Unresectable Gastrointestinal Stromal Tumor

WILMINGTON, Del.--( BUSINESS WIRE )--AstraZeneca’s TAGRISSO ® (osimertinib) ​ has been approved in the US for the treatment of adult patients with unresectable, Stage III epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy (CRT). TAGRISSO is indicated for patients with exon 19 deletions or exon 21 (L858R) mutations, as detected by a FDA-approved test. The approval follows a Priority Review by the Food and Drug Administration (FDA) that was based on results from the LAURA Phase III trial, which were presented during the Plenary Session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine . TAGRISSO reduced the risk of disease progression or death by 84% compared to placebo (hazard ratio 0.16; 95% confidence interval 0.10-0.24; p<0.001) as assessed by blinded independent central review. Median progression-free survival (PFS) was 39.1 months in patients treated with TAGRISSO versus 5.6 months for placebo. Overall survival (OS) results remain immature at this current analysis. The trial continues to assess OS as a secondary endpoint. Each year in the US, there are more than 200,000 people diagnosed with lung cancer, and 80-85% of these patients are diagnosed with NSCLC, the most common form of lung cancer. 1-3 Approximately 15% of NSCLC patients in the US have EGFR mutations. 4 Nearly one in five people diagnosed with NSCLC has an unresectable tumor. 5 Suresh Ramalingam, MD, Executive Director of Winship Cancer Institute of Emory University, Atlanta, US, and principal investigator in the trial, said: “ This approval represents a major breakthrough for patients with Stage III, EGFR-mutated lung cancer who will now have the opportunity to benefit from osimertinib. Patients treated with osimertinib lived without disease progression by more than three years in the LAURA trial, and this impressive benefit underscores the importance of diagnosing and testing lung cancer patients as early as possible.” Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “ The approval of TAGRISSO for patients with Stage III, unresectable EGFR-mutated non-small cell lung cancer addresses a critical need for patients with these mutations who have never had the option of targeted therapy before. The results of the LAURA trial show the powerful impact TAGRISSO can make as backbone therapy in this disease, and with this approval, patients across all stages of EGFR-mutated non-small cell lung cancer can now benefit.” The safety and tolerability of TAGRISSO in the LAURA trial was consistent with its established profile and no new safety concerns were identified. TAGRISSO is approved for patients with EGFR mutations in the 1st-line metastatic setting as a monotherapy and in combination with chemotherapy, and as an adjuvant treatment for early-stage disease. TAGRISSO is currently under review with regulatory authorities in other countries around the world for this indication. IMPORTANT SAFETY INFORMATION There are no contraindications for TAGRISSO TAGRISSO can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. ILD/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal ILD/Pneumonitis with TAGRISSO in combination with Pemetrexed and Platinum-based Chemotherapy : In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy (CRT): In the LAURA study, following definitive platinum-based CRT, ILD/pneumonitis including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO-treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3% For patients receiving TAGRISSO who have not received recent definitive platinum-based CRT, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed. For patients who have received recent definitive platinum-based CRT with Grade 1 ILD/pneumonitis, continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis TAGRISSO can cause heart rate-corrected QT (QTc) interval prolongation. Of the 1813 TAGRISSO monotherapy-treated patients in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia TAGRISSO can cause