Padcev (enfortumab vedotin-ejfv) / Astellas, Pfizer - LARVOL DELTA

Advancements in systemic therapy for muscle-invasive bladder cancer: A systematic review from the beginning to the latest updates. (PubMed, Bladder Cancer) - "Recently, the NIAGARA trial showed that perioperative durvalumab plus GC outperformed GC alone in terms of pCR rates, OS (HR: 0.75), and EFS (HR: 0.68). Nivolumab is the only ICI recommended as adjuvant therapy in patients who harbored adverse pathologic outcomes. Ongoing trials will provide further information on the impact of combination therapy, including chemotherapy, ICIs, and enfortumab vedotin, in both neoadjuvant and adjuvant settings."

Journal • Review • Bladder Cancer • Genito-urinary Cancer • Hematological Disorders • Oncology • Solid Tumor • Urothelial Cancer

A Review of NICE UK Submissions for Antibody-Drug Conjugates in Oncology (ISPOR 2025) - "All of these ADCs were assessed by NICE from inception to 2024 12 FDA-approved ADCs were identified: Trastuzumab emtansine, Trastuzumab deruxtecan, Sacituzumab govitecan, Inotuzumab ozogamicin, Polatuzumab vedotin, Loncastuximab tesirine, Tisotumab vedotin, Enfortumab vedotin, Mirvetuximab soravtansine-gynx, Belantamab mafodotin-blmf, Gemtuzumab ozogamicin, and Brentuximab vedotin. In conclusion, ADCs have revolutionized cancer treatment with their targeted delivery and significant therapeutic benefits. The evolution of ADCs since 2000 highlights their potential in both refractory and early-stage diseases. Continued advancements in ADC design and technology promise even greater therapeutic efficacy."

NICE • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Breast Cancer • Cervical Cancer • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

Cancer-induced Pain Is Associated With Poor Overall Survival of Urothelial Carcinoma Patients Treated With Enfortumab Vedotin. (PubMed, In Vivo) - "CIP before the treatment of EV was a significant predictor of reduced OS in patients with UC. Early management of CIP or initiation of EV therapy before CIP development may improve survival outcomes."

Journal • Oncology • Pain • Solid Tumor • Urothelial Cancer

Treatment Outcomes After Progression With Enfortumab Vedotin in Patients With Advanced Urothelial Carcinoma. (PubMed, Anticancer Res) - "Post-EV treatment did not significantly improve the survival compared with BSC in patients with advanced UC. However, patients with lymph node-only metastases may show better outcomes than others. Further research is required to identify effective treatment strategies for this population."

Journal • Oncology • Solid Tumor • Urothelial Cancer

Steroid Premedication Impact on Efficacy and Cutaneous Toxicity of Enfortumab Vedotin for Advanced Urothelial Carcinoma. (PubMed, In Vivo) - "In EV treatment, steroid premedication did not affect clinical outcomes. The incidence and severity of EV-related cutaneous toxicity tended to improve in patients who received steroid premedication, although no significant differences were observed."

Journal • Retrospective data • Oncology • Solid Tumor • Urothelial Cancer

Pfizer Reports Solid First-Quarter 2025 Results And Reaffirms 2025 Guidance (Pfizer Press Release) - "Padcev globally, up 25% operationally, driven primarily by increased market share in first-line metastatic urothelial cancer (mUC)....Ibrance globally, down 6% operationally, driven primarily by generic entry and timing of shipments in certain international markets, as well as lower net price in the U.S. mostly due to the impact of higher manufacturer discounts resulting from the IRA Medicare Part D Redesign."

