Patients with advanced urothelial cancer have a low overall survival rate after receiving platinum-containing chemotherapy and PD-1/PD-L1 immunotherapy. Recently, the European Medicines Agency's Committee on Human Medicines (CHMP) has confirmed its recommendation to approve the antibody-coupled compound (ADC) Padcev monotherapy for adult patients with locally advanced or metastatic urothelial carcinoma who have previously received platinum chemotherapy and immunotherapy.
Introduction to Padcev new drugs
Padcev is a first-in-class antibody drug coupling (ADC) that targets a cell surface protein highly expressed in bladder cancer. The drug is composed of enfortumab, a human IgG1 monoclonal antibody targeting connectin-4 (Nectin-4), coupled with the cytotoxic agent MMAE (monomethyl auristatin E, monomethyl auristatin E, a microtubule disruptor). Nectin-4 is a highly expressed therapeutic target in a variety of solid tumors, including urothelial carcinoma. In December 2019, Padcev received accelerated approval from the U.S. FDA for the treatment of patients with locally advanced or metastatic urothelial cancer.
Product name: Padcev
Drug name: Enfortumab vedotin
Manufacturer: Astellas Pharma
Padcev Clinical Trial Overview
In December 2021, CHMP held a positive opinion on the application of the drug in this indication and submitted its recommendation to the European Commission (EC) for review. The initial recommendation was based on data from the phase 3 EV-301 trial (NCT03474107). EV-301 recruited patients with urothelial carcinoma confirmed by histology or cytology, the baseline is a metastatic or non-resectable locally advanced disease recorded by radiology, they are at least 18 years old, ECOG manifestations are 0 or 1, and appear during or after treatment with PD-1 or PD-L1 inhibitors.Through radiology, the disease progresses or relapses. All patients need to have previously received platinum-containing chemotherapy regimen.
If the patient has previously had Grade 2 or higher sensory or motor neuropathy, or has experienced sustained clinically significant toxic reactions associated with previous treatment, active central nervous system metastasis, uncontrolled diabetes, active keratitis, or corneal ulcers, they will be excluded. If the patient has received more than one chemotherapy regimen due to locally advanced or metastatic disease before, they are also excluded.
Participants were randomized 1:1 to receive either intravenous (IV) Padcev at days 1, 8, and 15 of a 28-day treatment cycle (n = 301) or chemotherapy (n = 307) at a body weight of 1.25 mg/kg. According to International Medical, the control group received investigator-selected chemotherapy, which may include any of the following: intravenous docetaxel at a body surface area of 75 mg/m² (n = 117), intravenous paclitaxel at 175 mg/m² (n = 112), or intravenous ethephon at 320 mg/m² (n = 78). Chemotherapy drugs were administered on day 1 of each 21-day cycle.
Patients were stratified based on ECOG performance status (0 vs. 1), geographic area (Western Europe, the United States, or other parts of the world), and baseline liver metastasis (presence or absence). The baseline characteristics of the two groups are very balanced. The median age of participants was 68 years old (in the range of 30-88 years old), and 77.3% were male. In addition, 77.7% and 81.7% of patients in the survey group and the control group suffered from visceral diseases, respectively. In each group, the number of patients with liver metastasis was the same.
The main endpoint of the trial is OS, and the main secondary endpoints include the clinical response of the PFS and RECIST v1.1 standards evaluated by the researchers, as well as safety. With July 15, 2020 as the data deadline, the median treatment time in the study group was 5.0 months (range of 0.5-19.4), and the control group was 3.5 months (range of 0.2-15.0).
Padcev latest treatment results
The trial demonstrated that Padcev, compared with investigator-selected chemotherapy, improved overall survival by 12.88 months (95% CI, 10.58–15.21) and 8.97 months (95% CI, 8.05–10.74), respectively (HR, 0.70; 95% CI, 0.56–0.89; P = 0.001), with a median follow-up of 11.1 months. Compared with chemotherapy, ADC also prolonged progression-free survival (PFS) by 5.55 months (95% CI, 5.32–5.82) and 3.71 months (95% CI, 3.52–3.94), respectively, which translates to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.51–0.75; P < 0.001).
Other data show that the proportion of patients in the study group estimated to survive within one year is 51.5% (95% CI, 44.6%-58.0%), and the control group is 39.2% (95% CI, 32.6%-45.6%). In most patient subgroups evaluated by EV-301, the OS and PFS benefits achieved by Padcev were noted.
The confirmed objective response rate (ORR) induced by Padcev was 40.6% (95% CI, 34.9%–46.5%), compared to 17.9% (95% CI, 13.7%–22.8%) with chemotherapy (P < .001). Subgroup analysis results were consistent with those observed in the primary analysis of the trial. Complete response (CR) rates were 4.9% in the study group and 2.7% in the control group. Among patients achieving CR or partial response, the median time to response was 7.39 months in the study group and 8.11 months in the control group. Furthermore, the disease control rate (DCR) induced by ADC therapy was 71.9% (95% CI, 66.3%–77.0%), compared to 53.4% (95% CI, 47.5%–59.2%) with chemotherapy (P < .001).
Treatment-related toxicities were reported in 93.9% of patients receiving Padcev, compared to 91.8% of those receiving chemotherapy. These reactions were grade 3 or higher in 51.4% and 49.8% of patients, respectively. The most common treatment-related adverse events (TRAEs) with Padcev included maculopapular rash (7.4%), fatigue (6.4%), and neutropenia (6.1%). During chemotherapy, the most common TRAEs included neutropenia (13.4%), anemia (7.6%), decreased white blood cell count (6.9%), neutropenia (6.2%), and febrile neutropenia (5.5%).
In the study group, 32.4% of patients had a dose reduction due to TRAEs, 51.0% of patients had treatment interruption due to TRAEs, and 13.5% of patients had treatment suspension. In the chemotherapy group, 27.5% of patients had TRAEs that led to dose reduction, 18.9% of patients had effects that led to treatment interruption, and 11.3% of patients had effects that led to withdrawal.
Skin reactions and peripheral neuropathy are the most common TRAEs of Padcev. In addition, 43.9% of patients in the study group had treatment-related rashes, while only 9.6% of patients in the control group had treatment-related rashes. In the study group and the control group, 46.3% and 30.6% of patients had treatment-related peripheral neuropathy, respectively; 6.4% and 0.3% of patients had treatment-related hyperglycemia, respectively.
Reminder: Compared with standard chemotherapy, Padcev significantly prolongs the survival of patients with locally advanced or metastatic urothelial cancer who have received platinum therapy and PD-1 or PD-L1 inhibitors.
