CStone基石藥業 申請台灣上市 抑制劑RET融合/突變 肺癌、甲狀腺癌

The RET (REaranged during Transfection) proto-oncogene, situated on chromosome sub-band 10q11.2, encodes a receptor tyrosine kinase expressed in tissues and tumors derived from neural crest. RET is a receptor tyrosine kinase involved in cell proliferation, neuronal navigation, cell migration, and cell differentiation. Oncogenic activation can occur via mutation or rearrangement. Germline mutations in RET cause multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Somatic RET mutations have been found in a proportion of sporadic medullary thyroid carcinomas and pheochromocytomas, and are associated with sporadic and radiation-induced papillary thyroid cancer (3-6).Recently novel gene fusions involving the RET tyrosine kinase gene were described in lung adenocarcinomas: KIF5B, CCDC6, and NCOA4 . These fusions are generated by an inversion of the short and long arms of chromosome 10. All the proteins encoded by KIF5B-RET, CCDC6-RET, and NCOA4-RET have coiled-coil domains, inducing constitutive dimerization of the oncoprotein, with abnormal activation of RET kinase function, similarly to the ALK fusions (7,8). RET alterations are found in about 1–2% of unselected lung adenocarcinomas patients, reaching a frequency of about 6% among never-smokers patients, with tumors not-harbouring other known driver mutations (9-11). While the functional consequences and the clinical relevance of RET fusions in lung adenocarcinoma are not fully understood, they are oncogenic in vitro and in vivo. doi: 10.21037/tcr.2017.09.21

基石藥業宣佈普拉替尼用於治療RET融合非小細胞肺癌和RET變異甲狀腺癌的新藥上市申請在中國台灣獲受理 2022年2月17日 蘇州2022年2月17日 /美通社/ -- 基石藥業（香港聯交所代碼：2616），一家專注於開發及商業化創新腫瘤免疫療法及精準治療藥物的領先生物製藥公司，今日宣佈，選擇性RET抑制劑普拉替尼用於治療轉染重排（RET）基因融合陽性的局部晚期或轉移性非小細胞肺癌（NSCLC）、RET突變的晚期或轉移性甲狀腺髓樣癌（MTC）以及放射性碘難治（如放射性碘適用）的RET融合陽性的晚期或轉移性甲狀腺癌（TC）的新藥上市申請已在中國台灣獲受理。基石藥業首席醫學官楊建新博士表示：「我們高興的看到繼泰時維® 獲批用於攜帶 PDGFRA D842V突變的胃腸道間質瘤患者後，又一款重磅精準藥物普拉替尼成功在中國台灣遞交非小細胞肺癌和甲狀腺癌的上市申請。在全球I/II期ARROW臨床研究中，普拉替尼在RET融合陽性的局部晚期或轉移性NSCLC和RET突變的晚期或轉移性MTC患者中，表現出優異且持久的療效以及良好的耐受性。我們期待普拉替尼能夠早日在中國台灣獲批上市，惠及更多患者。」此次普拉替尼在中國台灣的新藥上市申請獲受理是基於一項全球I/II期ARROW臨床研究，該研究旨在評估普拉替尼在RET融合陽性的非小細胞肺癌、RET突變型甲狀腺髓樣癌和其他RET融合的晚期實體瘤患者中的安全性、耐受性和有效性。2021年6月美國臨床腫瘤學會（ASCO）年會上公佈了ARROW研究中全球RET融合陽性NSCLC患者的試驗結果。截至2020年11月6日的數據，在接受起始劑量400mg每日一次的療效可評估的RET融合陽性NSCLC患者中，普拉替尼具有持久的臨床獲益。在68例未經系統性治療的患者中，總體緩解率（ORR）為 79%（95% CI：68%、88%）。完全緩解率（CR）為6%，10%患者的靶病灶完全消失，74%的患者為部分緩解（PR）。中位緩解持續時間（DOR）尚未達到（95% CI：9.0個月，未達到）。在126例既往接受過含鉑化療的患者中，ORR為 62%（95% CI：53%、70%）。CR率為4%，12%患者的靶病灶完全消失，58%的患者達到PR。中位DOR為 22.3個月（95% CI：15.1個月，未達到）。截至數據截止日期，共有471例不同瘤種患者入組，最常見的不良事件（AE）是中性粒細胞減少、天冬氨酸氨基轉移酶升高、貧血、白細胞計數減少、丙氨酸氨基轉移酶升高、高血壓、便秘和乏力。2021年8月《柳葉刀·糖尿病與內分泌學》上發表了ARROW研究中全球RET變異甲狀腺癌患者的試驗結果。截至2020年5月22日，普拉替尼在RET突變的甲狀腺癌患者中顯示出強效而持久的抗腫瘤活性。所有患者接受的起始劑量為400毫克每日一次。在55例既往接受過卡博替尼或凡德他尼治療的RET突變MTC患者中，ORR為60%（95%CI：46%，73%），中位DOR尚未達到（95%CI：15.1個月，不可評估）。在21例未經系統性治療的RET突變MTC患者中，ORR為71%（95%CI：48%，89%），中位DOR尚未達到（95%CI：不可評估，不可評估）。在9例RET融合陽性甲狀腺癌患者中，ORR為89%（95%CI：52%，100%），中位DOR尚未達到（95%CI：不可評估，不可評估）。在142例RET變異的甲狀腺癌患者中，最常見的不良事件是貧血、肌肉骨骼疼痛、便秘、天門冬氨酸轉氨酶升高和高血壓。

