Imfinzi联合Lynparza将疾病进展或死亡的风险降低了45%. chemotherapy in advanced or recurrent endometrial cancer

Imfinzi reduced the risk of disease progression or death by 29% vs. chemotherapy

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

对DUO-E III期试验初步分析的阳性结果表明 Imfinzi (durvalumab) plus platinum-based chemotherapy, followed by either 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, Spain (Presentation #LBA41) and simultaneously published online in the Journal of Clinical Oncology.

In the overall trial population, results showed that treatment with Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza (Imfinzi plus Lynparza Arm) and treatment with Imfinzi plus chemotherapy followed by Imfinzi monotherapy (Imfinzi Arm) demonstrated a reduction in the risk of disease progression or death, 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), respectively, versus chemotherapy alone (Control Arm). Median PFS was 15.1 months in the Imfinzi plus Lynparza Arm and 9.6 months in the Control Arm.

Mismatch repair (MMR) status is a biomarker of interest in endometrial cancer, 因此,根据MMR状态对DUO-E进行预先指定的探索性亚组分析. 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), respectively, versus the Control Arm. 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), respectively, versus the Control Arm.

中期总生存期(OS)数据显示两种治疗方案在总体人群中的有利趋势.

Shannon N. Westin, 德克萨斯大学安德森癌症中心妇科肿瘤学和生殖医学教授, and principal investigator of the trial, said, “These findings showcase, for the first time, 结合免疫疗法和PARP抑制剂的潜力,为这些患者提供显著的临床改善. 这些DUO-E数据可能为肿瘤学家提供新的途径来提高子宫内膜癌患者的预后.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said, “大多数晚期子宫内膜癌患者的治疗选择是有限的, especially for those with mismatch repair proficiency, and have not changed for many years. 澳门第一赌城在线娱乐很高兴这些DUO-E数据显示了患者的临床改善 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 in other indications and a prespecified analysis based on PD-L1 status showed, in the PD-L1 positive population, that treatment reduced the risk of disease progression or death by 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 Arms, respectively, versus the Control Arm. 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, treatment reduced the risk of disease progression or death by 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 Arms, respectively, versus the Control Arm.

The safety and tolerability profiles of both regimens (Imfinzi plus Lynparza Arm and Imfinzi Arm)与先前临床试验中观察到的结果和已知的单个药物概况大致一致.1,2

报告中最常见的不良事件(ae)(影响20%或更多患者) Imfinzi plus Lynparza Arm during the overall study were anaemia (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%), leukopenia (20%) and urinary tract infection (20%).

The most common AEs reported in the Imfinzi Arm during the overall study were alopecia (50%), anaemia (48%), fatigue and asthenia (43%), nausea (41%), neutropenia (36%), diarrhoea (31%), arthralgia (30%), thrombo-cytopenia (28%), constipation (27%), peripheral neuropathy (26%), peripheral sensory neuropathy (26%) and vomiting (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, with the average age at diagnosis being over 60 years old.3-5 It is the 6th most common cancer in women worldwide.6 子宫内膜癌的发病率和死亡率预计将分别增加约46%和62%,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. 通常采用手术和/或放射治疗,5年生存率很高(约95%)。. 晚期患者(III-IV期)通常预后较差, with the 5-year survival rate falling to around 20-30%. 晚期子宫内膜癌的治疗标准传统上仅限于化疗.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
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) 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, 除了标准治疗铂类化疗外,每三周给予一次. 化疗4-6个周期后,患者(疾病未进展)接受两种化疗 Imfinzi (1500mg) or placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg片剂,每日两次])或安慰剂,直至疾病进展.

双主要终点是每个治疗组与标准治疗组的无进展生存期(PFS). Key secondary endpoints included overall survival (OS), safety and tolerability. 错配修复状态、复发状态和地理位置是分层因素. 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 该试验由澳门在线赌城娱乐独立赞助,在包括美国在内的22个国家的253个研究地点进行, Europe, South America and Asia.

