Editor's Note: Nectin-4 has emerged as a highly expressed adhesion molecule in various solid tumors, becoming a popular target in recent research. 9MW2821, developed using an internationally leading ADC development platform and automated high-throughput hybridoma antibody discovery platform, is a novel ADC drug targeting Nectin-4. Its Investigational New Drug (IND) application has received approval from the FDA. Currently, 9MW2821 is undergoing clinical trials for multiple indications, including urothelial carcinoma (UC), cervical cancer (CC), esophageal cancer (EC), and has shown promising therapeutic effects. At the 2024 ASCO meeting, the team from Fudan University Cancer Hospital reported the results of a phase 1/2a study of 9MW2821 in patients with advanced solid tumors, presenting the latest safety and efficacy data in UC, CC, EC, and triple-negative breast cancer (TNBC). "Oncology Frontier" interviewed Professor Jian Zhang from Fudan University Shanghai Cancer Center to discuss the latest progress of 9MW2821, summarized as follows.Study Overview
Phase 1/2a Study Results of the First Nectin-4 Targeting ADC Drug 9MW2821 in Patients with Advanced Solid Tumors
9MW2821 is a monoclonal antibody-drug conjugate (ADC) that delivers monomethyl auristatin E to cells expressing Nectin-4, a highly expressed adhesion molecule in various solid tumors, especially UC, CC, EC, and breast cancer. At ASCO 2024, the team from Fudan University Cancer Hospital reported the latest safety and efficacy data of 9MW2821.
The study included patients aged 18-80 with locally advanced or metastatic solid tumors, ECOG performance status of 0-1, good organ function, no uncontrolled diabetes, no active CNS metastases, and no severe corneal diseases. 9MW2821 was administered intravenously at doses ranging from 0.33 to 1.5 mg/kg on days 1, 8, and 15 of each 28-day cycle. The study included dose-escalation, “3+3+3” dose-expansion, and cohort expansion phases, involving UC, CC, EC, TNBC, and other Nectin-4-positive solid tumors that progressed after ≥1 systemic therapy. The primary objectives were to evaluate safety, preliminary antitumor activity, and pharmacokinetics.
Results: As of April 1, 2024, 260 patients were enrolled, with doses ranging from 0.33 to 1.5 mg/kg. In the 1.5 mg/kg group, only 1 of 6 patients experienced dose-limiting toxicity (DLT) (grade 4 neutropenia lasting more than 5 days). The maximum tolerated dose (MTD) was not reached at 1.5 mg/kg, and for tolerability considerations, the recommended phase 2 dose (RP2D) was chosen as 1.25 mg/kg. A total of 240 patients were enrolled at the 1.25 mg/kg dose. The most common treatment-related adverse events (TRAEs) (≥20%, all grades/≥5%, ≥G3) at 1.25 mg/kg included decreased WBC count (50.8%, 23.3%), decreased neutrophil count (46.3%, 27.9%), anemia (43.8%, 8.3%), elevated AST (42.1%, 2.9%), elevated ALT (35.4%, 2.1%), fatigue (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%), sensory neuropathy (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), and elevated GGT (15.8%, 5.4%).
For efficacy, 37 UC patients, 53 CC patients, 39 EC patients, and 20 TNBC patients were evaluated at the 1.25 mg/kg dose. 9MW2821 showed good efficacy in UC patients, with an objective response rate (ORR) and disease control rate (DCR) of 62.2% and 91.9%, respectively, surpassing enfortumab vedotin (EV). This superior performance is attributed to 9MW2821’s uniform and novel linker chemistry, enhancing conjugate stability in systemic circulation for efficient drug delivery. The ORR in the CC Nectin-4 3+ treatment group was 43.6%; in the EC group, the ORR and DCR were 23.1% and 69.2%, respectively; in the TNBC group, the ORR and DCR were 50.0% and 80.0%, respectively. All UC patients, 51% of CC patients, and 93% of EC patients had progressed after platinum-based chemotherapy and immune checkpoint inhibitors. Objective responses were also observed in other solid tumor types.
In summary, the data indicate that 9MW2821 demonstrates encouraging efficacy in advanced UC, CC, EC, and TNBC. 9MW2821 is the first ADC targeting Nectin-4, showing antitumor activity in CC, EC, and TNBC, with a safety profile demonstrating adequate tolerability.
Researcher’s Commentary
Oncology Frontier: Could you briefly introduce the mechanism of action of 9MW2821 as an ADC targeting Nectin-4 in the treatment of advanced solid tumors?
Professor Jian Zhang: 9MW2821 is a novel ADC targeting Nectin-4. In previous academic exchanges and conference reports, including at ESMO, we have detailed this drug. 9MW2821 has shown good efficacy not only in traditional UC treatment but also in large-scale exploratory studies for CC, EC, and TNBC. These results are very encouraging, suggesting that the Nectin-4 target has potential value in treating various tumor types.
Oncology Frontier: In this study, the maximum tolerated dose (MTD) of 9MW2821 was not reached at 1.5 mg/kg. Why was the recommended clinical dose set at 1.25 mg/kg, and what considerations led to this choice?
Professor Jian Zhang: The dosing regimen for Nectin-4 targeting drugs typically involves administration on days 1, 8, and 15 of a 28-day cycle. In the initial exploration phase of 9MW2821, we followed this regimen. During dose escalation, starting at 0.33 mg/kg and increasing to 1.5 mg/kg, we observed a dose-limiting toxicity (DLT) event at 1.5 mg/kg in 1 of 6 patients, specifically grade 4 neutropenia lasting more than 5 days.
Considering overall patient safety, efficacy (similar to the 1.5 mg/kg group), and pharmacokinetics, we chose 1.25 mg/kg as the recommended clinical dose based on a comprehensive assessment. This dose proved effective, with manageable toxicity.
Oncology Frontier: Can you share some of the most common treatment-related adverse events (TRAEs) observed with 9MW2821 and their incidence rates?
Professor Jian Zhang: The toxicities of Nectin-4 targeting drugs are partly related to the target itself but also closely linked to the overall drug platform. In the recent data on nearly 260 patients treated with 9MW2821, the safety profile was generally manageable. The most common adverse events were reductions in WBC and neutrophil counts, occurring in nearly 50% of patients, with about 25% experiencing grade 3-4 adverse events. However, most of these adverse events were effectively managed with G-CSF (granulocyte colony-stimulating factor) and our newly introduced management protocols. Other common adverse events included anemia and liver function abnormalities, primarily grade 1-2, with grade 3-4 liver function abnormalities occurring in only about 2% of patients. Overall, the safety profile of this drug is manageable. We paid particular attention to ocular toxicity and peripheral neuropathy during treatment, but these adverse reactions were relatively low. Therefore, this drug has the potential to achieve “better in class” or even “best in class” status.
Oncology Frontier: Looking ahead, how does your team plan to further explore the efficacy and safety of 9MW2821 in more types of advanced solid tumors? Are there plans for larger clinical trials or studies combining 9MW2821 with other treatments?
Professor Jian Zhang: We have already achieved some success with 9MW2821 in UC treatment and have initiated phase III clinical research, led by Professor Dingwei Ye from our hospital’s Urology Department. Additionally, we are conducting in-depth research on CC and EC. Notably, our drug has the potential for breakthrough designation from the FDA in both China and the US.
In TNBC research, we have also obtained encouraging data. In about 16 patients, the overall response rate was around 44%, with a progression-free survival (PFS) of about 5-6 months. For patients who have undergone multiple lines of treatment, these results are very promising. Compared to similar drugs like EV, 9MW2821 shows more significant advantages in treating TNBC. We believe this drug is worth further exploration and are actively designing and working towards this goal.
References: [1] Jian Zhang, et al. 9MW2821, a Nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumors: Results from a phase 1/2a study. ASCO 2024. Abstract 3013