關於RET融合陽性非小細胞肺癌 近年來肺癌發病率在中國持續增長。根據世界衛生組織國際癌症研究機構（IARC）發佈的2020年全球最新癌症負擔數據，中國在2020年約有82萬新發肺癌病例數，約有 71萬肺癌導致的死亡人數。在男性和女性癌症患者中，肺癌均為癌症相關死亡的主要原因。其中，非小細胞肺癌占肺癌的大多數。在肺癌領域，EGFR、ALK、ROS1等驅動基因突變已廣泛普及，針對這些驅動基因的靶向藥物均已獲批上市。RET融合是新近發現的肺癌驅動基因，在非小細胞肺癌中RET融合患者約占1- 2%，常見於不吸煙的年輕人群。

關於RET變異甲狀腺癌 甲狀腺癌是最常見的內分泌惡性腫瘤，近幾年發病率顯著上升。根據世界衛生組織國際癌症研究機構（IARC）發佈的2020年全球最新癌症負擔數據，中國在2020年約有22萬新發甲狀腺癌病例數，其中女性新發病例數約為17萬[1]。甲狀腺癌發病率位居中國城市地區女性所有惡性腫瘤的第4位。甲狀腺癌在臨床上分為乳頭狀癌、濾泡癌、未分化癌和髓樣癌等多個亞型，不同類型的甲狀腺癌根據其腫瘤特點，治療手段及預後均不相同。RET融合和激活突變是許多癌症類型（包括NSCLC和多種類型的甲狀腺癌）中的關鍵疾病驅動因素。大約10-20%的甲狀腺乳頭狀癌（最常見的甲狀腺癌）患者攜帶RET融合，大約90%的晚期甲狀腺髓樣癌（約占甲狀腺癌的2-5%）患者攜帶RET突變。中國RET突變型甲狀腺髓樣癌患者目前尚無有效的獲批標準治療方案。

