Vicineum (oportuzumab monatox)

In particular, enfortumab-vedotin (EV) has shown promising results with a recent cohort of a clinical trial demonstrating that EV is effective as neoadjuvant monotherapy as well as in combination with pembrolizumab in metastatic setting. Similar promising results have been shown by other classes of ADC in other trials including sacituzumab-govitecan (SG) and oportuzumab monatox (OM). ADCs are likely to become a mainstay treatment option in the urothelial carcinoma playbook as either a monotherapy or combination therapy. The cost of the drug presents a real challenge, but further trial data may justify the use of the drug as mainstay treatment.

The anti-Nectin-4 ADC enfortumab vedotin has demonstrated efficacy in prospective studies in patients with advanced urothelial carcinoma in several settings either alone or in combination with pembrolizumab...Common adverse events include rash and neuropathy for enfortumab vedotin and myelosuppression and diarrhea for sacituzumab govitecan. Several anti-human epidermal growth factor receptor 2 ADCs are in clinical trials, and in localized bladder cancer, the anti-epithelial cell adhesion molecule ADC oportuzumab monatox is being studied in patients refractory to intravesical bacillus calmette-guerin therapy. Antibody-drug conjugates for urothelial carcinoma are approved and emerging as therapies for patients with advanced urothelial carcinoma, filling a prior void for treatment of progressive disease. Ongoing studies are also evaluating these agents in the neoadjuvant and adjuvant settings.

P1, N=14, Completed, National Cancer Institute (NCI) | Recruiting --> Completed | N=40 --> 14 | Trial completion date: Dec 2024 --> Oct 2022 | Trial primary completion date: Aug 2024 --> Aug 2022

The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC...However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

P1, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

Clinical trial landscape evaluation for emerging therapies was performed by searching ClinicalTrials.gov for recruiting/ open interventional trials in 2020.  Novel treatment modalities for BCG failure include intravesical chemotherapy, BCG re-challenge or combination of BCG with IFN-α2β, valrubicin, radiotherapy, electromotive drug administration, vicinium, chemohyperthermia, photodynamic therapy, gene therapy, vaccine therapy and immunotherapy...However, after 2 or more BCG failures, especially in patients with earlier relapses or cancer persistence, single agent intravesical chemotherapy with valrubicin, gemcitabine or docetaxel appears to be less active than doublet/triplet intravesical chemotherapy or mitomycin chemothermotherapy. Gene therapy or conjugated antibodies may play a role upon further relapse. Single agent pembrolizumab is unlikely to be used as first line, but may be useful, along with multiple new immunotherapeutics, as part of a multimodal approach towards BCG unresponsive disease.  Results from ongoing trials will provide us useful information about many of the existing regimens and probably new drugs will soon be available for this group of patients.

The combination of Vicinium and Durvalumab is safe and well tolerated and has thus far a 12-week response rate of ~40%, with a prolonged (>12mo) effect in some patients with high risk NMIBC who have failed BCG treatment.

P1, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Aug 2022 --> Aug 2023

Patients included 6 (37%) high-risk non-muscle-invasive bladder cancer (NMIBC) patients who had progressed on BCG and enrolled on a trial of vicineum with durvalumab, as well as 10 (63%) muscle-invasive bladder cancer (MIBC) patients (6 pre- and 4 post-cystectomy)... Digital pathology and subtype assignment of CTCs is relevant in localized bladder cancer. Here, the “bad cell” signature seemed to identify MIBC patients who were locally advanced at cystectomy, though it was not useful in NMIBC patients. CTC heterogeneity was associated with worse PFS and was consistent across replicate time points.