On September 17, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncologic, autoimmune, cardiovascular and metabolic, ophthalmologic and other major diseases, reported that clinical data of IBI354 (HER2 monoclonal antibody-camptothecin derivative conjugate) in advanced solid tumors was presented at the 2024 ESMO (Free ESMO Whitepaper) Congress (ClinicalTrials.gov, NCT05636215) (Press release, Innovent Biologics, SEP 17, 2024, View Source [SID1234646710]).
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The data presented is from a Phase 1/2 study aimed at evaluating the safety, tolerability, and preliminary efficacy of IBI354 in participants with advanced solid tumors. A total of 368 participants with advanced solid tumors were enrolled and received different doses of IBI354 monotherapy, including 178 with breast cancer, 92 with ovarian cancer, 38 with colorectal cancer, and 60 with other tumors. Among them, 42.7% of the participants had previously undergone five or more systemic treatment regimens.
IBI354 monotherapy demonstrated excellent safety profile.
The dosage was escalated to 18mg, with no DLT events observed.
The most common treatment-related adverse events (TRAEs) were nausea, decreased white blood cell count and anemia. The incidence of interstitial lung disease (ILD) was only 1.6%, all of which were grade 1.
Overall, 21.5% of patients experienced TRAEs ≥ grade 3, 2.4% experienced TRAEs leading to dose reduction and 1.6% experienced TRAEs leading to discontinuation, with no TRAEs leading to death.
IBI354 monotherapy showed promising efficacy signals in multiple tumor types.
In platinum-resistant ovarian cancer cohort (n=87, treated at 6~12mg/kg IBI354), the overall objective response rate (ORR) was 40.2% and the disease control rate (DCR) was 81.6%. In the 12mg/kg subgroup (n=40), the ORR reached 52.5% and the DCR was 90.0%. In participants with HER2 1+ (n=27), the ORR reached 55.6% and the DCR was 88.9%. As of the data cutoff date, the median follow-up time was 6.5 months, and both progression-free survival (PFS) and duration of response (DoR) had not yet matured.
In HER2-positive breast cancer cohort (n= 59, treated at 6~15mg/kg IBI354), the ORR and DCR were 67.8% and 88.1%, respectively.
In HER2-low breast cancer cohort (n=67, treated at 6~15mg/kg IBI354), the ORR and DCR were 41.8% and 82.1%, respectively. In the 12mg/kg subgroup (n=26), the ORR and DCR were 61.5% and 88.5%, respectively.
In HER2-positive gastrointestinal malignancies cohort (n=35, treated at 6~15mg/kg IBI354), the ORR and the DCR were 57.1% and 91.4%, respectively. 26 participants were diagnosed with colorectal cancer, of which 14 achieved an objective response (1 subject with HER2 IHC2+ FISH+ achieved a confirmed objective response), resulting in an ORR and DCR of 53.8% and 92.3%, respectively. As of press date, another participant with HER2 low expression (IHC2+ FISH-) colorectal cancer achieved a confirmed objective response.
Professor Qi Zhou, Chief Physician at the Gynecologic Oncology Center of Chongqing University Affiliated Cancer Hospital and the Principal Investigator of the gynecologic oncology cohort study, stated, "Approximately 70% of ovarian cancer patients experience relapse within 3 years following surgery and platinum-based adjuvant therapy, eventually developing platinum resistance after multiple recurrences[1]. These patients have limited effective treatment options. Current evidence indicates that non-platinum single-agent chemotherapy or the addition of anti-angiogenic therapy results in an ORR of just 4-13.2% and a median OS of merely 10.9-14 months[2]-[3][4][5][6]. As a fully-validated target, HER2-targeted therapy has proven effective in breast and gastric cancers. IBI354, an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown good anti-tumor activity in platinum-resistant ovarian cancer with HER2 expression of 1+. In our Phase 1 study, the ORR was 67.5%, DCR was 88.9%, and median rate is 39.0% at the 12mg/kg Q3W dose level, while maintaining a favorable safety profile. Extending the PFS and OS remains a critical clinical challenge in platinum-resistant recurrent ovarian cancer. The development of antibody-drug conjugates for the treatment of resistant recurrent cancers has become a hot spot, and promising results have been observed. The clinical efficacy of antibody-drug conjugates targeting HER2 low expression warrants further clinical research and exploration, which could benefit more patients with platinum-resistant ovarian cancer."
Doctor Daphne Day from the Medical Oncology Department at Monash Health in Melbourne, Australia, stated: "Breast cancer is the second most commonly diagnosed cancer globally, the most common cancer in women, and a cause of cancer-related deaths. HER2 amplification or overexpression has been proven to play a significant role in the occurrence and progression of breast cancer, underscoring the importance of HER2-directed therapy. IBI354, as an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown promising preliminary results, with meaningful objective response and disease control rates in HER2-positive and -low breast cancer. Additionally, IBI354 has demonstrated excellent clinical safety and tolerability. Existing clinical data suggest that IBI354 has substantial development potential in the breast cancer population."
Professor Lin Shen from Peking University Cancer Hospital, stated, "Colorectal cancer (CRC) has become the second most common malignant tumor in China, and its incidence and mortality rates are still rising annually[7]. The HER2-targeted therapy plays an important role in the later-line treatment of CRC. Preliminary results suggest that IBI354, an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown positive efficacy in HER2-positive gastrointestinal malignancies. Notably, IBI354 has also demonstrated antitumor effects in HER2-low CRC populations, where HER2-targeted therapies are relatively less effective. IBI354 has exhibited good clinical safety and tolerability in later-line CRC patients, supporting further exploration and development in this population."
Dr. Hui Zhou, Senior Vice President of Innovent, stated: "With the rapid advancements in ADC drugs for oncology treatment, Innovent is strategically positioning itself in the ADC field. At this year’s ESMO (Free ESMO Whitepaper) conference, we are showcasing, for the first time, the safety and efficacy data of IBI354 across various advanced solid tumors, fully demonstrating Innovent’s platform capabilities in ADC drug development. We will continue to invest in research and development of ADC innovative molecules, with the aim of providing patients more and better treatment options."
About IBI354 (Anti-HER2 Antibody-Camptothecin Derivative Conjugate)
IBI354 is an innovative HER2-targeted antibody–drug conjugate developed using Innovent’s proprietary novel topoisomerase inhibitor NT3 platform. With a drug-to-antibody ratio (DAR) of 8, IBI354 delivers a high payload of effective drugs to tumors. The highly hydrophilic linker design contributes to its excellent biophysical and pharmacokinetic (PK) properties, while the hydrophobic payload enhances its bystander effect, targeting adjacent antigen-low or negative tumor cells. IBI354 exhibits extremely low exposure of free toxin in circulation and has an ideal safety profile based on pre-clinical and clinical studies. IBI354 has demonstrated remarkable anti-tumor activity in various tumor-bearing mice models, particularly in those resistant to HER2-targeted therapies and in metastatic tumors. Innovent Biologics is conducting clinical research in China, the United States, and Australia to assess the efficacy and safety of IBI354 for treating various advanced malignancies. Additionally, multiple new ADC molecules from Innovent’s NT3 platform are under clinical development and have shown promising safety and efficacy signals.