Papillary thyroid cancer (PTC) is the most common form of differentiated thyroid cancer (DTC). The traditional first line treatment for patients with advanced DTC after surgical resection is radioactive iodine (RAI) therapy. However, less than a quarter of patients with lung metastases will achieve a complete response to RAI therapy, and this therapy carries the risk of pulmonary fibrosis and an increasingly recognized risk of secondary malignancies.

开始日期2024-02-14

申办/合作机构

The Children's Hospital of Philadelphia

[+1]

NCT05725200 / Recruiting临床2期

Study to Investigate Outcome of Individualized Treatment Based on Pharmacogenomic Profiling & Ex Vivo Drug Sensitivity Testing of Patient-derived Organoids in Patients With Metastatic Colorectal Cancer

The purpose of the study is to investigate the effect and side effects of personalized cancer treatment in patients with metastatic colorectal cancer (bowel cancer). All patients included must have metastatic bowel cancer and receive or have received at least two lines of standard chemotherapy. The cancer must not be available for surgery with curative intent.

开始日期2022-09-27

申办/合作机构

Oslo universitetssykehus HF

NCT05236257 / CompletedN/A

A Comparison of Clinical Outcomes in Infantile Fibrosarcoma (IFS) Patients Treated With Larotrectinib in the Phase I/II SCOUT Study Versus (an) External Historical Cohort(s)

This is an observational study in which data from the past of children and young people with a specific cancer, called NTRK gene fusion positive infantile fibrosarcoma (IFS) is studied.
IFS is a rare type of childhood cancer that commonly affects legs and arms. IFS cancers typically have specific changes in their building plans (genes) called NTRK gene fusion. NTRK stands for the specific gene that has been altered, the neurotrophic tyrosine kinase (NTRK) gene.
This change to the building plan leads to the creation of an altered protein known as a TRK fusion protein, which can cause cancer cells to grow and to survive. The specific cancer is therefore also called TRK (tropomyosin receptor kinase) fusion-positive IFS.
The study drug, larotrectinib (also called BAY2757556) works by blocking the altered TRK fusion protein. Larotrectinib is already available in Europe and in many other countries and is approved for doctors to prescribe to patients with NTRK gene fusion cancer which has spread to nearby tissues and/or lymph nodes or to other parts of the body.
In France, HAS (the French authority in charge of evaluating health products and technologies) gave a positive opinion for the reimbursement of larotrectinib but only in the pediatric patients with IFS or another STS harboring a NTRK gene fusion, which is locally advanced or metastatic, and refractory or in relapse mainly due to the lack of comparative evidence.
The main purpose of this study is to collect more data to learn how well larotrectinib works compared with current standard of care chemotherapy in people up to 21 years of age with NTRK gene fusion positive IFS that has spread to nearby tissues and/or lymph nodes (locally advanced) or other parts of the body (metastatic).
To see how well larotrectinib works, researchers will make a comparison between
how long larotrectinib works well and
how long the standard of care works well.
Working well means that the treatments can prevent the following from happening:
need for a new treatment for the cancer
need for radiation therapy for the cancer
need for surgery to treat the cancer, but which causes major damage to body parts
death.
In addition to the above, data about medical problems related to the treatments in both groups and that may have required to stop the treatment will be compared.
The data for the comparison will come from
an ongoing international study called SCOUT which was started in December 2015 (larotrectinib group)
international databases (standard of care chemotherapy group). Data will be from the year 2000 up to the present.
There will be no required visits with a study doctor or required tests in this study.

开始日期2022-03-10

申办/合作机构

Bayer AG

100 项与硫酸拉罗替尼相关的临床结果

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100 项与硫酸拉罗替尼相关的转化医学

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100 项与硫酸拉罗替尼相关的专利（医药）

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342

项与硫酸拉罗替尼相关的文献（医药）

2024-03-15·Cancer

Identification of genetically predicted DNA methylation markers associated with non–small cell lung cancer risk among 34,964 cases and 448,579 controls

Article

作者: Schabath, Matthew B ; Kiemeney, Lambertus A ; Goodman, Gary E ; Jin, Guangfu ; Zhao, Xiaoyu ; Patel, Alpa V ; Qin, Na ; Johansson, Mattias ; Zhu, Meng ; Dai, Juncheng ; Hung, Rayjean J ; Le Marchand, Loïc ; Shete, Sanjay ; Chen, Chu ; Caporaso, Neil E ; Johansson, Mikael ; Grankvist, Kjell ; Ma, Hongxia ; Bojesen, Stig E ; Liu, Geoffrey ; Andrew, Angeline S ; Rennert, Gad ; Aldrich, Melinda C ; Risch, Angela ; Albanes, Demetrius ; Gorlov, Ivan P ; Amos, Christopher I ; Gorlova, Olga Y ; Zienolddiny, Shanbeh ; Lam, Stephen ; Brennan, Paul ; Tardón, Adonina ; Arnold, Susanne M ; Fan, Jingyi ; Bickeböller, Heike ; Woll, Penella J ; Jiang, Yue ; Hu, Zhibin ; Landi, Maria Teresa ; Shen, Hongbing ; Field, John K ; Davies, Michael P A ; Wang, Yifan ; Wang, Mei ; Lazarus, Philip ; Yang, Meiqi ; Christiani, David C ; Wichmann, H-Erich

Abstract:

Background:

Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non–small cell lung cancer (NSCLC) risk by a two‐stage case‐control design were investigated.

