Imfinzi plus Lynparza reduced the risk of disease progression or death by 45% vs. 晚期或复发子宫内膜癌的化疗

与对照组相比,Imfinzi将疾病进展或死亡风险降低了29%. chemotherapy

First Phase III trial to demonstrate clinical benefit of immunotherapy plus PARP inhibition in advanced or recurrent endometrial cancer

Positive results from the primary analysis of the DUO-E Phase III trial showed that Imfinzi (durvalumab)加铂类化疗,然后再进行任何一种 Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib), both demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to chemotherapy alone in the overall trial population of patients with newly diagnosed advanced or recurrent endometrial cancer.

These results will be presented today in a proffered paper session at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, 西班牙(Presentation #LBA41),同时在 the Journal of Clinical Oncology.

在整个试验人群中,结果显示用 Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza (Imfinzi plus Lynparza Arm) and treatment with Imfinzi plus chemotherapy followed by Imfinzi monotherapy (Imfinzi Arm)显示了疾病进展或死亡风险的降低, by 45% (hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.43-0.69; p<0.0001) and 29% (HR 0.71; 95% CI 0.57-0.89; p=0.003)分别与单独化疗相比(对照组). Median PFS was 15.1 months in the Imfinzi plus Lynparza Arm and 9.6 months in the Control Arm.

错配修复(MMR)状态是子宫内膜癌感兴趣的生物标志物, therefore a prespecified exploratory subgroup analysis by MMR status was conducted in DUO-E. Results from the analysis of mismatch repair proficient (pMMR) patients showed a reduction in the risk of disease progression or death in both the Imfinzi plus Lynparza and the Imfinzi Arms, by 43% (HR 0.57; 95% CI 0.44-0.73) and 23% (HR 0.77; 95% CI 0.60-0.97),分别与控制臂. Median PFS was 15 months in the Imfinzi plus Lynparza Arm and 9.7 months in the Control Arm.

Results from the analysis of mismatch repair deficient (dMMR) patients showed a similar reduction in the risk of disease progression or death in both the Imfinzi plus Lynparza and the Imfinzi Arms, by 59% (HR 0.41; 95% CI 0.21-0.75) and 58% (HR 0.42; 95% CI 0.22-0.80),分别与控制臂.

Interim overall survival (OS) data showed a favourable trend for both treatment regimens in the overall population.

Shannon N. Westin, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, 也是试验的主要研究者, said, “These findings showcase, for the first time, the potential of combining immunotherapy with a PARP inhibitor to deliver significant clinical improvements for these patients. These DUO-E data may offer oncologists novel avenues to enhance outcomes for endometrial cancer patients.”

Susan Galbraith,肿瘤学研究中心执行副总裁&D, AstraZeneca, said, “The treatment options for most patients with advanced endometrial cancer are limited, 特别是对那些错配修复熟练, 多年来一直没有改变. We are delighted that these DUO-E data show meaningful clinical improvements for patients when Imfinzi and Lynparza are combined or when Imfinzi is added alone. We look forward to discussing these data with global regulatory authorities and bringing these important new treatment approaches to patients as soon as possible.”

PD-L1 is a known biomarker for Imfinzi 其他适应症和基于PD-L1状态的预先指定分析显示, in the PD-L1 positive population, 该治疗将疾病进展或死亡风险降低了58% (HR 0).42; 95% CI 0.31-0.57) and 37% (HR 0.63; 95% CI 0.48-0.83) in the Imfinzi plus Lynparza and the Imfinzi 手臂,分别和控制手臂. Median PFS was 20.8 months in the Imfinzi plus Lynparza Arm and 9.5 months in the Control Arm.

In the PD-L1 negative population, 治疗将疾病进展或死亡的风险降低了20% (HR 0.80; 95% CI 0.55-1.16) and 11% (HR 0.89; 95% CI 0.59-1.34) in the Imfinzi plus Lynparza and the Imfinzi 手臂,分别和控制手臂.

两种治疗方案的安全性和耐受性(Imfinzi plus Lynparza Arm and Imfinzi Arm) were broadly consistent with those observed in prior clinical trials and the known profiles of the individual medicines.1,2

The most common adverse events (AEs) (affecting 20% or more of patients) reported in the Imfinzi plus Lynparza 在整个研究中有一半是贫血(62%)。, nausea (55%), fatigue and asthenia (54%), alopecia (51%), neutropenia (42%), constipation (33%), thrombo-cytopenia (30%), diarrhoea (28%), vomiting (26%), peripheral neuropathy (25%), peripheral sensory neuropathy (25%), arthralgia (24%), decreased appetite (23%), 白细胞减少(20%)和尿路感染(20%).

报告中最常见的ae Imfinzi 在整个研究中有一半是脱发(50%)。, anaemia (48%), fatigue and asthenia (43%), nausea (41%), neutropenia (36%), diarrhoea (31%), arthralgia (30%), thrombo-cytopenia (28%), constipation (27%), peripheral neuropathy (26%), 周围感觉神经病变(26%)和呕吐(21%).

Notes

Endometrial cancer
Endometrial cancer is a highly heterogeneous disease that originates in the tissue lining of the uterus and is most common in women who have already been through the menopause, 平均诊断年龄超过60岁.3-5 它是全球第六大最常见的女性癌症.6 Incidence and mortality of endometrial cancer are expected to increase by approximately 46% and 62% respectively (from 417,400 cases and 97,400 deaths in 2020 to 608,130 cases and 157,813 deaths) in 2040.6,7

The majority of patients with endometrial cancer are diagnosed at an early stage of disease where the cancer is confined to the uterus. They are typically treated with surgery and/or radiation and the 5-year survival rate is high (approximately 95%). Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, 5年生存率下降到20-30%左右. The standard of care for advanced endometrial cancer has traditionally been limited to chemotherapy.5,8,9,10,11,12 There is a high unmet need for novel treatment options and strategies that can improve long-term outcomes in advanced or recurring endometrial cancer.10,13

DUO-E
DUO-E试验(GOG 3041/ENGOT-EN10)是一个三臂试验, randomised, double-blind, placebo-controlled, 一线多中心III期临床试验 Imfinzi (durvalumab) 加铂类化疗(卡铂和紫杉醇) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib) as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.