關於普拉替尼 普拉替尼是一種口服、每日一次、強效高選擇性RET抑制劑，已獲中國國家藥品監督管理局批准，用於治療既往接受過含鉑化療的轉染重排（RET）基因融合陽性的局部晚期或轉移性非小細胞肺癌（NSCLC）成人患者。普拉替尼針對需要系統性治療的晚期或轉移性RET突變甲狀腺髓樣癌（MTC），以及需要系統性治療且放射性碘難治（如放射性碘適用）的晚期或轉移性RET融合陽性甲狀腺癌的新適應症申請也已經於2021年4月獲得中國國家藥品監督管理局（NMPA）受理並被納入優先審評。美國食品藥品監督管理局批准其以商品名為GAVRETO上市銷售，三項適應症分別為：用於治療經FDA批准的檢測方法檢測證實為轉移性RET融合陽性NSCLC的成人患者、需要系統性治療的晚期或轉移性RET突變甲狀腺髓樣癌成人和12歲及以上兒童患者，以及需要系統性治療且放射性碘難治（如適用）的晚期或轉移性RET融合陽性甲狀腺癌成人和12歲及以上兒童患者。這些適應症基於ORR 和 DOR 數據在加速審批途徑下獲得批准。針對這些適應症的持續批准可能取決於確證性試驗中臨床獲益的驗證和描述。歐盟委員會（EC）已授予GAVRETO有條件上市許可，作為一種單一療法，用於治療未接受過RET抑制劑治療的RET融合陽性晚期NSCLC成人患者。普拉替尼在中國、美國、歐洲還未獲批用於其他適應症。普拉替尼旨在選擇性地和有效地靶向致癌性RET突變，包括可能導致治療耐藥的繼發性RET突變。在臨床前研究中，普拉替尼抑制RET的濃度低於其他藥物相關激酶，包括VEGFR2、FGFR2和JAK2。普拉替尼是一種強效、選擇性RET抑制劑，由基石藥業合作夥伴Blueprint Medicines公司開發。基石藥業與Blueprint Medicines公司達成了獨家合作和許可協議，獲得普拉替尼在大中華地區的獨家開發和商業化權利。Blueprint Medicines和羅氏正在全球（不包括大中華地區）共同開發GAVRETO，用於治療RET突變的NSCLC、甲狀腺癌和其他實體瘤患者。Blueprint Medicines和羅氏集團成員公司基因泰克正在美國共同商業化GAVRETO，羅氏擁有GAVRETO在美國以外（不包括大中華地區）的獨家商業化權利。FDA授予GAVRETO突破性療法認定，用於治療鉑類化療後進展的RET融合陽性NSCLC，以及需要全身治療且尚無替代療法的RET突變陽性甲狀腺髓樣癌。

關於基石藥業 基石藥業（香港聯交所代碼: 2616）是一家生物製藥公司，專注於研究開發及商業化創新腫瘤免疫治療及精準治療藥物，以滿足中國和全球癌症患者的殷切醫療需求。成立於2015年底，基石藥業已集結了一支在新藥研發、臨床研究以及商業運營方面擁有豐富經驗的世界級管理團隊。公司以腫瘤免疫治療聯合療法為核心，建立了一條15種腫瘤候選藥物組成的豐富產品管線。目前，基石藥業已經獲得了六個新藥上市申請的批准。多款後期候選藥物正處於關鍵性臨床試驗或註冊階段。基石藥業的願景是成為享譽全球的生物製藥公司，引領攻克癌症之路。

基石藥業全稱是基石藥業(蘇州)有限公司，英文名為CStone Pharmaceuticals，是一家中國創新型生物製藥公司，主要研究腫瘤免疫藥物和靶向藥物。2015年在英屬開曼群島註冊，2019年在港交所掛牌上市，於新藥研發領域備受矚目，2020年9月與輝瑞達成規模4.8億美元的戰略合作。在此之前，基石藥業已分別透過第三方，於2019、2020年分別向台灣食藥署提出Ivosidenib、Avapritinib兩款藥物的上市申請，獲新藥優先審查資格認定，但目前還未通過。

