Shanghai, China, September 18, 2024 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the results on its first innovative product HANSIZHUANG (serplulimab) as well as its trastuzumab biosimilar approved in China, Europe and U.S., HANQUYOU were released as poster presentations at the 2024 European Society of Medical Oncology (ESMO) Congress.
HANSIZHUANG (serplulimab) is a recombinant humanised anti-PD-1 monoclonal antibody（mAb）injection independently developed by Henlius, and the world's first anti-PD-1 mAb approved for the first-line treatment of SCLC. The product has been approved in China, Indonesia, Cambodia and Thailand. Underpinned by the patient-centric strategy, Henlius has carried out a differentiated and multi-dimensional layout in the field of gastrointestinal cancer and lung cancer, covering a wide variety of indications. Up to date, HANSIZHUANG has been approved by the National Medical Products Administration (NMPA) for the treatment of MSI-H solid tumours, sqNSCLC, ES-SCLC, and esophageal squamous cell carcinoma (ESCC), benefiting about 80,000 patients. Meanwhile, HANSIZHUANG’s Marketing Authorisation Application (MAA) for ES-SCLC has been validated by the European Medicines Agency (EMA), which is expected to be approved in 2024. Moreover, a wide variety of clinical trials on immuno-oncology combination therapies in differentiated indications has been initiated by the company to further explore the efficacy of the product, such as HANSIZHUANG plus bevacizumab and chemotherapy as first-line treatment for patients with metastatic colorectal cancer (mCRC) , HANSIZHUANG plus chemotherapy as neoadjuvant/adjuvant therapy for gastric cancer (GC), and HANSIZHUANG plus chemotherapy and concurrent radiotherapy in patients with limited-stage small cell lung cancer (LS-SCLC), etc.
HANQUYOU is the trastuzumab biosimilar independently developed by Henlius in accordance with the National Medical Products Administration (NMPA), the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other international biosimilar guidelines. It is Henlius’ first FDA-approved product. HANQUYOU is indicated for the treatment of HER2-positive early breast cancer, metastatic breast cancer and metastatic gastric cancer, which corresponds to all the approved indications of the trastuzumab originator. Up to date, HANQUYOU has been approved in 48 countries and regions, benefiting 210,000+ patients, bringing affordable and high-quality treatment options to breast cancer and gastric cancer patients worldwide.
ASTRUM-005
Title
Smoking-related genomic mutation patterns in patients with small cell lung cancer treated in ASTRUM-005 study
Methods
ASTRUM-005 was a randomized, double-blind, placebo-controlled, global, phase 3 trial in patients with extensive-stage SCLC.
Smoking signature analysis
Genomic mutations in 302 patients with available baseline tumor samples were assessed by the Med1CDx panel, which included exon regions of 601 genes. Two bioinformatic methods, the transversion/transition ratio (TTR) method and the Catalogue of Somatic Mutations in Cancer (COSMIC) Signature 4 method, were applied to analyze tobacco-smoking–related signature.
For the TTR method: An R Bioconductor package, Maftools, was used to calculate the fraction of transversion and transition in each sample. TTR value was then defined as the transversion fraction divided by the transition fraction in each sample[2-3]. Specifically, Maftools classified single nucleotide variants (SNVs) into 6 different transition and transversion events (C>A:G>T, C>G:G>C, C>T:G>A, T>A:A>T, T>C:A>G, T>G:A>C). Synonymous SNVs were included in these analyses.
For the Signature 4 method: Mutational signatures were extracted and the contributions of tobacco-smoking–related signatures (Signature 4), annotated by the COSMIC, from the genomic mutation panels of each patient were estimated[4].6 R package “deconstructSigs” was used to calculate the contribution of the mutation[5]. Both methods were validated on targeted panel sequencing from a published NSCLC data set. Both methods were able to distinguish smokers from non-smokers in NSCLC[6].
Statistical analysis
For progression-free survival (PFS) and overall survival (OS), the median was calculated from product-limit (Kaplan–Meier) estimates, while n was the number of patients in each subgroup category. The hazard ratio (HR) and its 95% confidence interval (CI) were estimated using an unstratified Cox proportional hazards model; Efron’s method was used to handle ties. For the analyses of genomic-based smoking signatures, the Wilcoxon test was used to calculate the difference among patients with different smoking histories. The clinical data cutoff date was June 13, 2022.
Results
Baseline characteristics in smoking groups
Patients in the SCLC cohort (N = 302) were grouped based on their smoking history; 23% were current smokers, 55% former smokers, and 22% never smokers. Baseline patient characteristics are summarized in Table 1.
Mutation analysis demonstrated that the most frequently mutated genes were TP53 (90% and 91%), RB1 (68% and 69%), and LRP1B (31% and 28%) in current and former smokers versus never smokers, respectively. Differential analysis on the mutated genes demonstrated that smokers and non-smokers have similar top mutated genes, with never smokers having more mutation in EGFR, DMD, MED12, MTOR, NOTCH1, REL, PGR, DNMT1, GRM3, KMT2A, and CD22.
Smoking signatures in patients with SCLC
No significant differences in smoking signatures were found between groups with different smoking histories using both methods (TTR: P = 0.54; Signature 4: P = 0.38) .
Findings were validated by applying the same analyses on 2 cohorts’ data sets profiled with whole exome sequencing from published studies[1,6]. In 120 samples from 40 patients with SCLC, no correlation between mutation pattern and smoking history in either method was observed (TTR: P = 0.91; Signature 4: P = 0.70)[7].
We observed similar results in another independent data set with whole exome sequencing performed on 110 samples from patients with SCLC (data not shown).10 Patients were further grouped into high/low TTR groups using the median TTR of 1.12 as the cutoff value. The mutation analysis showed that REL was more frequently mutated in non-smokers (P < 0.001) .
Higher TTR resulted in shorter median OS (HR [95% CI], 1.65 [1.05-2.62]; P = 0.03) for patients who only received chemotherapy, while both the high and low TTR groups gained similar benefits for patients who received serplulimab plus chemotherapy (HR [95% CI], 0.97 [0.67-1.4]; P = 0.87) .
Patients in both treatment groups (chemotherapy and serplulimab plus chemotherapy) showed similar benefits in PFS, regardless of the TTR (HR [95% CI], 1.25 [0.83-1.88]; P = 0.29 and 0.95 [0.67-1.34]; P = 0.77, respectively) .
Conclusion
In our ASTRUM-005 study, 67 (22%) patients with SCLC had never smoked. Unlike what was observed with NSCLC, patients with SCLC from our study showed similar tobacco-smoking–related genomic mutation patterns, regardless of their smoking status. Patients with SCLC who have never smoked may develop transversion mutations from other sources unrelated to direct tobacco exposure. Patients with high TTR might gain less benefit from chemotherapy, suggesting mutations in SCLC might be predictive biomarkers for certain therapies.
ASTRUM-004
Title
Exploratory biomarker analysis of phase 3 ASTRUM-004 study: serplulimab plus chemotherapy as first-line treatment for advanced squamous non-small-