Methods:

The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed‐effect meta‐analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi‐omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways.

Results:

Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni‐corrected p ≤ 1.67 × 10−6) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni‐corrected p ≤ 1.28 × 10−3), including four novel CpGs. Multi‐omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty‐five genes within a 1‐Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified.

Conclusions:

Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby.

Plain Language Summary:

The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown.This study used summary data of large‐scale genome‐wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non–small cell lung cancer risk at the first time.This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins.These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

2024-03-01·Clinical orthopaedics and related research

Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing

Article

作者: Kohsaka, Shinji ; Endo, Makoto ; Ikeuchi, Hiroshi ; Sano, Kei ; Ishijima, Muneaki ; Takagi, Tatsuya ; Sasa, Keita ; Kato, Shunsuke ; Saito, Tsuyoshi ; Kikuta, Kazutaka ; Hasegawa, Nobuhiko ; Niizuma, Hidetaka ; Imanishi, Jungo ; Suehara, Yoshiyuki ; Hayashi, Takuo ; Hirabayashi, Kaoru

Abstract:

Background:

Approximately 1% of clinically treatable tyrosine kinase fusions, including anaplastic lymphoma kinase, neurotrophic tyrosine receptor kinase, RET proto-oncogene, and ROS proto-oncogene 1, have been identified in soft tissue sarcomas via comprehensive genome profiling based on DNA sequencing. Histologic tumor-specific fusion genes have been reported in approximately 20% of soft tissue sarcomas; however, unlike tyrosine kinase fusion genes, these fusions cannot be directly targeted in therapy. Approximately 80% of tumor-specific fusion-negative sarcomas, including myxofibrosarcoma and leiomyosarcoma, that are defined in complex karyotype sarcomas remain genetically uncharacterized; this mutually exclusive pattern of mutations suggests that other mutually exclusive driver oncogenes are yet to be discovered. Tumor-specific, fusion-negative sarcomas may be associated with unique translocations, and oncogenic fusion genes, including tyrosine kinase fusions, may have been overlooked in these sarcomas.

Questions/purposes:

(1) Can DNA- or RNA-based analysis reveal any characteristic gene alterations in bone and soft tissue sarcomas? (2) Can useful and potential tyrosine kinase fusions in tumors from tumor-specific, fusion-negative sarcomas be detected using an RNA-based screening system? (3) Do the identified potential fusion tumors, especially in neurotrophic tyrosine receptor kinase gene fusions in bone sarcoma, transform cells and respond to targeted drug treatment in in vitro assays? (4) Can the identified tyrosine kinase fusion genes in sarcomas be useful therapeutic targets?

Methods:

Between 2017 and 2020, we treated 100 patients for bone and soft tissue sarcomas at five institutions. Any biopsy or surgery from which a specimen could be obtained was included as potentially eligible. Ninety percent (90 patients) of patients were eligible; a further 8% (8 patients) were excluded because they were either lost to follow-up or their diagnosis was changed, leaving 82% (82 patients) for analysis here. To answer our first and second questions regarding gene alterations and potential tyrosine kinase fusions in eight bone and 74 soft tissue sarcomas, we used the TruSight Tumor 170 assay to detect mutations, copy number variations, and gene fusions in the samples. To answer our third question, we performed functional analyses involving in vitro assays to determine whether the identified tyrosine kinase fusions were associated with oncogenic abilities and drug responses. Finally, to determine usefulness as therapeutic targets, two pediatric patients harboring an NTRK fusion and an ALK fusion were treated with tyrosine kinase inhibitors in clinical trials.

Results:

DNA/RNA-based analysis demonstrated characteristic alterations in bone and soft tissue sarcomas; DNA-based analyses detected TP53 and copy number alterations of MDM2 and CDK4. These single-nucleotide variants and copy number variations were enriched in specific fusion-negative sarcomas. RNA-based screening detected fusion genes in 24% (20 of 82) of patients. Useful potential fusions were detected in 19% (11 of 58) of tumor-specific fusion-negative sarcomas, with nine of these patients harboring tyrosine kinase fusion genes; five of these patients had in-frame tyrosine kinase fusion genes (STRN3-NTRK3, VWC2-EGFR, ICK-KDR, FOXP2-MET, and CEP290-MET) with unknown pathologic significance. The functional analysis revealed that STRN3-NTRK3 rearrangement that was identified in bone had a strong transforming potential in 3T3 cells, and that STRN3-NTRK3–positive cells were sensitive to larotrectinib in vitro. To confirm the usefulness of identified tyrosine kinase fusion genes as therapeutic targets, patients with well-characterized LMNA-NTRK1 and CLTC-ALK fusions were treated with tyrosine kinase inhibitors in clinical trials, and a complete response was achieved.

