Simcere Pharmaceutical (China)

DNA polymerase theta (Polθ) is a key enzyme in the theta-mediated end-joining (TMEJ) and a promising target for synthetic lethality-based cancer therapy, particularly in homologous recombination (HR)-deficient tumors. Herein, we designed and optimized a series of Polθ polymerase inhibitors, exploiting a previously unexplored binding pocket to enhance potency, cellular activity, and pharmacokinetics. Compound 33 exhibited low-nanomolar Polθ inhibition, strong antiproliferative activity in DLD1 BRCA2 KO cells, and high sensitivity to MDA-MB-436 cells. In combination with Olaparib, it significantly enhanced DNA damage accumulation, induced γH2AX levels, and achieved 85% tumor growth inhibition (TGI) in the MDA-MB-436 xenograft model. Pharmacokinetic studies confirmed a favorable dose-dependent profile, and preliminary safety evaluations indicated good tolerability. These findings establish compound 33 as a potent Polθ inhibitor with strong synthetic lethality effects, supporting its further preclinical development as a novel Polθ-targeted therapeutic agent.

Lynch syndrome (LS) is a cancer syndrome caused by germline mutations in DNA mismatch repair genes. Patients with Lynch syndrome have higher risk of brain tumors, predominantly high-grade gliomas, including glioblastoma (GBM). Here, we present a case of a 31-year-old male patient with a frontal lesion by magnetic resonance imaging (MRI). The pathological diagnosis was isocitrate dehydrogenase (IDH) wildtype GBM (WHO grade 4) with 30% Ki-67 proliferation index. After surgery, this patient received radiotherapy and temozolomide chemotherapy following Stupp protocol. During over 60 months follow up, no sign of tumor recurrence was found after surgery. Therefore, next-generation sequencing was suggested to this patient. The result revealed a heterozygous germline variation of c.3261dup in exon 5 of MSH6 gene which resulted in a truncated MSH6 protein (MSH6 p.F1088Lfs*5) with a tumor mutation burden of 327.36 Mut/Mb. MMR deficiency may usually lead to TMZ resistance in GBM cells. However, this case had long-term benefits from standard Stupp protocol after surgery, probably due to the distinct molecular characteristics and tumor microenvironment. This finding provided insight to perform clinical studies to investigate the molecular characterization of Lynch associated GBM and the role of microglia in antitumor.

BackgroundAnti-LGI1 encephalitis is a subtype of autoimmune encephalitis characterised by cognitive dysfunction, psychiatric disorders, faciobrachial dystonic seizures, and hyponatraemia. However, its precise pathogenesis remains unclear. Brucellosis, a zoonotic disease prevalent globally, poses a significant threat to public health; nevertheless, the nonspecific nature of its clinical symptoms often results in diagnostic delays.Case presentationWe report the case of a middle-aged male patient diagnosed with anti-LGI1 antibody encephalitis through antibodies in serum and CSF combined with neurobrucellosis through serum antibodies and CSF NGS. Additional testing for paraneoplastic-related and demyelinating-related antibodies, CSF and blood culture yielded negative results, helping rule out other pathogens and etiologies. The patient exhibited symptom improvement after effective antimicrobial and immunomodulatory therapies.ConclusionsThis case raises awareness of autoimmune encephalitis following Brucella infection, revealing a potential association between Brucella infection and anti-LGI1 antibody encephalitis. Brucella may be a triggering factor for anti-LGI1 antibody encephalitis; however, more cases are needed to confirm our findings.

