In the past nine months of 2024, the National Medical Products Administration (NMPA) has approved more than 70 innovative drugs, including 22 oncology drugs, accounting for nearly 30%, which is on par with last year. The field of oncology remains a hotspot for innovative drugs. Pharma Insights will focus on reviewing five significant anti-cancer drugs expected to be approved for marketing in China in Q4 2024, providing insights for reference.Alpha Biopharma: Zorifertinib
Brain metastasis in non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is a hot and challenging topic in the era of targeted therapy. Zorifertinib is a novel-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting exon 19 deletion (19Del) or exon 21 L858R mutation (L858R) of the EGFR gene, specifically designed for patients with advanced NSCLC harboring EGFR-sensitive mutations and central nervous system (CNS) metastases. Following preclinical and clinical evaluations,The drug has a 100% blood-brain barrier penetration rate., which can produce and maintain effective drug exposure in brain tissue and cerebrospinal fluid. Zolitinib was initially developed by AstraZeneca. In January 2018, Alpha Biopharma signed a cooperation agreement with AstraZeneca to introduce the drug.Results from the randomized, open-label, international multi-center Phase II/III EVEREST study (NCT03653546) showed,Compared with the first-generation EGFR-TKIs gefitinib or erlotinib, zorifertinib demonstrated superior intracranial and systemic antitumor efficacy as a first-line treatment in patients with advanced NSCLC harboring EGFR-sensitive mutations and CNS metastases.，The median PFS (9.6 vs 6.9 months, HR=0.719, p=0.0024), ORR (68.6% vs 58.4%, p=0.027), and median DoR (8.2 vs 6.8 months, p=0.0997) in the Zoritini group were all superior to those in the control group. The intracranial PFS was 15.2 months in the Zoritini group and 8.3 months in the control group (HR=0.467, P<0.001); the intracranial ORR was 75.0% in the Zoritini group and 64.2% in the control group (OR=1.658). In terms of safety, the adverse events of Zoritini were as expected and manageable. When resistance developed after subsequent progression on Zoritini, the primary mutation was T790M, and patients could receive sequential third-generation TKI treatment, with a median overall survival of up to 37.3 months.Zoritini isThe world's first registrational clinical study specifically targeting EGFR mutation-positive NSCLC patients with untreated CNS metastases achieves significant results.In January 2023, Alpha Biopharma announced that it had submitted a New Drug Application (NDA) for Zoritini and was officially accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA).Third-generation EGFR-TKIs, such as osimertinib, almonertinib, and furmonertinib, have also demonstrated promising efficacy against CNS metastases in registration clinical studies for the first-line treatment of locally advanced/metastatic NSCLC (e.g., FLAURA, AENEAS, FURLONG). However, the data are derived from subgroup analyses with smaller sample sizes, imbalanced patient baselines, and relatively lower levels of evidence. The high-level clinical evidence generated by the EVEREST study shows that zorifertinib has confirmed consistent clinical benefits across patients with symptomatic CNS metastases and various stratifications. Once approved, zorifertinib will become a new treatment option for patients with EGFR mutation-positive advanced NSCLC accompanied by CNS metastases.Astellas: Zolbetuximab
Zolbetuximab is a first-in-class IgG1 antibody targeting Claudin-18.2 (CLDN18.2), initially developed by German company Ganymed Pharmaceuticals, which was acquired by Astellas in December 2016. CLDN18.2 is primarily expressed in gastric epithelial cells and is highly expressed in primary malignant tumors such as gastric cancer, breast cancer, colorectal cancer, and liver cancer. Preclinical studies have shown that zolbetuximab induces cancer cell death by activating two different immune system pathways: antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.The efficacy and safety of Zolbetuximab in combination with chemotherapy as a first-line treatment for patients with HER2-negative, CLDN18.2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma have been validated in two international multicenter, randomized, double-blind Phase III clinical trials (the SPOTLIGHT study and the GLOW study). The SPOTLIGHT study results showed that compared to placebo combined with mFOLFOX6 (oxaliplatin + leucovorin + fluorouracil), the Zolbetuximab plus mFOLFOX6 regimen significantly reduced the risk of disease progression or death in patients (HR=0.75, p=0.0066), with median PFS being 10.61 months in the Zolbetuximab group and 8.67 months in the placebo group. Compared with placebo, Zolbetuximab treatment also significantly reduced the risk of death in patients (HR=0.75, p=0.0053), with median OS being 18.23 months and 15.54 months in the two groups, respectively. Similarly, the GLOW study results showed that the Zolbetuximab plus CAPOX (capecitabine + oxaliplatin) regimen demonstrated superior efficacy compared to placebo plus CAPOX in such patients.Zotuximab isThe World's First CLDN18.2-Targeted Therapeutic Drug, which has been approved for marketing in Japan and Europe. In August 2023, the CDE accepted the marketing application for Zolbetuximab as a first-line treatment for gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma. Once approved, this drug will become a new treatment option for patients with HER2-negative, CLDN18.2-positive advanced gastric cancer.Huadong Medicine: Somytomab (mirvetuximab soravtansine）
Somiromab is a first-in-class folate receptor alpha (FRα) ADC developed by ImmunoGen (which has been acquired by AbbVie), consisting of an FRα-binding antibody, a cleavable linker, and the maytansine derivative DM4. In October 2020, Huadong Medicine reached an agreement with ImmunoGen to obtain the development and commercialization rights for somiromab in China.