Conclusion:

We identified useful potential therapeutic targets for tyrosine kinase fusions in bone and soft tissue sarcomas using RNA-based analysis. We successfully identified STRN3-NTRK3 fusion in a patient with leiomyosarcoma of bone and determined the malignant potential of this fusion gene via functional analyses and drug effects. In light of these discoveries, comprehensive genome profiling should be considered even if the sarcoma is a bone sarcoma. There seem to be some limitations regarding current DNA-based comprehensive genome profiling tests, and it is important to use RNA testing for proper diagnosis and accurate identification of fusion genes. Studies on more patients, validation of results, and further functional analysis of unknown tyrosine kinase fusion genes are required to establish future treatments.

Clinical Relevance:

DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible.

2024-02-01·Bioorganic & medicinal chemistry

Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors

Article

作者: Chen, Yinbo ; Chu, Yong ; Wang, Zhenghai ; Zhao, Wei ; Xu, Yunsheng ; Zhu, Xueyan ; Yu, Xihua ; Zhang, Xinyi ; Zhang, Peng

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRK^WT, TRK^G595R and TRK^G667C with IC₅₀ values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC₅₀ = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T_1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

131

项与硫酸拉罗替尼相关的新闻（医药）

2024-06-14

·FiercePharma

Bristol Myers bags FDA tumor-agnostic nod for Augtyro to challenge Bayer, Roche

To convert Augtyro's accelerated approval into a full nod, the FDA is asking Bristol Myers Squibb for more tumor response and duration of response data. A Bristol Myers Squibb drug has got an FDA approval to treat tumors with a specific biomarker regardless of their locations in the body. The drug, Augtyro, has won the FDA’s accelerated approval in solid tumors that have an NTRK gene fusion, Bristol Myers said Thursday. The tyrosine kinase inhibitor (TKI) can be used in patients 12 years of age and older, but the tumors must have been previously treated or have no satisfactory alternative therapy. This tumor-agnostic indication is familiar to the oncology community. Back in 2018, Bayer’s Vitrakvi became the first targeted therapy to get its initial FDA go-ahead for cancers based on a genetic biomarker rather than where the tumor originated, and the indication was NTRK gene fusion. Then Roche’s Rozlytrek followed with the same label addition in 2019. BMS got Augtyro from its $4.1 billion acquisition of Turning Point Therapeutics in 2022, and then in November 2023 pushed the drug across the FDA finish line in ROS1-positive non-small cell lung cancer, where it’s also competing with Roche’s Rozlytrek. In NTRK mutation-positive solid tumors, Augtyro differentiates itself as the only option that has been studied both in patients who had not tried a TKI before and in TKI-experienced patients, Bristol Myers said. In the phase 1/2 TRIDENT-1 trial, Augtyro triggered a response in 58% of 40 TKI-naïve patients, including 15% who had complete responses. Of those who responded, 83% were still in response after one year. Among 48 TKI-pretreated patients, Augtyro’s overall response rate was 50%, which included no complete response. At one year, 41% of responding patients were still in remission. The median duration of response was 9.9 months. Across the two subgroups, the TRIDENT-1 trial enrolled patients with 15 different types of cancer, including NSCLC, thyroid cancer, salivary gland cancer, glioblastoma, colorectal cancer and others. With the accelerated approval, BMS will need to provide additional data to confirm Augtyro’s benefits. To convert the nod into a full approval, the FDA is asking for tumor response and duration of response data from “a sufficient number of patients” across tumor types, with all responding patients being followed for at least 12 months from the onset of response or until disease progression, according to the agency. The FDA’s request for Augtyro is similar to those for Vitrakvi and Rozlytrek, neither of which has converted their accelerated approvals. Although a tumor-agnostic label covers tumors at different locations, NTRK gene fusions are rare. Last year, Rozlytrek only got Roche 86 million Swiss francs ($96 million) in sales across its two indications. Bayer didn’t specify Vitrakvi’s sales in its annual report. Augtyro marked Bristol Myers Squibb’s initial expansion into targeted therapies from an immunotherapy-focused oncology portfolio. The New Jersey pharma went deeper into targeted therapies with the acquisition of Mirati Therapeutics, which brought with it the KRAS inhibitor Krazati.