For more information about the trial please visit 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, 对抗肿瘤的免疫逃避策略,释放对免疫反应的抑制.

Imfinzi 在治疗目的为不可切除的情况下,唯一批准的免疫疗法和全球护理标准是不可切除的吗, 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 is approved in combination with a short course of Imjudo (tremelimumab)和化疗在美国用于治疗转移性NSCLC, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi also is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU, 日本和其他几个国家基于TOPAZ-1和HIMALAYA III期试验, respectively. Imfinzi 是否在少数国家被批准用于治疗晚期膀胱癌患者.

自2017年5月首次获批以来,已有超过20万名患者接受了治疗 Imfinzi.

As part of a broad development programme, Imfinzi 是否在SCLC患者的单独治疗和联合其他抗癌治疗中进行测试, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumours.

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, such as those with mutations in BRCA1 and/or BRCA2, 或由其他药物(如新激素制剂[NHAs])引起的缺乏.

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, 它们的崩溃,DNA双链断裂和癌细胞死亡.

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-negative metastatic breast cancer (in the EU and Japan, this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan, 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 is being jointly developed and commercialised by AstraZeneca and MSD, both as a monotherapy and in combination with other potential medicines. Independently, the companies are developing and will commercialise Lynparza in combination with their respective PD-L1 and PD-1 medicines, Imfinzi (durvalumab) and Keytruda (pembrolizumab). Lynparza has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, 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
澳门在线赌城娱乐正在引领肿瘤学领域的一场革命,致力于为各种形式的癌症提供治疗, 跟随科学去了解癌症及其所有的复杂性, 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, 有可能催化医学实践的变化,改变病人的体验.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, 澳门在线赌城娱乐在100多个国家开展业务,其创新药物被全球数百万患者使用. Please visit ccnmaster.com and follow the Company on social media @AstraZeneca.

Contacts
For details on how to contact the Investor Relations Team, please click here. For Media contacts, click here.


References

1. FDA. Highlights of prescribing information - Lynparza. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf. Accessed October 2023.

2. FDA. Highlights of prescribing information – Imfinzi. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf. Accessed October 2023.

3. Dork T, et al. 子宫内膜癌的遗传易感性:危险因素和临床管理. 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. 子宫内膜癌:ESMO诊断、治疗和随访临床实践指南. Ann Oncol. 2022;33(9):860-877.

6. World Cancer Research Fund International. Endometrial Cancer Statistics. Available at http://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/. Accessed October 2023.

7. IARC. WHO. Corpus Uteri. Estimated Numbers from 2020 to 2040, Females, Age [0-85+] World. Available at http://gco.iarc.fr/tomorrow/en/dataviz/trends Accessed October 2023.

8. Carlson R. Advanced Endometrial Cancer Carboplatin-Paclitaxel Regimen Promising. Oncology Times. 2003;25(22):36.

9. Ferris JS, et al. Uterine Serous Carcinoma: Key Advances and Novel Treatment Approaches. Int Gynecol Pathol. 2021;31(8):1165-1174.

10. Matrai CE, et al. 低级别、低分期子宫内膜癌伴和不伴复发的分子评价. Int Gynecol Pathol. 2022;41(3):207-219.

11. Wright JD, et al. Contemporary Management of Endometrial Cancer. Lancet. 2012 Apr 7;379(9823):1352-60.

12. Monk BJ, et al. 晚期子宫内膜癌患者的真实世界结局:美国电子健康记录的回顾性队列研究. Gynecol Oncol. 2022;164(2):325-332.

13. Soumerai T, et al. 晚期子宫内膜癌前瞻性分子表征的临床应用. Clin Cancer Res. 2018;24(23):5939-5947.

14. Assasi N, et al. 结直肠癌患者的DNA错配修复缺陷肿瘤检测:建议. CADTH Optimal Use Report, No. 5.3d. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. 2016.

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


tags

  • Corporate and financial