Sales • Bladder Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Urothelial Cancer

PlugIN: PLUG-IN: Pembrolizumab Combined With Enfortumab Vedotin for Advanced Melanoma Patients (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Grupo Español Multidisciplinar de Melanoma | Trial completion date: Apr 2025 ➔ Jun 2028 | Trial primary completion date: Apr 2025 ➔ Jun 2027

Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF

Real-World Clinical Outcomes with First-Line Systemic Treatment and Avelumab Maintenance in US Patients with Locally Advanced or Metastatic Urothelial Carcinoma: The SPEAR Bladder-II Study. (PubMed, Curr Oncol) - "The median OS (95% CI) from the start of 1L treatment was 20.4 (13.8, 30.0), 11.0 (8.5, 14.5), and 14.6 (12.6, 17.3) months for cisplatin-based only, carboplatin-based only, and IO monotherapy, respectively. After discontinuation of avelumab 1LM, 43.5% received 2L treatment, and 59.3% of those received enfortumab vedotin (EV); the median (95% CI) OS from start of 2L EV was 12.7 (7.2, 16.5) months. Survival outcomes among patients treated with avelumab 1LM and 2L EV are consistent with respective clinical trials and other real-world studies."

Clinical data • Journal • Real-world evidence • Retrospective data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Enfortumab Vedotin-Mediated Severe Insulin Resistance and Fatal Ketoacidosis (ENDO 2025) - "Cancer treatment history included ddMVAC, GC and adjuvant nivolumab. With biopsy proven lymph node recurrence, he started EV (1.25mg/kg) and pembrolizumab...Reporting to manufacturers remains a key step in post-marketing safety data, and publishing can promote education and awareness of this rare but severe adverse effect.*. .*"

Cardiovascular • Diabetes • Genetic Disorders • Hypertension • Hypotension • Metabolic Disorders • Nephrology • Obesity • Oncology • Renal Disease • Solid Tumor • Type 2 Diabetes Mellitus • Urothelial Cancer

Padcev + Keytruda: “Enfortumab vedotin (EV) (3/7): Study data by disease stage of UC”; Urothelial cancer (Astellas) - FY 2024 Results: “Statistically significant and clinically meaningful improvement over chemotherapy with nearly doubled mOS and mPFS”

P3 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Urothelial Cancer

Padcev + Keytruda: Data readout from P2 EV-202 trial (NCT04225117) for 1L head and neck cancer in Q1 FY2025 (Astellas) - FY 2024 Results

P2 data • Head and Neck Cancer • Oncology • Solid Tumor

Padcev + Keytruda: Interim analysis data readout from P3 EV-303 trial (NCT03924895) for cis-ineligible MIBC in Q2/Q3 FY2025 (Astellas) - FY 2024 Results: Interim analysis data readout from P3 EV-304 trial (NCT04700124) for cis-eligible MIBC in Q2/Q3 FY2025

P3 data • Bladder Cancer • Genito-urinary Cancer • Oncology

Padcev: Data readout from EV-104 trial (NCT05014139) for NMIBC in Q3 FY2025 (Astellas) - FY 2024 Results

P1 data • Bladder Cancer • Genito-urinary Cancer • Oncology

Multimodal cancer therapy consisting of antibody-drug conjugates and radiotherapy in cancer treatment (AACR 2025) - "Accordingly, combination of RT with ADCs targeting HER2: trastuzumab emtansine/deruxtecan/duocarmazine (T-DM1/T-DXd/T-Duo) and disitamab vedotin, TROP2: datopotamab deruxtecan and sacituzumab govitecan, EGFR: depatuxizumab MMAE, HER3: patritumab deruxtecan, Nectin4: enfortumab vedotin and CEACAM5: tusamitamab ravtansine were evaluated. Together, this study demonstrates that inherent sensitivity of tumor cells to different payload classes, DAR and TAA dynamic are of relevance for the efficacy of ADC. Informed selection of ADC exhibited synergistic effects with RT providing a novel multimodal and promising strategy for efficient cancer eradication."

Breast Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • CEACAM5 • EGFR • ERBB3 • HER-2 • NECTIN4

IMPROVE: Probiotics in Advanced Urothelial Carcinoma (clinicaltrials.gov) - P2 | N=222 | Recruiting | Sponsor: Sun Yat-sen University

New P2 trial • Oncology • Solid Tumor • Urothelial Cancer

Targeting Nectin-4 with a first-in-class triple MMAE/dual TOP1i payload ADC showing synergistic and durable activity across all target expression levels and favorable tolerability (AACR 2025) - "Notably, the tolerability in rats showed an HNSTD of more than 20 mg/kg in a dose-range-finder study (vs. Enfortumab vedotin (EV): 5mg/kg)...Further, in a low Nectin-4-expressing TNBC PDX model, the high anti-tumor activity was confirmed leading to high and complete anti-tumor responses at 2.5 mg/kg compared to EV and Sacituzumab govitecan, the FDA-approved ADC for TNBC. In conclusion, the first-in-class Nectin-4 targeting triple-payload ADC leads to very high anti-tumor efficacy in CDX and PDX models and is well tolerable in rats. We show for the first time, that combination of multiple payloads in one ADC can lead to synergistic effects in mouse models while still being well tolerable."

Biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NECTIN4 • TOP1

Novel humanized cell and murine models expressing tumor-associated antigens for ADC toxicity and IO combination evaluation (AACR 2025) - "Tumor-bearing models were treated with monotherapy of trastuzumab-deruxtecan (T-Dxd), sacituzumab govitecan or enfortumab vedotin, or combination therapy with anti-PD-1 antibodies. For the toxicity study, 180 mg/kg T-Dxd and 100 mg/kg trastuzumab-emtansine (T-DM1) were injected into hHER2 mice weekly for two doses by intravenous injection. A highly HER2-expressing HuCell line (clone #2) successfully grew in hHER2 models but not in WT models, with tumors displaying nearly 100% of human Her2 positive cells with high surface expression (2×105 molecules per cell)...Combination treatment of T-Dxd (4 mg/kg+2 mg/kg, QW) with Keytruda (5 mg/kg, BIW×2) resulted in a complete response rate (8/8) with 87% TGI (p<0.01) compared to T-Dxd monotherapy (7/8) with 96% TGI (p<0.001) in hHER2/PD-1 double knock in mice... HuCell and HuGEMM models provide an advanced platform to evaluate ADC drug monotherapy and combination therapies with immune checkpoint inhibitors...."

IO biomarker • Preclinical • Oncology • HER-2 • NECTIN4

Spatially resolved integrated omics profiling for ADC targets in urothelial carcinoma (AACR 2025) - "We aim to employ the integrated multi-omics setup to explore the expression of the ADC targets in sections from a retrospective cohort of mUC patients treated by monotherapy with Enfortumab Vedotin (EV) in the third line. We have already observed differences across patients with regard to Nectin-4, Trop-2 and HER-2 protein expression and aim to better characterize the spatial distribution and expression of these tumor-associated antigens with the inclusion of target transcripts and the association to treatment benefit from EV."

IO biomarker • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2

IPH4502, a differentiated Nectin-4 exatecan antibody-drug conjugate (AACR 2025) - "Enfortumab vedotin (EV, PADCEV®), an antibody-drug conjugate (ADC) targeting Nectin-4 with a monomethyl auristatin E (MMAE) payload, is approved for the treatment of urothelial cancer (UC), which exhibits the highest Nectin-4 expression among all solid tumor types. The strong internalization and bystander effect of IPH4502 enable an efficient anti-tumor activity in Nectin-4 positive tumor models independent of Nectin-4 expression levels. In addition, IPH4502 shows efficacy in models resistant to EV, indicating that IPH4502 has potential for UC patients relapsing or refractory to EV treatment, as well as for cancer patients treated with MMAE-based ADCs. Finally, IPH4502 shows anti-tumor activity in various preclinical cancer models, including PDX models from different indications, supporting its development beyond UC."

Breast Cancer • Esophageal Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • ABCB1

Enhancing urothelial carcinoma treatment with nectin-4-PET: A predictor of enfortumab vedotin efficacy (AACR 2025) - "[68Ga]AJ647-PET provides a non-invasive quantitative approach to assessing nectin-4 expression and EV-induced pharmacodynamics. Normalized ΔSUV values, which integrate pre- and post-treatment data, serve as reliable predictors of therapeutic efficacy. These findings highlight the potential of nectin-4 PET to optimize personalized EV dosing."