免疫疗法加速审批并购上市批准

2024-06-13

·CPHI制药在线

浅谈胰腺导管癌治疗进展：在研药物多样，诺华放弃，康宁杰瑞惨败

关注并星标CPHI制药在线胰腺癌是一组主要起源于胰腺导管上皮及腺泡细胞的恶性肿瘤，恶性程度极高，起病隐匿，早期诊断困难，进展迅速，生存时间短，是预后最差的恶性肿瘤之一，被称为"癌中之王"。即使在新疗法不断涌现的今天，胰腺癌的治疗也并未取得突破进展。下面笔者将浅谈下胰腺癌的主要类型--胰腺导管腺癌的治疗现状，以及近年该领域药物的研究进展。关于胰腺导管癌胰腺导管腺癌（PDAC）是一种发生于胰腺导管上皮的肿瘤，是胰腺癌中的主要类型，约占90%以上。PDAC起病隐匿，且具有高度侵袭性，大多患者确诊时已处于晚期。由于缺乏有效的治疗手段，PDAC患者总体5年生存率< 12 %。据2024年2月中国国家癌症中心（NCC）发布的2022年中国新发癌症病例数和死亡人数数据：2022年中国胰腺癌新发病例11.87万，死亡人数10.63万。手术和化疗是PDAC的主要治疗手段，但只有15%-20%的患者在诊断时符合手术条件。不过据《Nature》官网发布的相关研究论文数据，即便能手术，近90% 的PDAC患者在治疗平均7~9个月内会面临复发。而晚期PDAC标准治疗是化疗，常采用联合治疗方案，如AG（白蛋白紫杉醇联合吉西他滨）方案、改良FOLFIRINOX（mFOLFIRINOX，奥沙利铂+伊立替康+亚叶酸钙+氟尿嘧啶）方案或S-IROX（替吉奥+伊立替康+奥沙利铂）方案。据2023年6月美国国家综合癌症网络（NCCN）指南发表的2023年第2版胰腺癌诊治指南：（1）对于部分可切除性胰腺癌，指南推荐先行新辅助治疗（NAT）再手术，推荐方案包括FOLFIRINOX或改良FOLFIRINOX方案，以及吉西他滨联合白蛋白结合紫杉醇方案（AG方案），其中FOLFIRINOX或mFOLFIRINOX方案适用于美国东部肿瘤协作组（ECOG）评分0~1分的病人。术后指南建议患者常规开展化疗，化疗首选方案包括FOLFIRINOX/mFOLFIRINOX方案或吉西他滨联合卡培他滨方案；（2）对于晚期或转移性胰腺癌：PS评分良好（0~1分）局部晚期/转移性胰腺癌一线治疗新增NALIRIFOX方案，即脂质体伊立替康+5-氟尿嘧啶+亚叶酸+奥沙利铂，PS评分中等（2分）局部晚期胰腺癌一线治疗首选卡培他滨或吉西他滨单药化疗或AG方案，PS评分中等（2分）转移性胰腺癌首选AG方案，其次卡培他滨或吉西他滨，NALIRIFOX方案在某些情况下也可使用；（3）对于复发的局部进展期/转移性胰腺癌，PS评分良好者，当NTRK融合基因阳性，首选恩曲替尼或拉罗替尼；当存在微卫星高度不稳定（MSI-H）、错配修复缺陷（dMMR）或肿瘤突变负荷（TMB）≥10 mut/Mb者，建议使用帕博丽珠单抗。新版指南建议在其他治疗方案中新增以下内容：对于合并MSI-H、dMMR者，可使用多塔利单抗；若TMB≥10 mut/Mb，也可使用纳武利尤单抗+伊匹木单抗；PS评分中等者，无首选方案。胰腺导管癌药物研究进展上述方案对PDAC治疗效果有限，且有些药物只适用于特定患者。药企对PDAC新疗法的探索从未止步，今年2月FDA批准NALIRIFOX（脂质体伊立替康 (Onivyde)+奥沙利铂+氟尿嘧啶 (5-FU)/亚叶酸）方案一线治疗转移性PDAC。此外，目前全球还有多款在研PDAC新疗法，详见下表。这些在研疗法作用靶点各异，具体适应症有所不同，且药物类型多样，涉及化药、单抗、双抗、CAR-T疗法、疫苗以及溶瘤病毒等。研发进度上，NIS793、KN046等处于3期临床。其中NIS793是一种完全人源的单克隆抗体，通过阻断TGFβ细胞因子而发挥作用，2021年被FDA授予治疗胰腺癌的孤儿药资格，其联合吉西他滨和Nab-紫杉醇一线治疗PDAC的临床试验已进入3期阶段。值得一提的是，诺华曾于2015年从Xoma引进NIS793，但2024年诺华宣布停止研发NIS793，并将其退还给Xoma。 KN046是康宁杰瑞研发的一款PD-L1/CTLA-4靶向双抗。已公布的2期临床研究（NCT04324307）数据显示：对于31例无法切除的晚期胰腺癌患者，KN046联合AG方案的ORR为45.2%，DCR为93.5%。