CStone Pharmaceuticals Announces the Acceptance of New Drug Application (NDA) for Pralsetinib for the Treatment of RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) and RET-Altered Thyroid Cancers in Taiwan, China  2022-02-17 SUZHOU, China, Feb. 17, 2022 /PRNewswire/ -- CStone Pharmaceuticals ("CStone", HKEX: 2616), a leading biopharmaceutical company focused on research, development, and commercialization of innovative immuno-oncology therapies and precision medicines, today announced that the Taiwan Food and Drug Administration (TFDA) has confirmed the acceptance of the new drug application (NDA) for pralsetinib for the treatment of rearranged during transfection (RET) fusion-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC), and advanced or metastatic RET fusion-positive thyroid cancer (TC) who are radioactive iodine-refractory (if radioactive iodine treatment is appropriate). Discovered by CStone's partner Blueprint Medicines, pralsetinib is a potent and selective RET inhibitor. CStone has an exclusive collaboration and license agreement with Blueprint Medicines for the development and commercialization of pralsetinib in Greater China, which encompasses Mainland China, Hong Kong, Macau and Taiwan. Dr. Jason Yang, Chief Medical Officer of CStone, said, "We are very glad that the NDA of another innovative precision medicine, pralsetinib, is accepted in Taiwan, China for the treatment of NSCLC and thyroid cancers, after AYVAKYT® (avapritinib) was approved for the treatment of unresectable or metastatic PDGFRA D842V mutant gastrointestinal stromal tumors last year. In the global phase 1/2 ARROW study, pralsetinib demonstrated robust and durable anti-tumor activity and a generally well-tolerated safety profile in patients with RET fusion-positive locally advanced or metastatic NSCLC and advanced or metastatic RET-altered thyroid cancer. We look forward to the potential approval of pralsetinib in Taiwan, China to help benefit more patients as quickly as possible." The NDA acceptance of pralsetinib in Taiwan, China is based on the global phase 1/2 ARROW study, which is designed to evaluate the safety, tolerability and efficacy of pralsetinib in patients with RET fusion-positive NSCLC, RET-mutant MTC and other advanced solid tumors with RET fusions. Results from the ARROW trial in global patients with RET fusion-positive NSCLC were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in June 2021. As of a date cutoff date of November 6, 2020, pralsetinib showed durable clinical benefits in patients with RET fusion-positive NSCLC who had measurable disease at baseline and received a starting dose of 400 mg once daily. In 68 treatment-naïve patients, the overall response rate (ORR) was 79 percent (95% CI: 68%, 88%). The complete response (CR) rate was 6 percent, 10 percent of patients had complete regression of target tumors, and 74 percent of patients had a partial response (PR). The median duration of response (DOR) was not reached (95% CI: 9.0 months, not reached). In 126 patients who previously received platinum-based chemotherapy, the ORR was 62 percent (95% CI: 53%, 70%). The CR rate was 4 percent, 12 percent of patients had complete regression of target tumors, and 58 percent of patients had a PR. The median DOR was 22.3 months (95% CI: 15.1 months, not reached). As of the data cutoff date, a total of 471 patients were enrolled across tumor types with a pralsetinib dose starting at 400 mg once daily. The most common treatment-related adverse events (AEs) reported by investigators were neutropenia, increased aspartate aminotransferase, anemia, decreased white blood cell count, increased alanine aminotransferase, hypertension, constipation and asthenia. Results from the ARROW trial in global patients with RET-altered thyroid cancer were published in The Lancet Diabetes and Endocrinology in August 2021. As of a data cutoff date of May 22, 2020, pralsetinib showed durable anti-tumor activity in patients with RET-altered thyroid cancer who received a starting dose of 400 mg once daily. In 55 patients with RET-mutant MTC previously treated with cabozantinib or vandetanib, the ORR was 60 percent (95% CI: 46%, 73%), and the median DOR was not reached (95% CI: 15.1 months, not estimable). In 21 systemic treatment-naïve patients with RET-mutant MTC, the ORR was 71 percent (95% CI: 48%, 89%), and the median DOR was not reached (95% CI: not estimable, not estimable). In addition, the ORR was 89 percent (95% CI: 52%, 100%) in nine patients with RET fusion-positive thyroid cancer, and the median DOR was not reached (95% CI: not estimable, not estimable). In 142 patients with RET-altered thyroid cancer, the most common AEs were anemia, musculoskeletal pain, constipation, increased aspartate aminotransferase and hypertension.

