Mabwell and Astellas Pharma have recently achieved significant milestones in the treatment of urothelial carcinoma in China. Mabwell's novel Nectin-4 targeting antibody-drug conjugate (ADC), 9MW2821, has been granted Breakthrough Therapy Designation (BTD) by China's National Medical Products Administration (NMPA). Simultaneously, Astellas' PADCEV™ (enfortumab vedotin) has been approved for treating locally advanced or metastatic urothelial cancer (la/mUC) in adult patients who have previously undergone platinum-based chemotherapy and PD-1/PD-L1 inhibitors. These developments offer new hope for patients with limited treatment options.
Mabwell's 9MW2821: A Novel Nectin-4 Targeting ADC
Mabwell's 9MW2821 is the first site-specific conjugated novel Nectin-4 targeting ADC developed by the company, marking it as the first drug candidate among Chinese companies to enter clinical studies targeting Nectin-4. The BTD from China's NMPA is for the treatment of locally advanced or metastatic urothelial carcinoma that has failed previous platinum-based chemotherapy and PD-(L)1 inhibitor therapy. This designation aims to expedite the development of drug candidates that have demonstrated significant efficacy or safety advantages in early clinical trials.
The agent has also received fast track designation from the FDA for advanced, recurrent, or metastatic esophageal squamous cell carcinoma, recurrent or metastatic cervical cancer that has progressed on or following prior treatment with a platinum-based chemotherapy regimen, and locally advanced or metastatic Nectin-4 positive triple-negative breast cancer (TNBC). 9MW2821 has also received orphan drug designation from the FDA for the treatment of patients with esophageal cancer.
Clinical Efficacy of 9MW2821
Updated findings from the phase 1/2a dose-escalation and -expansion trial (NCT05216965) evaluating 9MW2821 in patients with advanced solid tumors were presented at the 2024 ASCO Annual Meeting. The study included patients with urothelial cancer, cervical cancer, esophageal cancer, TNBC, and other Nectin-4–positive solid tumors that progressed after at least 1 line of systemic therapy.
As of April 1, 2024, 260 patients had been enrolled. The maximum-tolerated dose was not reached, and 1.25 mg/kg was selected as the recommended phase 2 dose (RP2D) for tolerability. A total of 240 patients were enrolled at the RP2D level.
Among the 240 patients enrolled at the RP2D level, 37 had urothelial cancer. All patients with urothelial carcinoma had progressed after platinum-based chemotherapy and checkpoint inhibitors.
At a median follow-up of 10.9 months in the urothelial carcinoma cohort, the objective response rate was 62.2% (95% CI, 44.76%-77.54%) and the disease control rate was 91.9% (95% CI, 78.09%-98.30%). The median progression-free survival and overall survival were 8.8 months (95% CI, 3.81-not reached) and 14.2 months (95% CI, 10.90-NR), respectively.
A confirmatory phase 3 trial (NCT06196736) evaluating single-agent 9MW2821 is ongoing in which and chemotherapy will serve as the active comparator in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.
Astellas' PADCEV™ (enfortumab vedotin) Approved in China
Astellas Pharma Inc. announced that China's NMPA has approved PADCEV™ (enfortumab vedotin) for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) after prior treatment with platinum-containing chemotherapy and programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors. This approval is based on data from the global EV-301 and China EV-203 trials.
The EV-203 trial, a Phase 2 study in Chinese patients, demonstrated a statistically significant objective response rate (ORR) of 37.5% (95% CI: 22.7–54.2) in patients treated with enfortumab vedotin alone, compared to historical controls. The EV-301 trial, a Phase 3 randomized trial, showed that enfortumab vedotin significantly improved overall survival (OS) compared to chemotherapy (12.88 vs. 8.97 months; HR=0.70; p=0.001).
Implications for Urothelial Cancer Treatment
These regulatory advancements signify a crucial step forward in addressing the unmet needs of urothelial cancer patients in China. With both 9MW2821 and enfortumab vedotin demonstrating promising clinical efficacy and safety profiles, healthcare professionals now have additional tools to combat this aggressive disease. The ongoing Phase 3 trials will further elucidate the potential of these therapies in improving patient outcomes.