cardiomyopathy, including cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction. Cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. In the LAURA study, following platinum-based CRT, 3% (4/135) of TAGRISSO-treated patients and no placebo-treated patients experienced LVEF decreases ≥10% and a drop to <50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases ≥10% and a drop to <50%. For patients receiving TAGRISSO monotherapy, conduct cardiac monitoring in patients with cardiac risk factors, including assessment of LVEF at baseline and during treatment. For patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of LVEF at baseline and during treatment. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity Aplastic anemia has been reported in TAGRISSO-treated patients in clinical trials (0.06% of 1813) and postmarketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the last dose Because of the potential for serious adverse reactions in breastfed infants from TAGRISSO, women should not breastfeed during treatment with TAGRISSO and for 2 weeks after the last dose Most common (≥20%) adverse reactions, including laboratory abnormalities, were: TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue TAGRISSO monotherapy following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough and COVID-19 TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine INDICATIONS TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated in combination with pemetrexed and platinum-based chemotherapy, for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy Please see complete Prescription Information , including Patient Information for TAGRISSO. You may report side effects related to AstraZeneca products by clicking here . Notes Lung cancer Each year, an estimated 2.4 million people are diagnosed with lung cancer globally. 6 Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 6 Lung cancer is broadly split into NSCLC and small cell lung cancer. 2 The majority of all NSCLC patients are diagnosed with advanced disease. 7 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. 4,8-9 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signaling pathways that drive the growth of tumor cells. 10 LAURA LAURA is a randomized, double-blind, placebo-controlled, multi-center, global Phase III trial in patients with unresectable, Stage III EGFRm NSCLC whose disease has not progressed following definitive platinum-based CRT. Patients were treated with TAGRISSO 80 mg once-daily oral tablets until disease progression, unacceptable toxicity or other discontinuation criteria were met. Upon progression, patients in the placebo arm were offered treatment with TAGRISSO. The trial enrolled 216 patients in more than 145 centers across more than 15 countries, including in the US, Europe, South America and Asia. This is the analysis of the primary endpoint of PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS. TAGRISSO TAGRISSO ® (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. TAGRISSO (40 mg and 80 mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC. There is an extensive body of evidence supporting the use of TAGRISSO as standard of care in EGFRm NSCLC. TAGRISSO improved patient outcomes in early-stage disease in the ADAURA Phase III trial , locally advanced disease in the LAURA Phase III trial , late-stage disease in the FLAURA Phase III trial , and with chemotherapy in the FLAURA2 Phase III trial . As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, TAGRISSO is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial. The Company is also researching ways to address tumor mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test TAGRISSO plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including TAGRISSO and gefitinib; durvalumab and tremelimumab-aclt; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References Centers for Disease Control and Prevention. U.S. Cancer Statistics Lung Cancer Stat Bite. Available at: https://www.cdc.gov/united-states-cancer-statistics/publications/lung-cancer-stat-bite.html . Accessed August 2024. ​LUNGevity Foundation. Types of Lung Cancer. Available at: https://www.lungevity.org/lung-cancer-basics/types-of-lung-cancer . Accessed August 2024. American Cancer Society. What Is Lung Cancer? Available at: https://www.cancer.org/cancer/types/lung-cancer/about/what-is.html . Accessed August 2024. Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol . 2011;29(15):2121-2127. ​Quint LE. Lung cancer: assessing resectability. Cancer Imaging . 2004;4(1):15-18. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf . Accessed August 2024. ​Cagle P, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Arch Pathol Lab Med . 2013;137(9):1191-1198. Szumera-Ciećkiewicz A , et al . EGFR Mutation Testing on Cytological and Histological Samples in Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence . Int J Clin Exp Pathol. 2013;6(12): 2800-2812. Ellison G, et al . EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumour Tissue and Cytology Samples. J Clin Pathol. 2013;66(2):79-89. ​Cross DAE, et al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov . 2014;4(9):1046-1061. US-93979 Last Updated 9/24

IDRX-42, a highly potent, oral, multi-mutant-selective KIT inhibitor, demonstrated promising early evidence of antitumor activity and a favorable safety pro a monotherapy in heavily pre-treated patients with advanced metastatic gastrointestinal stromal tumors (GIST) Tumor shrinkage and confirmed partial responses were observed across all clinically relevant KIT mutations, including both primary drivers and secondary resistance mutations PLYMOUTH, Mass.--(BUSINESS WIRE)-- IDRx, Inc., a clinical-stage biopharmaceutical company dedicated to transforming cancer treatment with purpose-built precision therapies, today announced preliminary clinical data from the dose escalation portion of the company’s ongoing Phase 1 StrateGIST study of IDRX-42 in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) who have previously received one or more prior lines of tyrosine kinase inhibitor (TKI) therapy. IDRX-42 is a highly potent, multi-mutation-selective inhibitor of KIT targeting all major classes of primary drivers and resistance mutations in patients with KIT-mutant GIST (including mutations in exons 9, 11, 13 and 17). These early data, which demonstrate promising antitumor activity and a favorable safety pro IDRX-42 in a heavily pre-treated group of patients with advanced GIST after failure of imatinib and other lines of TKI therapies, will be presented by Professor Patrick Schöffski, MD, MPH, head of the Department of General Medical Oncology at the University Hospitals Leuven, in a poster at the Connective Tissue Oncology Society (CTOS) 2023 Annual Meeting, being held November 1‑4, in Dublin, Ireland. “Advanced GIST generally carries a poor prognosis after failure of imatinib and new therapies such as IDRX-42, that target key primary activating drivers as well as secondary resistance mutations in KIT, are urgently needed,” said Prof. Schöffski. “These preliminary data demonstrate exciting and clinically meaningful antitumor activity in a highly refractory and difficult to treat GIST patient population and warrant the investigation of IDRX-42 in earlier lines of therapy.” “We are highly encouraged by these initial data of IDRX-42, supporting a potentially best-in-class pro improve the outcomes of patients with GIST in all lines of therapy, which we believe remains one of targeted oncology’s great unmet medical needs,” said Ben Auspitz, co-founder and chief executive officer of IDRx. “Importantly, these preliminary data will help guide our discussions with physicians regarding development strategies for IDRX-42 in patients with GIST in early lines of therapy to prevent the emergence of genomically-driven resistance mutations. Early suppression of such resistance mutations in KIT is likely to benefit patients with GIST, versus trying to treat clinically heterogeneous disease in any individual with multiple resistant clones.” Presentation Highlights: Initial data (October 5, 2023 cut-off date) from the dose escalation portion of the ongoing Phase 1 StrateGIST study include 33 patients (all with KIT-mutant GIST) who received IDRX-42 across doses ranging from 120 mg once daily (QD) to 400 mg twice daily (BID). Patients were heavily pretreated, with a median of 4 prior lines of therapy. 