Innovent Biologics and Xuanzhu Biopharma have entered into a clinical trial collaboration and supply agreement to investigate combination therapies of sintilimab injection (TYVYT®) with KM-501, a novel HER2 bispecific Antibody-drug Conjugate (ADC), as potential treatment options for advanced solid tumors.
Under the agreement, Innovent supplies sintilimab for the collaborated clinical trial, while Xuanzhu Biopharma conducts a Phase 1b clinical study to evaluate the anti-tumor activity and safety of the combination therapy in Chinese patients with advanced solid tumors.
Sintilimab, a PD-1 inhibitor co-developed by Innovent and Eli Lilly and Company, has been approved in China and is included in the country’s national reimbursement drug list (NRDL) for seven indications. It is also the only PD-1 inhibitor for the first-line treatment of five high-incidence cancer types included in the NRDL.*
Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells 
Trials results: ORIENT-11 trial
Outcomes rom the randomized, double-blind, phase 3 ORIENT-11 trial (ClinicalTrials.gov ID NCT03607539) in which 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were positive. In the study patients were randomly assigned 2:1 to receive sintilimab plus pemetrexed (Alimta®; Eli Lilly and Company) and platinum chemotherapy (n=266) or placebo plus pemetrexed and platinum chemotherapy (n=131). The primary analysis of Progression Free Survival (PFS) showed that the median PFS was significantly improved in the combination arm compared with the placebo arm (8.9 months vs 5.0 months, respectively; hazard ratio [HR], 0.48; 95% CI, 0.36-0.66; P =.0000004).
In addition, a secondary analysis of Overall Survival( OS) with a data cut-off date of January 15, 2021, the median OS was not reached in the combination arm compared with 16.8 months in the placebo arm (HR, 0.60; 95% CI, 0.45-0.79; P =.0003). The median OS was not reached in the combination arm compared with 16.8 months in the placebo arm (HR, 0.60; 95% CI, 0.45-0.79; P =.0003).
Finally, the combination arm demonstrated a significant improvement in PFS in patients with high or medium immune cell infiltration compared with the placebo arm. Based on the trial outcome, there was no additional benefit in patients with low or absent immune cell infiltration.
KM-501 is designed by Mebs-Ig (antibody-edited bispecific antibody) platform with independent intellectual property rights to target dual-antibody ADC with two different domains of HER2. The drug is investigated for the treatment of locally advanced/metastatic solid tumors with HER2+ expression, amplification or mutation, including related advanced tumors with low HER2 expression.
The Investigational New Drug (IND) application was approved by the Chinese National Medical Products Administration (NMPA) in March 2023 and it is currently in the phase I dose escalation study. Pre-clinical studies showed that KM-501 was better than control-drugs DS-8201 and Herceptin in terms of endocytosis rate, internalization rate and in vitro inhibitory activity; KM-501 was better than DS-8201 in tumor models with high and low expression of HER2.
PD-1 inhibitor + ADC
Combining a PD-1 inhibitor and an ADC candidate represents a new direction for the development of cancer therapy in terms of potentially improving the effect of immunotherapy and overcoming potential drug resistance. The PD-1 immunotherapy can release the suppressed state of T cells while the ADC drug can achieve the anti-tumor killing effect through cytotoxic payload, thus bringing in synergistic tumor inhibition effect.
“We are pleased to collaborate with Xuanzhu Biopharma to explore the synergistic anti-tumor effects of the combination therapy of sintilimab and a novel ADC candidate,” noted Dr. Hui Zhou, Senior Vice President of Innovent.
“The leading position and clinical value of sintilimab as a backbone immunotherapy are further strengthened. In light of the synergistic mechanism of two novel medicines, we hope to bring new treatment options for cancer patients in the future,” Zou added.
“The collaboration with Innovent is an important milestone for KM-501 in the development and commercialization strategy. We look forward to new opportunities for KM-501 in combo with sintilimab so as to potentially improve patient benefit and overcome tumor resistance,” Dr. Xiaodong Zhu, General Manager of Xuanzhu Bio. concluded.
Note: * Sintilimab is an investigational programmed death receptor-1 (PD-1) inhibitor which is not approved by the US Food and Drug Administration (FDA).
Efficacy and Safety Evaluation of Sintilimab in Patients With Advanced or Metastatic Non-squamous NSCLC – ClinicalTrials.gov ID NCT03607539
A Study of KM501 in Patients With Solid Tumors – ClinicalTrials.gov Identifier: NCT05804864
Highlights of prescribing information
Pemetrexed (Alimta®; Eli Lilly and Company)[Prescribing Information]
 Wang J, Fei K, Jing H, et al. Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit. mAbs 2019;11(8): 1443-1451.
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