遗憾的是，今年5月，康宁杰瑞宣布KN046联合AG方案一线治疗不可切除局部晚期或转移性PDAC的3期临床试验KN046-303惨遭失败，OS结果未达到统计学终点。索凡替尼治疗胰腺癌方面处于2/3期临床，2024年5月其联合卡瑞利珠单抗和化疗（白蛋白结合型紫杉醇+吉西他滨)一线治疗转移性PDAC的2/3期临床试验启动。该药是和黄医药开发的一种新型的口服酪氨酸激酶抑制剂，已被NMPA批准用于无法手术切除的局部晚期或转移性、进展期非功能性、分化良好（G1、G2）的非胰腺（2020年12月）和胰腺（2021年6月）来源的神经内分泌瘤。已公布的索凡替尼治疗胰腺癌的临床试验结果显示：索凡替尼联合TAS-102三线或后线治疗方案对mPDAC患者有令人鼓舞的抗肿瘤活性，特别是对无肝转移患者。此外，与索凡替尼仅联合化疗相比，索凡替尼联合卡瑞利珠单抗和化疗一线治疗胰腺癌可显著延长患者的OS和PFS。 CAN-2409、Motixafortide等处于2期临床。其中CAN-2409是一种复制缺陷的腺病毒，旨将单纯疱疹病毒胸苷激酶（HSV-tk）基因递送至患者的肿瘤并诱导个体化的全身抗肿瘤免疫反应。HSV-tk是一种酶，可局部将口服伐昔洛韦转化为杀死附近癌细胞的有毒代谢物，从而释放多种癌症抗原。该疗法通过局部注射将免疫应答局部聚焦于肿瘤，能够最大限度地减少与全身静脉给药相关的全身毒性。2024年4月，CAN-2409被FDA授予治疗胰腺癌的孤儿药资格。已公布的CAN-2409联合抗病毒药物与标准护理（SoC）放化疗用作可切除PDAC术前辅助治疗的2期临床试验结果显示：截至2024年3月29日数据，在边缘性可切除PDAC中，CAN-2409组患者的mOS为28.8个月（Vs 对照组的12.5个月）；24个月时，CAN-2409治疗组患者的生存率为71.4%（Vs 对照组的16.7%），；36个月时，CAN-2409治疗组的生存率为47.6%（Vs 对照组的16.7%）。CAN-2409还显示出良好的耐受性，没有显著的额外局部或全身毒性。而且，对切除肿瘤的分析显示，患者在使用CAN-2409联合疗法后，其PDAC组织中出现密集的免疫细胞聚集，包括CD8+细胞、细胞毒性肿瘤浸润淋巴细胞和树突状细胞，这证实该疗法能够激活强大的抗肿瘤免疫反应。安全性方面，在SoC中添加CAN-2409方案显示出良好的耐受性，没有观察到剂量限制性毒性。 Motixafortide是Biokine Therapeutics 研发的一款靶向CXCR4的长效合成多肽拮抗剂，后授权给BioLineRx。2023年9月，该疗法被FDA批准联合filgrastim（G-CSF），以在多发性骨髓瘤患者中动员造血干细胞到外周血进行采集，辅助进行自体干细胞移植。治疗PDAC方面，已公布的临床研究结果显示：Motixafortide联合帕博利珠单抗和化疗在治疗PDAC方面表现出良好的安全性和耐受性，且在预后不良和病情凶险的PDAC人群中显示出疗效。 2023 AACR上公布的Motixafortide联合帕博利珠单抗和AG方案一线治疗转移性胰腺癌的单臂2期临床试验结果显示：可评估患者(11人)的ORR为55%，36%患者出现PR，1例患者的肝转移病灶得到缓解。此外，27%的患者(3例)病情稳定，DCR为82%。 Mitazalimab是一种靶向CD40的单克隆抗体，通过激活树突状细胞、B细胞和巨噬细胞等免疫细胞，使肿瘤对化疗敏感，大幅增强抗肿瘤的能力。今年2月，该药被欧盟授予孤儿药资格，联合与mFOLFIRINOX方案一线治疗转移性PDAC。 2024年1月，Alligator Bioscience宣布Mitazalimab联合mFOLFIRINOX化疗一线治疗胰腺癌的2期临床研究达到主要研究终点。具体数据为：57名可评估患者的ORR为40.4%，DCR为79%，mOS为14.3个月，中位缓解持续时间为12.5个月（优于FOLFIRINOX标准治疗的5.9个月）。 CEND-1是一种由9个氨基酸构成的环肽药物，可与肿瘤中选择性表达的alpha-v整合素结合，然后被肿瘤微环境中表达的蛋白酶切割，释放出被称为CendR片段的肽片段，该片段再与第2个受体neuropilin-1结合，从而激活一种新的摄取途径（CendR途径），使抗癌药物能够穿透实体瘤。