The DUO-E trial randomised 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either Imfinzi (1120mg) or placebo, given every three weeks in addition to standard-of-care platinum-based chemotherapy. After 4-6 cycles of chemotherapy, patients (whose disease had not progressed) then received either Imfinzi (1500mg)或安慰剂作为维持,每四周加300mg Lynparza (300mg BID [2x150mg tablets, twice a day]) or placebo until disease progression.

The dual primary endpoint was progression-free survival (PFS) of each treatment arm versus standard of care. Key secondary endpoints included overall survival (OS), safety and tolerability. Mismatch repair status, recurrence status and geographic location were stratification factors. Mismatch repair deficient (dMMR) status reflects an inability to correct DNA replication errors and therefore results in an increased risk of cancer, while mismatch repair proficient (pMMR) status indicates when DNA repair pathways remain intact and where the mismatch repair pathway is active and functional.14,15 The trial was sponsored independently by AstraZeneca and conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

有关试验的更多信息,请访问 ClinicalTrials.gov.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour's immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial. Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi 与短期疗程的 Imjudo (tremelimumab)和化疗在美国用于治疗转移性NSCLC, 欧盟和日本基于POSEIDON III期试验.

除了对肺癌的适应症, Imfinzi also is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo 在美国不可切除的肝细胞癌中, EU, Japan and several other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

作为广泛发展计划的一部分, Imfinzi is being tested as a single treatment and in combination with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, 一些胃肠道癌症和其他实体肿瘤.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination-related (HRR) genes, 比如那些BRCA1和/或BRCA2突变的人, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]).

Inhibition of PARP with Lynparza 导致捕获与DNA单链断裂结合的PARP, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), her2阴性转移性乳腺癌(在欧盟和日本), this includes locally advanced breast cancer); for gBRCAm, her2阴性的高危早期乳腺癌(日本), this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) when chemotherapy is not clinically indicated (EU only) and for BRCAm mCRPC (US and Japan); and as monotherapy for HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated mCRPC as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza 是由澳门在线赌城娱乐和默沙东联合开发和商业化的, 既可作为单一疗法,也可与其他潜在药物联合使用. 这些公司正在独立发展,并将商业化 Lynparza 结合各自的PD-L1和PD-1药物, Imfinzi (durvalumab) and Keytruda (pembrolizumab). Lynparza 已经用于治疗全球超过75,000名患者. Lynparza 是否有广泛的临床试验开发计划, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

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, 开发并向患者提供改变生活的药物.

该公司专注于一些最具挑战性的癌症. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

澳门在线赌城娱乐的愿景是重新定义癌症治疗和, one day, 消除癌症作为死亡原因.

AstraZeneca
澳门在线赌城娱乐(LSE/STO/Nasdaq: AZN)是一家全球性制药公司, 以科学为主导的澳门第一赌城在线娱乐公司,专注于发现, development, 以及肿瘤学处方药的商业化, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit toms-lawncare.com 并在社交媒体上关注公司 @AstraZeneca.

Contacts
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References

1. FDA. 处方信息要点- Lynparza. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf. Accessed October 2023.

2. FDA. 处方信息要点- Imfinzi. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf. Accessed October 2023.

3. Dork T, et al. Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management. Cancers (Basel). 2020;12(9):2407.

4. American Cancer Society. What is Endometrial Cancer? Available at http://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html. Accessed October 2023.

5. Oakin A, et al. ESMO Guidelines. Endometrial Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol. 2022;33(9):860-877.

6. 国际世界癌症研究基金会. Endometrial Cancer Statistics. Available at http://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/. Accessed October 2023.

7. IARC. WHO. Corpus Uteri. 2020年至2040年估计数量,女性,年龄[0-85+]世界. Available at http://gco.iarc.fr/tomorrow/en/dataviz/trends Accessed October 2023.

8. Carlson R. 晚期子宫内膜癌卡铂-紫杉醇方案前景看好. Oncology Times. 2003;25(22):36.

9. Ferris JS, et al. 子宫浆液性癌:关键进展和新的治疗方法. Int Gynecol Pathol. 2021;31(8):1165-1174.

10. Matrai CE, et al. Molecular Evaluation of Low-grade Low-Stage Endometrial Cancer With and Without Recurrence. Int Gynecol Pathol. 2022;41(3):207-219.

11. Wright JD, et al. 子宫内膜癌的当代治疗. Lancet. 2012 Apr 7;379(9823):1352-60.

12. Monk BJ, et al. Real-World Outcomes in Patients with Advanced Endometrial Cancer: A Retrospective Cohort Study of US Electronic Health Records. Gynecol Oncol. 2022;164(2):325-332.

13. Soumerai T, et al. Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer. Clin Cancer Res. 2018;24(23):5939-5947.

14. Assasi N, et al. DNA Mismatch Repair Deficiency Tumour Testing for Patients With Colorectal Cancer: Recommendations. CADTH Optimal Use Report, No. 5.3d. 渥太华(安):加拿大卫生药品和技术署. 2016.

15. Fight Colorectal Cancer. Available at http://fightcolorectalcancer.org/blog/dna_mismatch_repair_and_5-fu_whats_the_connection/. Accessed October 2023.


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