China’s NMPA Grants Breakthrough Therapy Designation to 9MW2821 in Advanced Urothelial Cancer

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China’s National Medical Products Administration (NMPA)’s Center for Drug Evaluation has granted breakthrough therapy designation to the novel Nectin-4–directed antibody-drug conjugate (ADC) 9MW2821 for the treatment of patients with locally advanced or metastatic urothelial carcinoma that has failed prior platinum-based chemotherapy and PD-1/PD-L1 inhibition.¹ 

The designation is one of many for Mabwell’s first site-specific conjugated novel Nectin-4–directed ADC. In 2024, 9MW2821 also received fast track designation from the FDA for the treatment of patients with 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 as well as breakthrough therapy designation from China’s NMPA.

The agent is also the first of the Nectin-4-directed ADCs developed by Chinese companies to enter clinical study and the first investigational agent targeting Nectin-4 to demonstrate antitumor activity in cervical cancer, esophageal cancer, and breast cancer.

9MW2821 is designed to provide site-specific modification of the antibody through proprietary conjugation technology linkers and an optimized ADC conjugation process. After injection, 9MW2821 binds to Nectin-4 on the cell membrane surface before permeating the cell, resulting in cytotoxic drug release and cell death.

Updated findings from the phase 1/2a dose-escalation and -expansion trial (NCT05216965) evaluating the agent in patients with advanced solid tumors were presented at the 2024 ASCO Annual Meeting.² To be eligible for the study patients had to be between the ages of 18 and 80 and have received a diagnosis of a locally advanced or metastatic solid tumor. Other parameters for enrollment included an ECOG performance status of 0 or 1, adequate organ function, and no uncontrolled diabetes, active central nervous system metastases, or severe corneal diseases.

Per the study design 9MW2821 was given as an intravenous infusion in escalating doses of 0.33 mg/kg, 1.0 mg/kg, 1.25 mg/kg, and 1.5 mg/kg on days 1, 8 and 15 of each 28-day cycle. 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. One of 6 patients in 1.5-mg/kg group had a dose-limiting toxicity of grade 4 neutropenia that lasted more than 5 days. 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.

Of the 240 patients who were enrolled at the RP2D level and were evaluable for response, 37 had urothelial cancer, 53 had cervical cancer, 39 had esophageal cancer, and 20 had TNBC. The median number of prior lines of therapy was 2 (range, 1-4). Notably, all patients with urothelial carcinoma, 95% of those with esophageal cancer, and 58% of those with cervical cancer had progressed after platinum-based chemotherapy and checkpoint inhibitors.

A total of 190 patients who had received 9MW2821 at 1.25 mg/kg or above and reached tumor assessment were evaluated for response. In this population the objective response rate (ORR) was 35.3% and the disease control rate (DCR) was 78.4%.

At a median follow-up of 10.9 months in the urothelial carcinoma cohort, the ORR was 62.2% (95% CI, 44.76%-77.54%) and the DCR 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 [NR]) and 14.2 months (95% CI, 10.90-NR), respectively.

Regarding safety in the overall population the most common all grade and grade 3 or greater treatment-related adverse effects (TRAEs) that occurred in at least 20% and at least 5% of patients, respectively, in this dose level were decreased white blood cell count (50.8%; 23.3%), decreased neutrophil count (46.3%; 27.9%), anemia (43.8%; 8.3%), increased aspartate aminotransferase (42.1%; 2.9%), increased alanine aminotransferase (35.4%; 2.1%), asthenia (32.1%; 2.9%), rash (30.0%; 5.0%), decreased appetite (28.8%; 1.3%), nausea (26.7%; 0%), hyperglycemia (25.4%; 2.1%), decreased platelet count (24.2%; 4.6%), alopecia (24.2%; 0%), hypoesthesia (22.5%; 1.7%), constipation (21.3%; 0%), vomiting (20.9%; 1.3%), hypertriglyceridemia (20.4%; 2.1%), and increased gamma-glutamyl transferase (15.8%; 5.4%).

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.

References

1. Mabwell’s novel nectin-4 targeting ADC 9MW2821 granted breakthrough therapy designation by China’s NMPA. News release. Mabwell. August 12, 2024. Accessed August 12, 2024. https://www.prnewswire.com/news-releases/mabwells-novel-nectin-4-targeting-adc-9mw2821-granted-breakthrough-therapy-designation-by-chinas-nmpa-302219866.html
2. Zhang J, Liu R, Gao S, et al. 9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: results from a phase 1/2a study. J Clin Oncol. 2024;42(suppl 16):3013. doi:10.1200/JCO.2024.42.16_sup