olaratumab三期STS未达临床终点
先前产品幻灯请见：Olaratumab in Advanced STS
上周末，礼亲王府发了个公告：LARTRUVO(Olartumab)治疗STS的三期结果，在整体人群及LMS患者群体未达到主要终点OS，但是也未发生新的安全事件。
Lilly Reports Results of Phase 3 Soft Tissue Sarcoma Study of LARTRUVO®
- Study did not meet the primary endpoints of overall survival (OS) in the full study population or in the leiomyosarcoma (LMS) sub-population; there was no difference in survival between the study arms for either population.
- There were no new safety signals identified and the safety profile was comparable between treatment arms.
重点红字标出：olaratumab+doxorubicin vs doxorubicin, olaratumab未能在整体及LMS群体中带来生存获益，会尽快在学术会议披露结果。
INDIANAPOLIS, Jan. 18, 2019 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today reported that the results of ANNOUNCE, the Phase 3 study of LARTRUVO®(olaratumab), in combination with doxorubicin in patients with advanced or metastatic soft tissue sarcoma (STS), did not confirm the clinical benefit of LARTRUVO in combination with doxorubicin as compared to doxorubicin, a standard of care treatment. Specifically, the study did not meet the primary endpoints of overall survival (OS) in the full study population or in the leiomyosarcoma (LMS) sub-population; there was no difference in survival between the study arms for either population. LARTRUVO was well tolerated; there were no new safety signals identified and the safety profile was comparable between treatment arms. Lilly plans to present the ANNOUNCE data at an upcoming medical conference and will publish the results in a medical journal.
先前根据一项133人的2期临床结果获得FDA加速批准及EMA有条件批准，进一步的批准需要在验证性研究中确认临床获益。但这次没有确认有临床获益，礼亲王需要和全球药监部门沟通决定下一步。与此同时在医生建议下接受LARTRUVO治疗的患者如果有获益将会持续疗程。而未接受过LARTRUVO治疗的患者，3期结果也不支持他们开始接受LARTRUVO。礼亲王将暂停LARTRUVO的推广。
LARTRUVO in combination with doxorubicin previously showed an OS benefit in STS in a 133-patient, U.S.-only, randomized Phase 2 trial, which led to accelerated approval by the U.S. Food and Drug Administration and conditional marketing authorization by the European Medicines Agency. Continued approval is contingent upon verification of clinical benefit in a confirmatory trial. As ANNOUNCE did not confirm clinical benefit, Lilly is working with global regulators to determine the appropriate next steps for LARTRUVO. While these discussions are ongoing, patients who are currently receiving LARTRUVO may, in consultation with their physician, continue their course of therapy if they are receiving clinical benefit. For patients who have not previously received LARTRUVO, the results of the Phase 3 trial do not support initiating treatment with LARTRUVO in patients with STS, outside of participation in a clinical trial. At this time, Lilly is suspending promotion of LARTRUVO.
"Lilly was surprised and disappointed that LARTRUVO did not improve survival for patients with advanced soft tissue sarcoma in this study," said Anne White, president, Lilly Oncology. "Lilly is committed to helping people who have soft tissue sarcoma and we will carefully study the detailed data in an effort to better understand the different results between the two trials. We are thankful for the patients and physicians who have participated in the ANNOUNCE study."
LARTRUVO is also being studied in an ongoing global, randomized, double-blind, placebo-controlled Phase 2 trial in advanced STS in combination with gemcitabine and docetaxel.
Olaratumab靶向在肉瘤中高表达的PDGFRα
临床2期研究设计：ola+dox vs dox，主要终点PFS，dox组在PD后可以接受ola单药直至进展
说结果之前提一下统计假设：
The phase 2 planned sample size was 130 patients, which assumed a 50% improvement in median progression-free survival(hazard ratio [HR] 0·67) for the olaratumab plus doxorubicin group, a statistical power of 80%, and a twosided significance level of 0·20.
所以说PFS达到预设，OS有11.8 mo的显著提升
OS的森林图（部分）：LMS患者死亡风险降低53%，而上图整体死亡风险降低54%
另外大家注意：在PFGFRα pos的患者中，ola降低36%死亡风险，但是在PFGFRα neg的患者中，ola降低60%死亡风险，这是不是意味着PDGFRα expression did not predict olaratumab benefit ？
所以张指导看了这图再去看公告估计也要吐槽，这结果不合理啊 ！