1068 Background: SIM0270 is a highly potent oral selective estrogen receptor degrader (SERD) which has shown ER degradation and robust antitumor activity across variety of preclinical models. Here, we present results of SIM0270 combined with palbociclib cohort(dose escalation and dose expansion) from Phase I study in patients with ER+/HER2- advanced breast cancer (NCT05293964). Methods: Patients with ER+/HER2- advanced breast cancer were enrolled. The key inclusion criteria for dose escalation and dose expansion were the same as follows: ≥ 1 prior endocrine therapy (ET) with disease recurrence/ progression while being treated with adjuvant ET for ≥ 24 months and/or first line ET for ≥ 6 months in advanced setting; ≤2 prior chemotherapies in advanced setting; and prior fulvestrant was allowed. A Bayesian Optimal Interval design (BOIN) was adopted for dose escalation. The key endpoint of dose escalation was dose limiting toxicities (DLT), and the key endpoints of dose expansion included safety and tolerability, pharmacokinetics (PK) and efficacy. Results: As of December 26, 2024, 44 patients were enrolled including 12 from dose escalation and 32 from dose expansion, with a median follow up of 11.8 months. No DLT was reported in dose escalation. In total, 38 patients (86.4%) had visceral disease, and 8 patients (18.2%) had ESR1 mutation at baseline. 22 patients (50%) received prior endocrine therapy in the advanced setting, of which, 15 patients (34.1%) had aromatase inhibitor (AI), 12 patients (27.3%) had fulvestrant. 13 patients (29.5%) received prior chemotherapy in the advanced setting.The most common treatment emerged adverse events (TEAEs) were white blood cell count decreased (95.5% ) and neutropenia (95.5%). Sinus bradycardia was reported in 77.3% (34/44) of the patients, 85.3% (29/34) were grade 1 (asymptomatic) requiring no dose modification. Grade 3/4 treatment-related AEs (TRAEs) occurred in 77.3% of the patients with most commonly reported events including neutropenia (70.5%) and white blood cell count decreased (40.9%). No fatal AEs were reported. TRAEs led to dose reduction were reported in 38.6% for palbociclib and 9.1% for SIM0270. No TRAEs led to treatment discontinuation. And 24 patients remain on study treatment. In the response evaluable patients, confirmed overall response rate (ORR) was 41.5% (17/41) and clinical benefit rate (CBR, defined as complete response, partial response or stable disease ≥ 24 weeks) was 82.5% (33/40). Median progression free survival (PFS) was not reached (NR). In patients with ESR1 mutation at baseline, ORR and CBR were 87.5% (7/8) and 100% (8/8), respectively. Conclusions: SIM0270 in combination with palbociclib showed acceptable safety and tolerability, promising clinical activity in patients with ER+/HER2- advanced breast cancer. Clinical trial information: NCT05293964 .

2595 Background: Tumor mutational burden (TMB) has emerged as a predictive biomarker of immune checkpoint blockade response in cancers. Envafolimab, a humanized single-domain anti-PD-L1 antibody subcutaneous administration (s.c.), has been approved in China for the treatment of advanced solid tumors with MSI-H. The study is to explore the potential anti-tumor activity in patients with TMB-high (TMB-H) in China. Methods: The study consists of two parts. Part 1 is to explore the association of single agent envafolimab activity with tissue TMB (tTMB) measured by Onco500 assay in patients with advanced solid tumors. Part 2 will further evaluate the efficacy of envafolimab in advanced solid tumor patients base on the cutoff of TMB value identified from Part 1. Envafolimab is administrated s.c. at 400 mg every 4 weeks until disease progression, adverse events, or other reasons causing treatment discontinuation. Efficacy and safety are assessed in all patients who received at least one dose of envafolimab. tTMB is assessed by a central lab using SimcereDx Onco500 assay (Jiangsu Simcere Medical Device Co., Ltd, China). The primary endpoint was objective response rate (ORR) assessed by independent review committee per RECIST v1.1 criteria. Results: As of Nov 15, 2024, a total of 70 patients with advanced cancers (colorectal cancer [9,12.6%], cervical cancer and soft tissue sarcoma [8 each; 11.4%], and other 18 tumor types) have received envafolimab in Part 1. 30 (42.9%) patients had received ≥3 systemic therapies (median 2; range 1-19). Median follow-up time was 31.2 months (range: 0.6-36.8). 49 (70%) patients had at least one treatment-related adverse events (TRAEs), and 6 (8.6%) had grade 3 or 4 TRAEs. The most common TRAEs were anemia and alanine aminotransferase increased (9 each; 12.9%). Grade 2 decreased appetite was the only TRAE resulting in treatment discontinuation. No treatment-related death reported. TMB≥13 mut/Mb with Onco500 panel was selected as the threshold of TMB-H based on the clinical data and previous comparison of platforms for determining TMB value in patients. Key efficacy outcomes are presented (Table). ORR and DOR were higher in patients with tTMB ≥13mut/Mb (33.3% and 20.2m) than patients with tTMB < 13mut/Mb (4.3% and 3.8m). Conclusions: tTMB could be a useful predictive biomarker for response to envafolimab in patients with pre-treated advanced solid cancer. The Part 2 of this study is ongoing (NCT04891198). Clinical trial information: NCT04891198 . tTMB≥13 mut/Mb(n = 24) tTMB<13 mut/Mb(n = 46) Objective response rate, n (%) [95% CI] 8 (33.3) [15.6-55.3] 2 (4.3) [0.5-14.8] Complete / partial response 1 (4.2) / 7(29.2) 0 (0) / 2 (4.3) Stable disease / progressive disease 2 (8.3) / 9 (37.5) 16 (34.8) / 24 (52.2) Median DoR, months (95% CI) 20.2 (4.4-NE) 3.8 (NE-NE) Median PFS, months (95% CI) 2.8 (1.8-8.7) 1.9 (1.8-3.6) Median OS, months (95% CI) 13.2 (5.7-NE) 12.7 (7.4-18.2)