CEND-1改变肿瘤微环境以增强联合治疗药物的递送和功效的能力已在一系列实体瘤模型中得到证实。2021年2月，齐鲁制药与Cend Therapeutics签订合作和许可协议，获得CEND-1在大中华区开发和商业化权益。柳叶刀杂志上发表的CEND-1联合标准治疗化疗（吉西他滨和白蛋白紫杉醇）一线治疗转移性PDAC的1期临床研究数据显示：29例疗效可评估患者中的ORR为59%，mOS为13.2个月。 Efineptakin Alfa治疗胰腺癌方面处于1/2期临床。该药是一种长效人类白细胞介素 7，其联合帕博利珠单抗对胰腺癌患者展示出良好的疗效：7.7％的患者肿瘤大幅缩小或消失，34.6％的患者疾病得到有效控制。2024年2月，该疗法被FDA授予治疗晚期胰腺癌的孤儿药资格。 ELI-002、D-1553等处于1期临床。其中ELI-002是一款针对KRAS突变的治疗型疫苗，主要针对KRAS突变阳性实体瘤，尤其是PDAC、结直肠癌。该疫苗由两个关键组件构成，即AMP-CpG（一种特有的免疫激活剂，可刺激免疫系统产生强烈的反应）和AMP-mKRAS-肽。其中AMP-mKRAS-肽是一种经修饰的KRAS突变肽，可特异性地引导机体免疫系统，追踪并摧毁携带KRAS突变的癌细胞。 2024年1月《Nature》杂志上发表的1期临床试验AMPLIFY-201结果显示：ELI-002可显著降低患者肿瘤标志物水平，并产生强烈的T细胞应答，从而降低患者复发及死亡的风险，且总体上被认为是安全可控的。 IBI389是信达生物自主研发的一种抗CLDN18.2/CD3双特异性抗体。2024 ASCO上公布的IBI389治疗晚期不可手术或转移性PDAC的1期临床数据显示：600μg/kg治疗组疗效更佳，在27例至少进行了一次基线后肿瘤评估的受试者中，ORR为29.6% ，确认的客观缓解率（cORR）为25.9%，DCR达70.4%（95%CI：49.8-86.2）。在CLDN18.2 IHC 2/3+≥40%的18例受试者中，cORR达38.9%。此外，截至2024年5月1日，中位随访时间为4个月，mPFS尚未成熟，3个月的PFS率达57.1%。 CT041是一种潜在全球同类首创、靶向CLDN18.2蛋白的自体CAR-T细胞疗法，用于治疗Claudin18.2阳性实体瘤，主要治疗胃癌/食管胃结合部腺癌及胰腺癌。最近公布的CT041治疗难治性转移性胰腺癌的两项多中心、开放标签的1/1b期临床试验数据显示：24例患者中有12例观察到肿瘤靶病灶不同程度缩小，ORR为16.7%，DCR为70.8%，临床获益率为37.5%。mDoR为9.5个月，12个月的DoR率为50%，mPFS为3.3个月，mOS为10.0个月，12个月时OS率为45.8%。 D-1553是益方生物自主开发的一款新型、高效、口服KRAS G12C抑制剂。已公布的D-1553针对KRAS G12C突变晚期胰腺癌的早期临床试验结果显示：D-1553单药治疗在KRAS G12C突变胰腺癌患者中展现出良好的耐受性和临床活性，确认的ORR为35.7%（5/14），DCR为85.7%（12/14），mPFS为8.54个月。今年5月，该药被CDE纳入突破性治疗品种，用于治疗经一线治疗失败的伴KRAS G12C突变局部晚期或转移性PDAC。 IMM-1-104是Immuneering 开发一款高选择性第三代小分子MEK抑制剂，每日口服一次。该药通过深度循环抑制MAPK途径，实现对RAS基因的通用抑制活性。在一项1/2a期研究中，IMM-1-104对包括PDAC、恶性黑色素瘤、NSCLC在内的多种实体瘤展现出良好的初步疗效。2024年2月，该药被FDA授予一线治疗PDAC的快速通道认定。总结整体来看，多款在研PDAC新疗法进入临床试验，且早期临床试验结果积极。监管机构也通过授予突破性疗法、快速通道资格等方式加速PDAC的研发进程。但PDAC的治疗较其他恶性肿瘤，如NSCLC、黑色素瘤，并未取得很大突破。而且，与其他恶性肿瘤在研药物不同，在研PDAC药物作用靶点相当分散，笔者分析这可能与PDAC自身的特性，以及诊断上缺乏特异的生物标志物有关。期待在研究人员的不懈努力下，PDAC治疗可以早日迎来新局面。【企业推荐】【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