28 patients are evaluable for objective response. Median duration on treatment was 16 weeks and continuing, with 70% (23/33) of patients remaining on treatment at time of data cutoff. Maximum tolerated dose (MTD) has not yet been reached. Confirmed partial responses (PRs) by modified RECIST have been demonstrated to date in four patients (at 120 mg QD, 400 mg QD, and 600 mg QD [n=2]). Although an MTD has not yet been reached, a 68% (19/28 patients) clinical benefit rate (confirmed complete response/PR or stable disease ≥16 weeks) was observed across the initial doses studied to date. 4/28 patients are on study for <16 weeks and continuing on study drug. Tumor shrinkage and confirmed partial responses were observed across all major classes of KIT mutational variants, including both primary driver mutations in exons 9 and 11, and secondary resistance mutations in exons 13 and 17. Additionally, notable reductions in mutant allele fraction were observed in circulating tumor DNA across these classes of KIT variants. Preliminary pharmacokinetic analyses demonstrate dose-dependent increases in exposure, with a long half-life (approximately 125 hours), and a 5 to 8-fold accumulation between single-dose and steady-state at Cycle 2 (Day 28). IDRX-42 exhibited a favorable safety and tolerability pro most adverse events being mild (Grade 1) in severity. Treatment related adverse events included diarrhea (70%), nausea (52%), and vomiting (27%). No safety-related treatment discontinuations have been observed to date. Two events coded as dose-limiting toxicities were reported (Grade 3 syncope at 600 mg QD, and Grade 3 vomiting at 400 mg BID); both patients chose to continue on study with dose reduction and are continuing on treatment for 5 months and 2 months, respectively. Four dose levels (120, 240, 400 and 600 mg QD) have been cleared to date, and dose escalation continues with accrual to the 800 mg (400 mg BID) cohort ongoing. Presentation Details: Title: Phase 1 Study of IDRX-42 in Patients with Advanced Gastrointestinal Stromal Tumors Resistant to Prior Systemic Therapy: Early Results Presenter: Patrick Schöffski, MD, MPH Abstract Number: P 26 Presentation Type: Poster Session: CTOS Poster Reception 5:30-6:30 p.m. GMT, Thursday, November 2nd Location: The Convention Center, Dublin, Ireland About GIST Gastrointestinal stromal tumors (GIST) are the most common subtype of soft tissue sarcoma. Approximately 80% of cases arise from gain of function mutations in the KIT receptor tyrosine kinase, driving the malignancy through constitutive activation of aberrant signaling. Resistance mutations in KIT emerge in ~90% of patients treated with imatinib, the current standard of care for GIST. In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type. About the StrateGIST Study StrateGIST1 is an ongoing, open-label, first-in-human Phase 1/1b study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of IDRX-42 in patients with metastatic and/or surgically unresectable GIST after failure of imatinib and other approved drugs. The study is currently enrolling patients with documented pathogenic mutation in KIT or any platelet-derived growth factor receptor alpha (PDGFRA) mutation (other than PDGFRA exon 18) at sites in the U.S., Belgium, Germany, and Spain. The Phase 1b portion will include expanded exploratory cohorts based on defined lines of prior TKI therapy. About IDRX-42 IDRX-42 is a potent, oral, highly selective KIT inhibitor targeting all major categories of activating and resistance mutations in patients with KIT-mutant GIST (including variants in exons 9, 11, 13 and 17). In preclinical studies, IDRX-42 demonstrated superior antitumor activity compared to imatinib, the current first-line of therapy, in GIST human xenograft models expressing mutations in KIT exons 9 and 11. In xenograft models expressing secondary resistance mutations in KIT exon 13 or 17, IDRX-42 treatment resulted in potent and dose-dependent antitumor activity superior to the second-line standard of care agent, sunitinib. IDRX-42 is current being evaluated in a first-in-human Phase 1/1b study. About IDRx IDRx is a clinical-stage biopharmaceutical company dedicated to transforming cancer care with intelligently designed precision therapies. IDRx aims to address the limitations of today’s precision cancer medicines with highly potent and selective targeted therapies to stop key tumor escape mechanisms and prolong response to therapy. IDRx’s pipeline programs include small molecule tyrosine kinase inhibitors, IDRX-42 and IDRX-73, designed to inhibit key genetic drivers and drug-resistant mutations of gastrointestinal stromal tumor (GIST). Founded in 2021, IDRx’s leadership team has extensive experience in drug development and collectively has been involved in the discovery, development, and commercialization of more than 10 approved drugs. To learn more, please visit and follow us on LinkedIn. View source version on businesswire.com: Contacts 1AB Katie Engleman katie@1abmedia.com Source: IDRx, Inc. View this news release online at:

惰性SM占SM病例的绝大多数，此次申请标志着第一款治疗惰性SM的药物上市申请。基石药业授权获得Ayvakit在大中华区的开发与商业化权利。 图片来源：摄图网 2022年11月22日讯 /生物谷BIOON/ --基石药业（CStone）合作伙伴Blueprint Medicines近日宣布，已向美国食品和药物管理局（FDA）提交了靶向抗癌药Ayvakit（中文商品名：泰吉华®，通用名：avapritinib，阿伐替尼）的补充新药申请（sNDA）：用于治疗惰性系统性肥大细胞增多症（indolent systemic mastocytosis，ISM）成人患者。值得一提的是，此次sNDA标志着第一款治疗惰性SM的药物上市申请。Ayvakit能够强效和选择性地抑制D816V突变型KIT，这是约95%病例中导致SM的根本原因。 此次sNDA纳入了注册PIONEER临床试验（NCT03731260）的数据。这是有史以来在ISM患者中开展的最大规模的随机安慰剂对照临床研究。该研究达到了主要终点和全部关键次要终点，所有指标均有统计学意义的显著改善。此前，FDA已授予Ayvakit突破性疗法（BTD）：用于治疗中度至重度惰性SM。 Blueprint Medicines首席医疗官Becker Hewes表示：“Ayvakit的这份监管文件标志着一个重要的里程碑，它将满足广大系统性肥大细胞增多症（SM）患者的医疗需求，该病特征是虚弱的症状和跨多个器官的终身疾病负担。通过利用Ayvakit瞄准SM的主要驱动因素，我们正在寻求将疾病治疗超越症状导向治疗，改变疾病进程，最终为患者的生活带来有意义的变化。我们sNDA申请标志着第一个寻求批准治疗惰性SM的监管申请，我们期待着与该机构密切合作，实现我们的目标：尽快将Ayvakit带给惰性SM患者。” 系统性肥大细胞增多症（SM）是一种罕见的、使人衰弱的血液系统疾病，主要由KIT D816V突变驱动。肥大细胞不受控制的增殖和激活会导致SM患者出现慢性、严重和经常无法预测的症状。SM分为2种亚型：（1）非晚期SM（又称为：惰性[indolent]或阴燃[smoldering]SM），这是SM的最常见类型，占SM病例的绝大多数；（2）晚期SM，这是一组高危SM亚型，占SM病例的少数，包括侵袭性SM（ASM）、伴有相关血液肿瘤的SM（SM-AHN）和肥大细胞白血病（MCL）。除了肥大细胞激活症状外，晚期SM还与肥大细胞浸润导致的器官损伤和较差的生存预后相关。在晚期SM亚型中，ASM的中位总生存期约为3.5年，SM-AHN约为2年，MCL不到6个月。 Ayvakit是第一款针对SM疾病主要驱动因素的精准疗法，于2021年6月获得美国FDA批准：用于治疗晚期SM成人患者，包括：ASM、SM-AHN和MCL。该适应症通过优先审查程序获得批准。此前，FDA已授予Ayvakit治疗晚期SM的孤儿药资格（ODD）和突破性药物资格（BTD）。 Ayvakit的批准上市，使晚期SM患者首次有了一种靶向治疗方法。Ayvakit能够强效、选择性抑制D816V突变KIT，这是SM疾病的中心驱动因素。用药方面，晚期SM患者推荐的Ayvakit剂量为200mg，每日口服一次。对于血小板计数小于50x10E9/L的晚期SM患者，不建议使用Ayvakit治疗。 在Ayvakit之前，还没有批准的治疗方法能够选择性地抑制KIT D816V突变。多激酶抑制剂midostaurin已被批准用于治疗晚期SM，根据IWG标准，总缓解率（ORR）仅为28%。在临床试验中，Ayvakit治疗显示出高缓解率：ORR为57%、完全缓解率（CR）为28%、部分缓解率（PR）为28%。Ayvakit治疗显示快速、持久缓解，中位缓解持续时间（DOR）为38.3个月（95%CI:19-NE），从治疗到缓解的中位时间为2.1个月。最常见的不良反应（发生率≥20%）为水肿、腹泻、恶心、疲劳/乏力。 2018年6月，基石药业与Blueprint Medicines达成独家合作及授权协议，获得了包括avapritinib（阿伐替尼，强效KIT/PDGFRA激酶抑制剂）、pralsetinib（普拉替尼，强效RET抑制剂）在内的三款候选药物在大中华区（大陆、香港、澳门、台湾）的开发与商业化权利。 avapritinib可选择性和强效地抑制KIT和PDGFRA突变激酶。该药是一种I型抑制剂，旨在靶向活性激酶构象；所有致癌激酶都通过这种构象进行信号传导。avapritinib已被证实对GIST相关的KIT和PDGFRA突变具有广泛的抑制作用，包括针对与当前批准疗法耐药相关的激活loop突变的强劲活性。与已批准的多激酶抑制剂相比，avapritinib对KIT和PDGFRA的选择性明显高于其他激酶。此外，avapritinib经独特的设计可选择性结合并抑制D816突变KIT，这是大约95%的系统性肥大细胞增多症（SM）患者中的一种常见疾病驱动因素。临床前研究表明，avapritinib能以亚纳摩尔效力强效抑制KIT D816V，并具有最小的脱靶活性。 在美国、欧盟、中国，avapritinib分别于2020年1月、2020年9月、2021年4月获得批准（商品名分别为：Ayvakit、Ayvakyt、泰吉华®），用于治疗PDGFRA外显子18突变（包括PDGFRA D842V突变）不可切除或转移性胃肠道间质瘤（GIST）成人患者。值得一提的是，Ayvakit是第一个被批准用于GIST的精准疗法，也是第一个对PDGFRA基因18号外显子突变型GIST具有高活性的药物。（生物谷Bioon.com） 原文出处：Blueprint Medicines Submits Supplemental New Drug Application to FDA for AYVAKIT® (avapritinib) for the Treatment of Indolent Systemic Mastocytosis