Gliomas are a heterogeneous type of central nervous system tumor. The etiology of glioma formation remains elusive, with approximately 5% of gliomas being familial, underscoring the significance of understanding genetic susceptibility in glioma development. In this study, a dual germline PTCH2 mutation [Ser391*, Leu104Pro] was identified in a family with a history of glioma, and sequencing data from WES/SimcereDx Neuro-Onco 360 including 910 Chinese patients with glioma and 1666 patients with solid tumors were analyzed. A potential link between PTCH2 mutations and glioma development was observed in the Chinese population. Comprehensive analysis revealed that gliomas harboring dual PTCH2 mutations were segregated into two distinct clinical subtypes, indicating that the presence of PTCH2 is a novel genetic risk factor for glioma. These findings expand the genetic risk profile of glioma and offer promising avenues for the development of targeted diagnostic and therapeutic strategies. The results of this study emphasize the necessity for a comprehensive investigation into the genetic predisposition to gliomas, particularly in Asian populations, to achieve a better understanding of and management strategy for this complex disease.

Methylthioadenosine phosphorylase (MTAP)-deletion occurs in about 15% of all cancers. The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in MTAP-deleted cancers. Here, we commented on a novel MAT2A inhibitor SCR-7952, and discussed the potential of MAT2A inhibitors as single agents or in combination for cancer therapy, including solid tumors and hematologic malignancies. Several MAT2A inhibitors with high efficacy and selectivity have been discovered. And MAT2A inhibitors synergize strongly with protein arginine N-methyltransferase 5 (PRMT5) inhibitors, taxanes, platinum, topoisomerase inhibitors, and antibody-drug conjugates (ADC). A MAT2A inhibitor IDE397 and the combination strategies with chemotherapies or other targeted therapies are under investigation in clinical. The promising preliminary clinical results demonstrate the potential of MAT2A inhibitors for the treatment of MTAP-deleted tumors.

Sarcomas, including bone sarcomas and soft tissue sarcomas (STSs), are a heterogeneous group of mesenchymal malignancies. Recent advancements in next-generation sequencing (NGS) have enabled the identification of novel chromosomal translocations and fusion genes, which play a critical role in sarcoma subtypes. Our study focuses on gene fusions in sarcomas among Chinese patients, comparing their genomic profiles to those of Western populations. We analyzed 1048 sarcoma samples from Chinese patients using a panel of over 500 genes, identifying 481 gene fusions in 329 patients. The most common fusions included EWSR1, HMGA2, and SS18, with notable subtype-specific fusions such as EWSR1-FLI1 in Ewing sarcoma and NAB2-STAT6 in solitary fibrous tumors. In comparison to Chinese and Western populations, variations in fusion spectrum exist, potentially necessitating distinct treatment strategies; however, further validation of these fusions is warranted. Our findings highlight the importance of gene fusions as diagnostic markers and potential therapeutic targets. Actionable fusions, including kinase-related fusions like ALK, NTRK3, and BRAF, were detected in 67 patients (6.4%) and may guide precision therapies. Additionally, we observed the frequent co-occurrence of genomic alterations, particularly in cell cycle regulators such as CDK4 and MDM2. Genomic profiling of sarcomas offers valuable insights into their molecular drivers and can support personalized therapeutic approaches. Further research is needed to validate these findings and optimize treatment strategies for sarcoma patients.

Intrahepatic cholangiocarcinoma is a malignant tumor that starts from the epithelium of the bile duct and has a poor prognosis. They are characterized by poor response to chemotherapy and lack of effective targeted therapies; thus, therapeutic options are limited. A 59-year-old man was admitted to the hospital for a workup of abnormal CA19-9 levels. He was diagnosed with ICC, underwent surgery and was found to have pT1bNx disease. He developed rapid disease recurrence on adjuvant gemcitabine + capecitabine. Following recurrence, he received first-line systemic pembrolizumab + lenvatinib and second-line pembrolizumab + lenvatinib + chemotherapy and had mild tumor regression followed by progression. Next-generation sequencing was performed on the baseline surgical sample. This revealed a novel RBPMS-MET fusion, and based on the literature, crizotinib 250mg twice a day was administered. After 3 months of crizotinib treatment, magnetic resonance imaging revealed a significant reduction in liver lesions, and 4 months after initiating treatment, scans demonstrated a partial response. Our case report strengthens the evidence that crizotinib may be a viable treatment option for patients with ICC with a c-MET tyrosine kinase fusion, necessitating additional clinical investigation.