In November 2022, mirvetuximab soravtansine received accelerated FDA approval for marketing based on the positive results of the single-arm Phase III SORAYA study. Following the successful completion of the confirmatory Phase III MIRASOL study, mirvetuximab soravtansine also gained full FDA approval in March this year for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously undergone up to three treatments. The MIRASOL study results showed that, compared with single-agent chemotherapy (including paclitaxel, pegylated liposomal doxorubicin, or topotecan), mirvetuximab soravtansine significantly extended OS (16.46 vs. 12.75 months, HR=0.67, P=0.005) and PFS (5.62 vs. 3.98 months, P<0.001) in FRα-positive, platinum-resistant ovarian cancer patients.
In October 2023, the marketing application for Simitumomab was accepted by the CDE and included in the priority review directory. Simitumomab isWorld's First FRα ADC，once approved for marketing in China, will provide a new treatment option for patients with platinum-resistant advanced ovarian cancer.Lilly: Pirtobrutinib
Pirtobrutinib is a first-in-class non-covalent BTK C481S inhibitor developed by Eli Lilly. Covalent BTK inhibitors, including ibrutinib, zanubrutinib, acalabrutinib, and orelabrutinib, all exert their anti-tumor effects by binding to the C481 residue of BTK, blocking the ATP-binding pocket, and inhibiting BTK enzyme activity. However, mutations at C481 can lead to drug resistance. The non-covalent inhibitor pirtobrutinib, on the other hand, does not rely on C481 and can still bind to BTK with high selectivity.Capable of overcoming drug resistance caused by the C481 mutation。The Phase I/II BRUIN study showed that pirtobrutinib achieved an ORR of 50% and a complete response rate of 13% in patients with relapsed or refractory mantle cell lymphoma (MCL) who had previously been treated with covalent BTK inhibitors. Based on this, in January 2023, pirtobrutinib received accelerated FDA approval for adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least two prior lines of systemic therapy, including a BTK inhibitor. The drug has becomeThe First Non-Covalent BTK Inhibitor Approved by the FDAIn December of the same year, Pirtobrutinib was granted accelerated approval by the FDA for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of systemic therapy, including a BTK inhibitor and a BCL-2 inhibitor.Eli Lilly submitted a marketing application to the CDE in December 2023 for Pirtobrutinib to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have previously received BTK inhibitor therapy, and it was granted priority review. Pirtobrutinib is the world's first non-covalent BTK inhibitor, and once approved in China, it will become a new treatment option for patients resistant to covalent BTK inhibitors due to the C481 mutation.Kelon Botai: Lukansatuzumab
Lukansatuzumab (sac-TMT/MK-2870) is the first China-produced novel antibody-drug conjugate (ADC) targeting advanced solid tumors, specifically targeting human trophoblast cell surface antigen 2 (TROP2). The drug utilizes a novel linker for development, with a belotecan-derived topoisomerase I inhibitor as the payload, achieving a drug-to-antibody ratio (DAR) of 7.4. The hydrolysable linker allows for extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release a membrane-permeable payload, enabling a "bystander effect." This design aims to achieve a more effective balance between stability in systemic circulation and payload release within tumor cells. Lukansatuzumab adopts a differentiated design concept that enhances ADC stability while maintaining its bioactivity, thereby strengthening its targeting ability and reducing off-target and on-target off-tumor toxicity, which is expected to broaden the therapeutic window.The Phase III OptiTROP-Breast01 study in patients with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC) demonstrated that, compared to chemotherapy, lurkonstatuzumab reduced the risk of disease progression or death by 69% (HR=0.31, P<0.00001). The median PFS was 5.7 months in the lurkonstatuzumab group and 2.3 months in the chemotherapy group. In the first planned interim analysis of OS, lurkonstatuzumab showed a statistically significant advantage over chemotherapy in terms of OS (HR: 0.53; 95% CI: 0.36~0.78; P=0.0005); the median OS for lurkonstatuzumab has not yet been reached, while the median OS for chemotherapy was 9.4 months. The ORR was 43.8% in the lurkonstatuzumab group and 12.8% in the chemotherapy group.In December 2023, Kelun-Biotech submitted a marketing application to the CDE for Luprociximab for the treatment of adult patients with unresectable locally advanced or metastatic TNBC who have received at least two prior systemic therapies (at least one for advanced or metastatic stage), and it was granted priority review. Gilead's Sacituzumab Govitecan is the world’s first and China’s first approved TROP2 ADC. Luprociximab, asChina's First TROP2 ADC, once approved, will become a new treatment option for TNBC patients.Copyright © 2024 PHARMCUBE. All Rights Reserved.Welcome to forward, share, and reasonably cite. When citing, please clearly indicate the source of the article in a prominent position;For reprinting, please leave a message or send a message to the WeChat Official Account backend, and indicate the name and ID of the official account.Disclaimer: The information in this WeChat article is for general reference only and should not be directly used as decision-making content. PharmaCube assumes no responsibility for any loss incurred by any party due to the use of the content herein.
