Padcev (enfortumab vedotin-ejfv)

Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

Since the FDA's approval of Enfortumab Vedotin and Sacituzumab Govitecan, the therapeutic landscape has expanded, heralding a shift towards antibody-drug conjugates as potential first-line therapies. These findings affirm the increasing significance of antibody-drug conjugates in urothelial carcinoma treatment, transitioning them from posterior-line to frontline therapies. Future research is poised to focus on new therapeutic targets, combination therapy optimization, treatment personalization, exploration of double antibody-coupled drugs, and strategies to overcome drug resistance.

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer...Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells...The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

Studies to date have shown that patients with high levels of the protein NECTIN4 on their cancer cells respond well to EV. This information has the potential to guide future treatment strategies for mUC.

PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

In 2019, the Food and Drug Administration approved enfortumab vedotin, the first antibody-drug conjugate targeting Nectin-4, for the treatment of urothelial carcinoma...However, the exact mechanisms by which Nectin-4 affects tumorigenesis and progression are still unclear, and the emergence of drug resistance and treatment-related adverse reactions poses challenges. This article reviews the diagnostic potential, prognostic significance, and molecular role of Nectin-4 in tumors, with a focus on clinical trials in the field of Nectin-4-related tumor treatment and the development of new drugs targeting Nectin-4.

P2, N=32, Not yet recruiting, University of Michigan Rogel Cancer Center

However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin...However, the recent combination of enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials...Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies.

P1, N=30, Recruiting, ALX Oncology Inc. | Trial primary completion date: Jan 2024 --> Dec 2024

P2, N=500, Not yet recruiting, National Cancer Institute (NCI)

Our findings suggest that AR is the promising target for UTUC treatment, especially in PD-L1-negative cases.

EV prolonged OS in mUC following pembrolizumab therapy in real-world data.

P1/2, N=390, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=21, Not yet recruiting, Jonsson Comprehensive Cancer Center | Initiation date: Jan 2024 --> Jun 2024

P2, N=20, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2027

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

Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.

For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression...Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

I-EV was successfully prepared with high specificity and binding affinity of Nectin-4. This radioactive probe completely simulates the internal circulation of ADC drugs and tumour uptake and retention, which will greatly improve the clinical application of ADC therapy.

P2, N=28, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

The survival time of advanced urothelial carcinoma has been significantly prolonged (or 'doubled' from 1 to 2 years) after the advent of pembrolizumab, which will be further improved with novel agents such as avelumab and enfortumab vedotin. This review summarizes the latest evidence on clinical outcomes and prognostic factors of advanced urothelial carcinoma in the contemporary era of immune checkpoint inhibitors.

P2, N=23, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

SYS6002 (CRB-701) is a next generation Nectin-4 ADC that makes use of third-generation conjugation technology designed to overcome dose-limiting toxicities observed with the commonly approved linker-payload system involved in agents like enfortumab vedotin (EV). SYS6002 (CRB-701) was well tolerated in escalation, and relative to EV demonstrates early signs of a differentiated safety and PK (longer half-life and lower free-MMAE) profile. Continued development of SYS6002 (CRB-701) as both a monotherapy and in combination are planned. Clinical trial information: SYS6002-001.

Of 96 (45%) pts who received 2L treatment post avelumab 1LM, enfortumab vedotin (EV) monotherapy (55%) was most common, followed by carboplatin-based therapy (11%). Of 40 (42%) pts who received 3L treatment, EV monotherapy was most common (25%), followed by sacituzumab govitecan (20%)... Clinical outcomes in this study are aligned with those of the JAVELIN Bladder 100 trial (NCT02603432), further supporting avelumab 1LM as a standard of care. With each additional line of therapy, substantial treatment attrition and less favorable clinical outcomes were observed. This study provides insights into the sequencing of treatments and management of pts with la/mUC after disease progression with avelumab 1LM in this rapidly evolving therapeutic landscape.

In this group, 43 pts received ICI [38 (88%) pembrolizumab; 5 (12%) atezolizumab] and 37 EV [31 (82%) monotherapy; 6 (18%) combination regimen]. In this single institution retrospective analysis, pts with aUC and HER2-high IHC expression had longer PFS relative to pts with HER2-negative expression when treated with EV-based regimens. No differences were observed in ICI outcomes based on HER2 expression. These hypothesis-generating results should be validated in larger cohorts.

Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153.

According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer (v3.2023), platinum-based chemotherapy (PBC) followed by avelumab maintenance therapy (maintA, only if there is no progression on first-line [1L] PBC), pembrolizumab (P, for platinum-ineligible), and P in combination with enfortumab vedotin (P+EV, for cisplatin-ineligible) are the preferred regimens. Despite many recent advances in the therapy for mUC, these patients had poor prognosis. Notably, many 1L patients did not have the opportunities to receive 2L+ treatment, which demonstrated continuing unmet need for mUC patients. ICI monotherapy continues to be a prevalent option, especially for older patients.

Most patients (71%) received enfortumab vedotin (EV) in the direct prior line. This study is the largest analysis of SG use in a real-world population with LA/mUC to date; it provides insights into the safety of SG in this setting. Compared with prior data, this real-world population was older, with poorer functionality, and the majority received EV in the direct prior line. Observed AEs were consistent with the known safety profile of SG and indicate that this sequencing is feasible.

We showed longersurvival in pts with FGFR2/3 alt aUC who received both EV and E regardless of sequence, which may reflect guarantee-time bias. Additional limitations include retrospective nature, modest sample size, no central scan review, lack of data for pts who received E only, selection and confounding biases. Larger prospective studies are needed to determine optimal sequencing and putative biomarkers.

Our study highlights the value of NECTIN4 amplifications to predict EV responses in patients with mUC. NECTIN4 amplifications occur frequently in different cancer types and therefore have the potential to be a novel tumor-agnostic genomic biomarker that enables tailored NECTIN4-targeted therapies in various entities.

Enfortumab vedotin, an antibody‑drug conjugate targeting PVRL4, is clinically used for the treatment of urothelial bladder cancer...Furthermore, RNA‑seq analysis using breast cancer cells treated with PVRL4 small interfering RNA revealed its possible involvement in the cytokine response and immune system. These data suggested that FOS was involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate the response of cancer cells to cytokines and the immune system.

In chRCC a small subset of tumors expresses Nectin-4 potentially amenable to Nectin-4 directed treatment. Expression of Nectin-4 is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.

Novel targets and drugs such as antibody drug conjugates have been developed, and enfortumab vedotin targeting nectin-4 and sacituzumab govitecan (SG) targeting trophoblast cell surface antigen 2 (TROP-2), the protein product of the TACSTD2 gene, have been approved. Given the treatment response based on the expression level of TROP-2, SG would be effective in almost all cases of UC. However, it would also have an effect on the normal urothelium.

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

P2, N=25, Recruiting, Emory University | Not yet recruiting --> Recruiting

Enfortumab vedotin (EV) gained Food and Drug Administration approval for advanced UC treatment, but patient selection based on NECTIN-4 expression remains challenging...In summary, the study from Duan and colleagues introduces a promising molecular imaging technique that could aid in patient selection for EV therapy and the development of targeted drugs for UC. It also highlights the potential of LAFOV PET/CT in enhancing imaging precision and expanding future therapeutic possibilities for UC.

P3, N=784, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting