2025 ASCO Highlights: Breakthroughs in Chinese ADCs, Bispecific/Trispecific Antibodies, and Small Molecule Innovations"

Domestic ADCs Shine on the International Stage

Domestic ADCs have begun to enter a harvesting period. Currently, two domestic ADCs have been approved and marketed in China: Lucentisatozumab vedotin (Kelun-Botai) and Vedicituzumab (Rongchang Bio). In addition, Lepu Biopharma’s Vibecotuzumab, Hengrui’s Ruikang Trastuzumab, and Kelun’s Bodu Trastuzumab have also been submitted for approval.

This year at ASCO, the latest research results of these products were released. Notably, phase II clinical data of Lucentisatozumab vedotin treating advanced EGFR-mutated NSCLC, Ruikang Trastuzumab treating salivary gland carcinoma phase II data, Vedicituzumab as first-line treatment for gastric cancer phase II data, and Vibecotuzumab for nasopharyngeal carcinoma phase IIb data were selected for oral presentations. The latter two were also LBA reports.

OptiTROP-Lung03 is a randomized, multicenter, parallel-group, open-label phase II clinical trial. A total of 137 patients with advanced EGFR-mutated NSCLC who progressed after EGFR-tyrosine kinase inhibitor (TKI) therapy and platinum chemotherapy were enrolled and randomized 2:1 to receive Lucentisatozumab vedotin or docetaxel. Median follow-up was 12.2 months (data cutoff December 31, 2024).

Results showed that compared to docetaxel, Lucentisatozumab vedotin achieved statistically significant and clinically meaningful improvements in efficacy: BIRC-assessed confirmed objective response rate (cORR) was 45.1% vs. 15.6% (one-sided p=0.0004); BIRC-assessed median progression-free survival (mPFS) was 6.9 months vs. 2.8 months (HR=0.30, one-sided p<0.0001); investigator-assessed mPFS was 7.9 months vs. 2.8 months (HR=0.23).

Due to 36.4% of patients in the docetaxel group crossing over to Lucentisatozumab vedotin, median overall survival (OS) was not reached in either group. Adjusted median OS by the rank-preserving structural failure time (RPSFT) model was 9.3 months for the docetaxel group and not reached for the Lucentisatozumab vedotin group (HR=0.36).

Regarding safety, grade ≥3 treatment-related adverse events (TRAEs) occurred in 56.0% and 71.7% of patients in the Lucentisatozumab vedotin and docetaxel groups, respectively. No interstitial lung disease (ILD) was reported in the Lucentisatozumab vedotin group.

This is a single-center, open-label phase II clinical trial. Advanced SGC patients were divided into four groups based on genetic subtypes; this analysis focused on group 1 (HER2 overexpression: IHC 3+ or IHC 2+/ISH+) and group 4 (HER2 low expression: IHC 1+ or IHC 2+/ISH-).

33 patients were enrolled. The ORR in group 1 (21 evaluable patients) was 85.7%, with a disease control rate (DCR) of 100%. Group 4 (10 evaluable patients) had an ORR of 30.0%, and DCR was 100%. After median follow-up of 9.9 months (group 1) and 6.0 months (group 4), median OS and PFS were not reached. Only one patient in group 4 experienced disease progression.

Regarding safety, 32 patients (97%) experienced TRAEs. The most common grade 3/4 TRAEs were neutropenia (36%), leukopenia (15%), anemia (12%), and lymphocytopenia (12%). Two patients had treatment-related serious adverse events (SAEs), and one patient had grade 1 ILD. No treatment discontinuation or treatment-related deaths occurred.

Additionally, Maiwei Biotech presented Ib/II phase data of Nectin-4 ADC 9MW2821 for urothelial carcinoma as an oral report. Fuhong Hanlin disclosed advanced solid tumor clinical data of HLX-43 (PDL1 ADC) for the first time, and Innovent released phase I clinical data of IBI343 (CLDN18.2 ADC) for pancreatic cancer.

Bispecific and Trispecific Antibodies Take the Stage One After Another

From innovative target combinations and molecular structure optimization to differentiated clinical layouts, domestic bispecific and trispecific antibodies are making breakthroughs on multiple fronts and becoming industry highlights.

Zelgen's potential FIC ZG006 for third-line and beyond small cell lung cancer (SCLC) won an oral presentation; Sansheng Pharma’s recently completed 43 billion RMB licensing deal SSGJ-707 updated phase II data for NSCLC monotherapy; CTTQ presented HER2 bispecific antibody TQB2930 combined with chemotherapy for HER2-positive breast cancer patients who received ≥2 lines of therapy with Ib/II phase results; Kangfang Bio’s PD1xCTLA4 bispecific antibody will have a rapid oral presentation and three posters.

TQB2930 is a HER2-targeting bispecific antibody independently developed by CTTQ, targeting the ECD2 antigen epitope of HER2 (pertuzumab binding site) on one end and the ECD4 antigen epitope (trastuzumab binding site) on the other.

In the ongoing Ib/II phase trial, TQB2930 showed good tolerability and durable efficacy in heavily pretreated metastatic HER2-positive breast cancer patients. ASCO 2025 presented data from cohort 4, assessing safety and efficacy of TQB2930 plus chemotherapy in patients who had received at least two prior therapies.

By December 15, 2024, 55 patients received TQB2930 combined with chemotherapy. Median follow-up was 4.14 months. Among 52 evaluable patients, ORR was 48.1%, with 88.5% (46/52) experiencing tumor shrinkage. Median PFS and OS were not reached; 6-month PFS rate estimated at 71%.

For patients who progressed after T-DM1, ORR was 36.8%; for those who failed other HER2-ADCs (including RC48, DS-8201), ORR was 50%.

Regarding safety, grade ≥3 TRAEs were mainly hematologic, including decreased white blood cell counts, neutropenia, thrombocytopenia, and infusion-related reactions. No grade ≥3 cardiotoxicity, sinus bradycardia, or QT prolongation occurred (incidence <3%).

ZG006 is a trispecific antibody targeting CD3 and two distinct DLL3 epitopes. According to official sources, it is the world's first trispecific antibody targeting DLL3-expressing tumors, a pioneering molecular form with potential to become best-in-class.

This randomized, multicenter, open-label phase II trial evaluated ZG006 monotherapy in patients with advanced SCLC who failed at least two lines of standard systemic therapy. Dose optimization evaluated 10 mg and 30 mg Q2W doses (starting at 1 mg). 60 patients were planned for random 1:1 assignment. The primary endpoint was objective response rate (ORR) by RECIST 1.1.

As of December 31, 2024, 40 SCLC patients were randomized (19 at 10 mg, 21 at 30 mg) and received ≥1 dose of ZG006. Among 27 evaluable patients (13 at 10 mg, 14 at 30 mg) with at least one post-baseline tumor scan, 18 achieved partial response (PR) (7 at 10 mg, 11 at 30 mg).

Overall ORR was 66.7%, disease control rate (DCR) 92.6%. ORR was 53.8% and DCR 84.6% at 10 mg; ORR 78.6% and DCR 100% at 30 mg. Duration of response (DoR) and progression-free survival (PFS) remain to be updated with follow-up.

Among 27 patients, 21 (77.8%) had baseline DLL3 expression low (N=17) or medium (N=4), showing strong antitumor efficacy; 15 patients had PR (ORR 71.4%).

Safety: 35 patients experienced TRAEs; common (≥20%) events included fever, cytokine release syndrome (CRS), vomiting, rash, decreased appetite, elevated AST, leukopenia, and thrombocytopenia. Five patients had grade 3/4 TRAEs, including one grade 3 CRS. No TRAEs led to treatment discontinuation or death. Five patients had serious TRAEs. No significant safety differences between dose groups.

Innovative Small Molecules Make a Stunning Debut

On the international stage, the innovation influence of domestic small molecule drugs continues to rise.

CTTQ's small molecule tyrosine kinase inhibitor anlotinib earned 9 oral presentations covering NSCLC, endometrial cancer, bone and soft tissue sarcoma, colorectal cancer, glioma, and head and neck squamous cell carcinoma; Dizal released new data on the novel non-covalent LYN/BTK dual inhibitor DZD8586 and fourth-generation EGFR TKI DZD6008; Ascentage Pharma disclosed clinical data of Bcl-2 inhibitor Lisaftoclax in patients with venetoclax-refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) for the first time.

This study includes clinical data from TAI-SHAN5 and TAI-SHAN8. As of January 3, 2025, 40 subjects were enrolled and treated once daily with DZD8586 at doses ranging from 25 mg to 100 mg.

Results showed that at all dose levels, 15 of 30 subjects achieved tumor remission, ORR 50%. At the recommended phase II dose (50 mg), ORR was 64.3%. Efficacy was observed in patients previously treated with BTK inhibitors (ORR 52.2%) and Bcl-2 inhibitors (ORR 46.2%). 75% of patients treated with BTK degraders achieved partial remission. The longest remission duration recorded was 12.1 months, with deepening remission over time.

Safety: DZD8586 was well tolerated at all dose levels. At the recommended phase II dose, most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (15%) and pneumonia (10%). No major bleeding or atrial fibrillation reported. No grade 4/5 adverse events.

This is an open-label, multicenter Ib/II phase clinical trial. As of January 6, 2025, 97 patients were enrolled with a median treatment duration of two cycles. ORR for treatment-naive MDS/CMML patients was 64%, CR rate and marrow CR rate were 29% and 36%, respectively. Among relapsed/refractory AML patients receiving 28-day or 14-day lisaftoclax treatment in a 28-day cycle, ORRs were 39% and 50%, CR rates 28% and 37.5%. ORR for venetoclax-refractory AML/MPAL and HR-MDS patients were 17% and 50%, respectively.

Safety: Maximum tolerated dose (MTD) was not reached; no dose-limiting toxicities (DLTs). Common grade 3/4 treatment-emergent adverse events (TEAEs) included neutropenia (40%), febrile neutropenia (31%), and thrombocytopenia (22%). Febrile neutropenia (26.8%) was the most common serious adverse event (SAE). Only 3% of patients required lisaftoclax dose reductions due to neutropenia. No deaths occurred within 60 days of treatment.