Clinical • Oncology • Solid Tumor • Urothelial Cancer • NECTIN4

Assessment of response and overall survival (OS) for various systemic therapies in ERBB2-altered advanced urothelial carcinoma (aUC) (AACR 2025) - "Based on available data, we hypothesized that ERBB2-altered aUC would respond less favorably to immune checkpoint inhibitor (ICI), enfortumab vedotin (EV), and sacituzumab govitecan (SG) than ERBB2-wildtype aUC. This single-center retrospective study included patients (pts) diagnosed with aUC between 5/6/2016 and 9/23/2022 who underwent panel-based somatic tumor sequencing (120 tissue-based, 9 ctDNA) and received ICI, EV, or SG in first line (1L) or as salvage (2L+). In pts receiving 2L+ ICI, significantly higher ORR and longer OS were noted in pts with ERBB2alt vs ERBB2wt aUC, contrary to our hypothesis; ERBB2alt was also associated with higher ORR to 2L+ EV. Limitations include retrospective design, limited sample size and power for subsets, lack of randomization, selection/confounding biases, and lack of HER2 protein IHC assessment. Results are hypothesis-generating and need external validation.Table 1."

Clinical • IO biomarker • Metastases • Oncology • Solid Tumor • Urothelial Cancer • HER-2

Identification of predictive biomarkers of response to ADCs by HTS of highly molecularly characterized panels of patient-derived organoids (PDOs) (AACR 2025) - "Background: Antibody-drug conjugates (ADCs) such as the HER2-targeting agent trastuzumab deruxtecan, the TROP-2 targeting agent sacituzumab govitecan, and the NECTIN4 targeting agent enfortumab vedotin-ejfv, have resulted in increased clinical response rates in previously difficult to treat solid tumor indications, but only a minority of patients exhibit such responses. The results shown here demonstrate that screening pan indication panels of PDOs can reveal ADC specific differences in efficacy which are rooted in molecular factors that include, but are not limited to target expression. Further analysis is ongoing, including establishing the prevalence of non-ADC target biomarkers in real-world patient populations via the projection of our screen-derived data onto Tempus RWD."

Biomarker • Clinical • Oncology • Solid Tumor • HER-2 • HNF1A • NECTIN4 • VIL1

Organoids and immune cells co-culture for evaluating the efficacy of enfortumab vedotin and pembrolizumab combination therapy. (AACR 2025) - "Notably, this study highlighted a critical finding: while the combination has shown superiority over current treatment options, it does not overcome resistance to EV. Overall, this co-culture system is highly adaptable to other immunotherapeutic agents and presents a valuable tool for developing novel therapies, particularly in addressing resistance to EV."

Combination therapy • Immune cell • IO biomarker • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • NECTIN4

Combination therapy with TB511 and anti-nectin-4 antibody drug conjugate in a human pancreatic cancer mouse model (AACR 2025) - "As a result, TB511, PADCEV, and their combination significantly reduced tumor growth and Ki67 expression. No significant off-target effects were observed in the spleen, liver, lung, or brain. In conclusion, combination therapy with TB511 and ADC effectively suppresses pancreatic tumor growth and reprograms the immune microenvironment by decreasing M2 macrophages and enhancing cytotoxic T and NK cell responses, offering a promising strategy for pancreatic cancer treatment."

Combination therapy • IO biomarker • Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • CD163 • CD8 • CDH1 • FOXP3 • GZMB • IFNG • ITGAM • ITGB2 • LAG3 • VIM

Pre-operative abemaciclib in localized cisplatin-ineligible MIBC with tissue and ctDNA molecular response validation (CLONEVO) (AACR 2025) - P1 | "Background: Up to 40% of patients with muscle-invasive bladder cancer (MIBC) are ineligible to receive standard-of-care neoadjuvant cisplatin-based chemotherapy, creating a significant unmet need for effective neoadjuvant therapies. This first trial of short-term pre-operative abema in MIBC demonstrated favorable efficacy and tolerability while modulating cell cycle-dependent pathways, including DSB repair. Our findings support future trials investigating sequential therapy combining abema with antibody-drug conjugates such as enfortumab vedotin, where abema's effects on DSB repair enhance treatment responses."

Circulating tumor DNA • Bladder Cancer • Oncology • CCNA2 • CCND1 • MKI67 • PCNA • RAD51 • TOPBP1