About RET fusion-positive NSCLC In recent years, China has had rising lung cancer incidence. According to the latest estimates on the global burden of cancer released by International Agency for Research on Cancer (IARC), in 2020, an estimated 0.82 million new lung cancer cases and 0.71 million new lung cancer deaths occurred in China. Among all Chinese cancer patients, lung cancer is the leading cause of cancer-related deaths. NSCLC is the most common type of lung cancer. In lung cancer, there are a number of somatic mutations, including EGFR, ALK, and ROS1, that can be targeted with approved therapies. RET fusions account for 1-2% of NSCLC patients, the majority of whom are non-smokers.

About RET-altered Thyroid Cancer Thyroid cancer is the most common endocrine malignancy with significantly increasing incidence in recent years. According to the latest estimates on the global burden of cancer released by International Agency for Research on Cancer (IARC), in 2020, there were about 220,000 new cases of thyroid cancer and the number of new cases in females reached about 170,000 in China[1]. The incidence of thyroid cancer ranked 4th among all malignant tumors in females in urban areas. Thyroid cancer is clinically divided into multiple subtypes, including papillary, follicular, undifferentiated and medullary. The treatment and prognosis of different types of thyroid cancer vary according to the characteristics of the tumor. RET fusions and mutations are key disease drivers in many cancer types, including NSCLC and several types of thyroid cancer. Approximately 10-20% of patients with papillary thyroid cancer (the most common type of thyroid cancer) carry RET fusions, and approximately 90% of patients with advanced MTC (approximately 2-5% of thyroid cancers) carry RET mutations. There is currently no effective approved standard treatment regimen for patients with RET-mutant MTC in China.

About Pralsetinib Pralsetinib is a once-daily oral targeted therapy approved by the National Medical Products Administration (NMPA) of China under the brand name GAVRETO® for the treatment of adults with locally advanced or metastatic rearranged during transfection (RET) fusion-positive NSCLC after platinum-based chemotherapy. In April 2021, the NMPA of China accepted the supplemental new drug application for pralsetinib with priority review designation for the treatment of patients with advanced or metastatic MTC who require systemic therapy, and advanced or metastatic RET fusion-positive thyroid cancers who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). GAVRETO is approved by the U.S. Food and Drug Administration (FDA) for the treatment of three indications: adult patients with metastatic RET fusion-positive NSCLC as detected by an FDA approved test, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). These indications are approved under accelerated approval based on ORR and DOR. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. The European Commission (EC) has granted conditional marketing authorization for GAVRETO as a monotherapy for the treatment of adult patients with RET fusion-positive advanced NSCLC not previously treated with a RET inhibitor. Pralsetinib is not approved for the treatment of any other indication in China, U.S. or Europe. Pralsetinib is designed to selectively and potently target oncogenic RET alterations, including secondary RET mutations predicted to drive resistance to treatment. In preclinical studies, pralsetinib inhibited RET at lower concentrations than other pharmacologically relevant kinases, including VEGFR2, FGFR2, and JAK2. Blueprint Medicines and Roche are co-developing GAVRETO globally (excluding Greater China) for the treatment of patients with RET-altered NSCLC, thyroid cancer, and other solid tumors. Blueprint Medicines and Genentech, a member of the Roche Group, are co-commercializing GAVRETO in the U.S., and Roche has exclusive commercialization rights for GAVRETO outside of the U.S. (excluding Greater China). The FDA granted breakthrough therapy designation to pralsetinib for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no alternative treatments.

About CStone CStone Pharmaceuticals (HKEX: 2616) is a biopharmaceutical company focused on researching, developing, and commercializing innovative immuno-oncology and precision medicines to address the unmet medical needs of cancer patients in China and worldwide. Established in 2015, CStone has assembled a world-class management team with extensive experience in innovative drug development, clinical research, and commercialization. The company has built an oncology-focused pipeline of 15 drug candidates with a strategic emphasis on immuno-oncology combination therapies. Currently, CStone has received six drug approvals. CStone's vision is to become globally recognized as a world-renowned biopharmaceutical company by bringing innovative oncology therapies to cancer patients worldwide.