Padcev (enfortumab vedotin-ejfv)

Enfortumab vedotin(EV)is an antibody-drug conjugate (ADC) targeting Nectin-4, which has been approved by FDA for the treatment of urothelial carcinoma...These therapies offer novel strategies for delivering targeted treatments to Nectin-4-expressing cancer cells, enhancing treatment efficacy and minimizing off-target effects. In conclusion, this review aims to provide an overview of the latest advances in understanding the role of Nectin-4 in breast cancer and discuss the future development prospects of Nectin-4 targeted agents.

Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now...Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC...This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.

Enfortumab vedotin demonstrated meaningful clinical activity with a manageable safety profile in Chinese patients with previously treated locally advanced or mUC.

P=N/A, N=22, Completed, Hospices Civils de Lyon

Significant differences were observed in PFS and OS among the three groups (p<0.001 and p<0.001, respectively) and c-indices were 0.766 for PFS and 0.800 for OS. The risk classification using CRP and hypercalcemia is useful for predicting the outcomes of patients with advanced UC treated with EV.

The characterization of metastatic tumour samples can improve response prediction to immunotherapy, the anti-NECTIN4 antibody-drug conjugate enfortumab vedotin and the FGFR inhibitor erdafitinib. Routine metastatic biopsy can thus improve the precision of identifying driver druggable alterations, thus improving treatment selection for patients with mUC.

P=N/A, N=80, Recruiting, LMU Klinikum

ETx-22 has a highest non severely toxic dose of over 20 mg/kg in non-human primates without signs of important skin toxicity. ETx-22 represents a valuable therapy, for the treatment of patients with nectin-4 expressing tumors including those that have become resistant to enfortumab vedotin treatment.

P2, N=20, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2028 --> Jun 2029 | Trial primary completion date: Jun 2027 --> Jun 2028

Immunohistochemically abnormal p53 tumors were found to respond well to EV, while high FGFR3 tumors had a poorer response. Thus, p53 and FGFR3 are potential biomarkers for predicting response to EV treatment in patients with urothelial carcinoma.

P1/2, N=230, Recruiting, Merck Sharp & Dohme LLC | Phase classification: P2 --> P1/2

P1/2, N=41, Suspended, M.D. Anderson Cancer Center | Not yet recruiting --> Suspended

P1/2, N=47, Not yet recruiting, University of California, San Francisco | Trial completion date: Jun 2027 --> Sep 2027 | Initiation date: Aug 2024 --> Nov 2024 | Trial primary completion date: Jun 2027 --> Sep 2027

P2, N=40, Active, not recruiting, Astellas Pharma China, Inc. | Trial completion date: Sep 2024 --> Oct 2025

P1/2, N=645, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Nov 2027 --> May 2026

P3, N=595, Active, not recruiting, Merck Sharp & Dohme LLC | N=857 --> 595

Our real-world data align with existing literature regarding adjuvant nivolumab in localized invasive muscle urothelial carcinoma.

P3, N=608, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Aug 2024 --> Feb 2025

P1/2, N=19, Recruiting, University of Texas Southwestern Medical Center | Not yet recruiting --> Recruiting

P2, N=329, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively...Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%...Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

These novel combinations are revolutionizing the treatment standard for metastatic urothelial carcinoma and necessitate a new approach to managing side effects.

P2, N=827, Recruiting, Gilead Sciences | Trial completion date: Jul 2026 --> Jun 2030 | Trial primary completion date: Jul 2024 --> Jun 2030

P2, N=40, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=32, Recruiting, Emory University | Trial completion date: Jan 2025 --> Jan 2026

P1, N=58, Recruiting, Astellas Pharma Global Development, Inc. | Trial primary completion date: Jun 2024 --> Jun 2026

Patients without these factors had a significantly prolonged OS compared to those with both factors. In real-world practice, EV therapy is an effective treatment for patients with la/mUC after ICI treatment.

Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.

In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.

Enfortumab vedotin and free MMAE exposures were statistically significant predictors of grade ≥ 3 treatment-related adverse events (both P < 0.0001). This analysis supports enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle.

The agent, now given in combination with pembrolizumab, frequently induces cutaneous reactions. An emerging literature of small series and case reports, largely from oncologic literature, presents the histopathology of EV-induced cutaneous eruption as a vacuolar interface dermatitis with the inconsistently reported feature of arrested mitotic figures. This case study demonstrates distinctive clinical and histopathologic features of EV-induced eruption, which may inform dermatologic and oncologic management.

Of great note, the US Food and Drug Administration (FDA)-approval of the first Nectin-4-directed ADC, enfortumab vedotin (EV), in urothelial cancer (UC) not only introduced Nectin-4 as a clinically validated and reliable target antigen but also confirmed the evolving role of Nectin-4-directed ADCs as novel and promising cancer therapeutics. In addition to EV, there have been or are currently being seven and eleven Nectin-4-directed ADCs, respectively, in various stages of clinical trials and preclinical development, offering a promising future for the treatment of Nectin-4-positive cancer patients. This study reviewed clinical- and preclinical-stage Nectin-4-directed ADCs.

Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease.

The approval of nivolumab in combination with gemcitabine and cisplatin and pembrolizumab with antibody-drug conjugate enfortumab vedotin has revolutionized the first-line treatment of advanced bladder cancer in many countries. We further discuss newer novel treatment options in the second and subsequent lines of treatment on progression, like immunotherapy in combination with other agents, including fibroblast growth factors receptor inhibitors, human epidermal growth factor inhibitors, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Finally, we discuss the integration of these novel therapies into current clinical practice amidst the rapidly evolving landscape of advanced bladder cancer treatment, aiming to enhance patient outcomes.

In addition to enfortumab vedotin and sacituzumab govitecan, various HER2-targeted antibody drug conjugates and ADC-anti-PD-1 combination regimens have demonstrated efficacy in clinical trials and are poised for clinical advancement.

P2/3, N=700, Not yet recruiting, Vasgene Therapeutics, Inc

P1/2, N=98, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

For patients without disease progression after completing platinum-based chemotherapy, avelumab first-line maintenance treatment is recommended by international guidelines...Additionally, following results from a recent phase 3 trial, nivolumab plus cisplatin-based chemotherapy has also received Food and Drug Administration approval and is an additional first-line treatment option for cisplatin-eligible patients. Later-line options for patients with advanced urothelial carcinoma, depending on prior treatment, may include enfortumab vedotin, erdafitinib (for patients with FGFR2/3 mutations or fusions/rearrangements), sacituzumab govitecan, and platinum rechallenge. For the small proportion of patients ineligible for any platinum-based chemotherapy (i.e., unsuitable for cisplatin or carboplatin), immune checkpoint inhibitor monotherapy with pembrolizumab or atezolizumab is a first-line treatment option, although approved agents vary between countries. In summary, this podcast discusses recent developments in the treatment landscape for advanced urothelial carcinoma, eligibility for platinum-based chemotherapy, potential first-line treatment options, and treatment sequencing. Supplementary file1 (MP4 246907 KB).

In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

P1/2, N=98, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=34, Recruiting, University of Utah | Trial completion date: Sep 2026 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2025