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83%患者肿瘤显著缩小甚至消失！拉罗替尼为难治性肿瘤带来救赎

客观缓解率为 83%，其中有2名幸运的患者接受治疗后肿瘤病灶消失，评效达到完全缓解，拉罗替尼为难治性甲状腺癌患者带来全新的治疗选择！在中国，甲状腺癌的发病率占所有恶性肿瘤的第七位，是内分系统最为常见的恶性肿瘤。甲状腺癌种类较多，可分为分化型甲状腺癌、髓样甲状腺癌和未分化甲状腺癌。目前，大部分甲状腺癌首选手术切除，近年来，随着分子靶向药物的迅速发展，甲状腺癌已有多款靶向药研发成功，终于迎来手术之外的“救命”手段！ 83%患者肿瘤显著缩小甚至消失！拉罗替尼为难治性甲状腺癌带来救赎 2018年，全球首个不区分肿瘤来源用于初始治疗的靶向药-拉罗替尼（Vitrakvi ®，larotrectinib，下文统称拉罗替尼），让整个医疗界和癌友圈沸腾，这在肿瘤治疗史上是一个振奋人心的里程碑。自此，无论多么罕见难治的癌症类型，无论长在什么部位，无论是否扩散...对于存在NTRK融合的患者来说，拉罗替尼是一款可能改变生死的新药。近期，这款药物公布了在难治性甲状腺癌中的临床数据，同样非常鼓舞人心。 2018 年至 2022 年间，对 184 名非髓性晚期 TC 患者进行了NTRK基因融合的检测，共有8/184 (4%) 为NTRK融合阳性。其中4名NTRK1和2名NTRK3基因融合的放射性碘 (RAI) 难治性甲状腺癌患者接受了 larotrectinib 治疗，所有患者在治疗开始前病情都处于进展状态。结果显示：客观缓解率（ORR）为 83%，包括2例完全缓解。从 TRK 抑制剂治疗开始起中位无进展生存期（ PFS ）为 23 个月。值得一提的是，67 岁的M女士曾在 2017 年 11 月首次诊断为甲状腺滤泡癌，出现了淋巴结、肝脏和肺部的转移。在接受了氢化可的松和乐伐替尼等方案治疗后，病情出现进展。为了寻求更有效的治疗方案，M女士进行了全基因组测序，结果惊喜的发现存在SQSTM1/NTRK3 基因融合。 M女士开始接受拉罗替尼的治疗，仅仅4周， Tg 降低至 1690 ng/mL。截至文献发表时，M女士已经接受拉罗替尼治疗 30 个月，整体病情稳定，播散性肝转移转移性病灶显著缩小，评效达到部分缓解（PR）。图3 “传奇”抗癌药拉罗替尼已上市，国内多中心启动临床！值得所有中国病友们振奋的是，2022年4月13日，全球首个不区分肿瘤来源的广谱靶向药-larotrectinib（硫酸拉罗替尼胶囊，Vitrakvi ®，下文统称拉罗替尼）终于获得中国国家药品监督管理局批准正式上市，用于治疗患有NTRK基因融合的局部晚期或转移性实体瘤的成人和儿童患者！该药的最大看点在于：一：不区分肿瘤来源，对25类癌症有效它是一款针对特定基因突变，而不针对特定癌症种类的抗癌新药。因此，只要基因检测存在有NTRK的融合，不管是什么类型的癌症，不论早期还是晚期，不论成人还是儿童，都可以尝试拉罗替尼。研究证实，拉罗替尼可治疗成人和儿童肿瘤 25种存在NTRK融合的不同的肿瘤类型，最常见的是：软组织肉瘤（STS [43%]，包括婴儿纤维肉瘤 [18%] 和其他类型[25%]）、甲状腺（11%）、肺癌（10%）、唾液腺（9%）和结肠直肠（7% ）等。二：长期生存，64%患者生存时间超4年近期对 larotrectinib 的临床研究进行的汇总分析报告了其对多种癌症类型的长期疗效。总客观缓解率高达 69% ，其中64名幸运的患者（26%）肿瘤全部消失，达到完全缓解（CR，影像学检查靶病灶全部消失），104（43%）部分缓解；更值得一提的是，48 个月总生存率（OS）为 64%，这意味着，参加临床试验中 64%的NTRK融合患者生存时间都超过了4年！治疗持续时间从 0.1 至 67.9 个月，最长的患者治疗持续长达近6年！三：强大的入脑活性，迄今为止在原发性中枢神经系统癌症中最大规模的 TRK 抑制剂研究（NCT02637687、NCT02576431）结果显示：所有患者的客观缓解率（ORR）为 30% ，24 周的疾病控制率为 73%，这意味着，30%的患者肿瘤显著缩小30%以上甚至消失， 82% 的患者肿瘤不同程度的缩小（23/28）。因此，在 TRK 融合阳性中枢神经系统肿瘤患者中，拉罗替尼具有强大的入脑活性，展现出快速和持久的反应、高疾病控制率和良好的安全性。值得庆幸是，中国的癌症患者迎来了好时代！目前拉罗替尼针对成人实体瘤和儿童实体瘤的两项试验仍在国内进行临床招募，已经有大量NTRK融合的患者通过全球肿瘤医生网医学部成功入组并接受抗癌新药治疗，成功逆转了病情，我们希望有更多的病友知道这个好消息，有更多的病友能够获益于这些新型的抗癌药物，战胜癌症！除了拉罗替尼，还有多款美国及中国自主研发的NTRK抑制剂正式在国内获批开展临床试验。以前这些美国研发上市的抗癌新药对于国内的患者来说遥不可及，近两年随着国家的重视，加快了各类抗癌药物研发上市的审批速度，相信这些效果好的抗癌药都会加快在我国上市和纳入医保的步伐，让更多的百姓获益，让我们共同期待吧！参考资料： Koehler, V.F., Achterfeld, J., Sandner, N. et al. NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer. J Cancer Res Clin Oncol 149, 14035–14043 (2023). https://doi-org.libproxy1.nus.edu.sg/10.1007/s00432-023-05134-x

上市批准临床结果临床研究

100 项与硫酸拉罗替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11138	硫酸拉罗替尼	L01XE53	DB14723

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
NTRK融合阳性实体瘤	欧盟	Bayer AG	2019-09-19
NTRK融合阳性实体瘤	冰岛	Bayer AG	2019-09-19
NTRK融合阳性实体瘤	列支敦士登	Bayer AG	2019-09-19
NTRK融合阳性实体瘤	挪威	Bayer AG	2019-09-19
实体瘤	美国	Bayer HealthCare Pharmaceuticals, Inc.	2018-11-26

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
甲状腺癌	临床2期	美国	Bayer AG	2024-02-14
晚期恶性实体瘤	临床2期	美国	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	澳大利亚	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	加拿大	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	丹麦	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	法国	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	德国	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	爱尔兰	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	意大利	Bayer AG	2015-12-16
晚期恶性实体瘤	临床2期	荷兰	Bayer AG	2015-12-16

