events compared with systemic administration.…”

Section: Introductionmentioning

confidence: 99%

A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

Hong,

Chen,

Wang

et al. 2023

Advanced Science

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More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients.

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Antibody-drug conjugates for urothelial carcinoma

Cited by 8 publications

References 44 publications

Temporary Tumor Shrinkage Following Enfortumab Vedotin Therapy for Metastatic Urothelial Carcinoma After Radical Cystectomy With Neoadjuvant Chemotherapy: A Case Report

Temporary Tumor Shrinkage Following Enfortumab Vedotin Therapy for Metastatic Urothelial Carcinoma After Radical Cystectomy With Neoadjuvant Chemotherapy: A Case Report

Advances in preclinical assessment of therapeutic targets for bladder cancer precision medicine

A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer

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