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05192642 (VICTORIA, ASCO2024) 人工标引	N/A	肿瘤 TRK fusion	164	Larotrectinib	獵製膚選鏇醖製顧選醖(鹽廠廠願觸醖網範製鑰) = 選鏇鹹夢鑰壓膚鏇簾網廠壓築齋夢醖鑰廠簾繭 (願壓鹹蓋壓遞網壓淵簾 ) 更多	积极	2024-05-24
NCT05192642 (VICTORIA, ASCO2024) 人工标引	N/A	肿瘤 TRK fusion	164	non-TRK inhibitor therapies	獵製膚選鏇醖製顧選醖(鹽廠廠願觸醖網範製鑰) = 糧鏇淵鹽範蓋顧構襯顧廠壓築齋夢醖鑰廠簾繭 (願壓鹹蓋壓遞網壓淵簾 ) 更多	积极	2024-05-24
NCT02576431 \| NCT02637687 \| NCT02122913 (ASCO2024)	N/A	RET融合阳性甲状腺癌	31	Larotrectinib 100 mg	鑰餘淵齋膚憲蓋鹽壓淵(襯構餘窪壓鏇齋襯築遞) = Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 3 (10%) pts. There were no treatment discontinuations due to TRAEs. 廠製醖憲糧壓糧糧膚壓 (艱醖鑰製遞窪鹽窪醖醖 ) 更多	积极	2024-05-24
NCT04477681 (SACHA-France, ASCO2024)	N/A	实体瘤 NTRK3 \| NTRK2 \| NTRK1	21	Larotrectinib	遞壓網蓋願憲夢選憲淵(衊衊築構壓鬱淵夢衊膚) = 壓衊膚憲餘窪淵構網蓋壓襯醖鏇窪繭廠憲鏇觸 (淵壓醖獵襯鬱蓋遞築膚 ) 更多	积极	2024-05-24
NCT02576431 \| NCT02122913 (ASCO2024)	N/A	肺癌 NTRK1 \| NTRK3	32	Larotrectinib 100 mg	繭繭鹽鹽廠憲範遞鹽願(襯觸選積願範憲遞觸襯) = Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in nine patients. One patient discontinued treatment due to TRAEs (increased alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase) 鹽遞餘製選網簾襯窪遞 (簾範製繭繭範觸蓋鏇鹽 )	积极	2024-05-24
NCT02576431 \| NCT02122913 (ESMO_ELCC2024) 人工标引	N/A	肺癌 NTRK gene fusion	27	Larotrectinib 100 mg	築淵艱觸積窪鹹餘齋鏇(淵範醖積壓蓋窪鹹蓋觸) = Treatment-related adverse events were mostly Grade 1/2 艱築繭淵蓋遞繭膚襯壓 (繭獵壓鹽衊選製窪齋蓋 )	积极	2024-03-22
NCT02576431 (NAVIGATE, ASCO_GI2024) 人工标引	临床2期	胃肠道肿瘤 MSI-High	42	Larotrectinib	積鹽壓窪窪鏇選選獵衊(願齋襯簾鏇憲襯選膚糧) = 鏇窪淵選蓋構積簾獵築製艱範鏇顧窪壓淵糧餘 (廠憲觸積糧選鏇鑰鑰製, 15 ~ 47) 更多	积极	2024-01-18
ESMO2023	N/A	肿瘤一线	-	Larotrectinib	獵願艱鬱憲獵鏇窪鹹簾(遞鑰蓋夢餘夢積觸獵窪) = 淵憲廠淵築簾餘廠壓衊淵鑰鬱觸憲鹹餘夢醖範 (襯網鏇遞淵齋鹽鑰蓋艱, 70 ~ 88) 更多	-	2023-10-23
ESMO2023	N/A	肿瘤	-	Larotrectinib	觸鏇襯網淵醖製膚觸襯(製憲鹹夢壓鹽製積蓋遞) = 繭廠構膚鹽餘糧廠網築淵襯鏇壓遞鬱觸構獵築 (獵網餘糧繭鹽網鑰構鹹 ) 更多	积极	2023-10-23
NCT02576431 (NAVIGATE, ESMO_GI2023)	临床2期	胃肠道肿瘤 MSI-H	42	Larotrectinib	積膚鑰糧夢齋衊醖蓋築(鬱積艱廠艱遞遞顧鏇蓋) = Grade 3/4 TRAEs occurred in seven (17%) patients (two increased transaminases; one each abnormal hepatic function, anaemia, hyperaesthesia, leukopenia, nausea, neutropenia and thrombopenia) 襯鑰選觸齋製齋襯襯選 (鹽製範衊鬱製齋糧壓衊 ) 更多	积极	2023-07-01
NCT03834961 (ADVL1823, ASCO2023) 人工标引	临床2期	纤维肉瘤 NTRK Fusion	18	Larotrectinib	夢選範繭夢蓋鑰願鹹構(窪齋選鹽繭築憲廠餘艱) = 選遞膚鹹構壓簾餘壓築製鹽顧膚選衊膚製鹽構 (鹽顧築繭鹽壓鹹構憲製 ) 更多	积极	2023-05-31