Second-Line nal-IRI (MM-398) Shows Consistent Improvement in Clinical
Outcomes in Metastatic Pancreatic Cancer
移转性胰脏癌第二线用药，奈米化微脂体修饰抗癌妥 (nal-IRI:nanoliposomal
irinotecan) MM-398在临床上有一致性的改善
Jan 16, 2015
http://gicasym.org/ 2015 Gastrointestinal Cancers Symposium Daily News
A deeper dive of data from NAPOLI-1, a randomized, controlled, open-label
phase III trial conducted in patients with gemcitabine-refractory metastatic
pancreatic cancer, bolsters support for use of MM-398 plus 5-fluorouracil
(5-FU)/leucovorin over 5-FU/leucovorin in the second-line setting (Abstract
234). Patients who received at least 80% of planned treatment during the
first 6 weeks of the study achieved a 3.8-month improvement in survival when
MM-398 was added to the chemotherapy backbone, according to data presented by
Li-Tzong Chen, MD, PhD, of the National Institute of Cancer Research and the
National Health Research Institutes in Taiwan.
抗药性 ( gemcitabine, 中文商品名健择，抗肿瘤作用之核苷
酸类似物) 移转性胰脏癌三期临床实验，在深入分析控制组与
对照组数据之后，5-fluorouracil(5-fluorouracil, 5-FU 服
乐癌注射剂) 与 leucovorin(若克瘤注射液，可保护正常细胞
并防止叶酸拮抗剂引起严重之毒性) 化学疗法与增加MM-398的
合并疗法相比，在前六周至少 80%使用本研究规画的处方，在
增加使用MM-398一组存活期应加 3.8个月，数据来自于陈立宗
领导的国家卫生研究院与癌症研究所研究计画。
MM-398 is a nanoliposomal formulation of irinotecan encapsulated in a lipid
sphere, which enables the drug to circulate longer compared with standard
irinotecan. Additionally, the nanoliposomal technology is said to promote
drug uptake by tumor cells, where irinotecan is then converted to its active
form, SN-38.
MM-398是由微脂体包覆抗癌药irinotecan的球体结构，如此能
够延长药物周期，并能够增加癌细胞对药物的吸收有效转成活
化型态的 SN-38分子。
NAPOLI-1, a pivotal trial evaluating MM-398, enrolled 417 patients with
metastatic pancreatic cancer who progressed on first-line gemcitabine across
76 sites in 14 countries worldwide. Following stratification by ethnicity,
Karnofsky performance status, and baseline albumin level, patients were
randomly assigned in a 1:1:1 ratio to MM-398 monotherapy, 5-FU/leucovorin
(control), or MM-398 plus 5-FU/leucovorin.
之前的研究画NAPOLI-1，收纳了接受过移转性胰脏癌一线疗法
(gemcitabine)，来在于14国76个点的 417位病人，透过总族
和体能表现指标分类，与分析了血蛋白基线，分成MM-398单独
疗法，5-FU/leucovorin疗法 (控制组) 和5-FU/leucovorin结
合MM-398三组。
MM-398 monotherapy fell out of favor, as it did not demonstrate superior
efficacy compared with 5-FU/leucovorin and produced greater toxicity on its
own than when used in combination with 5-FU/leucovorin. As such, efficacy and
safety of combination treatment with MM-398 plus 5-FU/leucovorin held greater
interest.
MM-398单独疗法因为比常用 5-FU/leucovorin疗法没有显著的
疗效优势，且比和 5-FU/leucovorin疗法合并使用毒性高而未
被偏爱。但 5-FU/leucovorin疗法结合MM-398后的疗效和安全
性引起高度兴趣。
The NAPOLI-1 investigators previously reported that second-line treatment
with MM-398 plus 5-FU/leucovorin significantly improved overall survival
(OS), progression-free survival (PFS), and the overall response rate (ORR)
and led to greater decreases in CA19-9 levels compared with 5-FU/leucovorin
alone in the intent-to-treat (ITT) population. More specifically, a
comparison of MM-398 plus 5-FU/leucovorin versus 5-FU/leucovorin revealed:
NAPOLI-1 研究结果指出在意向分析之下 (intent-to-treat,
ITT)， 5-FU/leucovorin疗法结合MM-398后，在总存活期
(overall survival, OS) 与无恶化存活期 (progression-
free survival, PFS) 和整体疗效 (overall response rate
, ORR)都有显著改善 (significantly)，此外并降大大地低了
CA19-9肿瘤指标。达到下述成果：
Median OS of 6.1 months versus 4.2 months (stratified hazard ratio [HR]
0.57; 95% CI [0.41, 0.80]; p = 0.0009)
总存活期中位数由 4.2个月改善到6.1个月
Median PFS of 3.1 months versus 1.5 months (p = 0.0001)
ORR of 16% versus 1% (p < 0.001)
无恶化存活期中位数由1.5个月改善至3.1个月
At least 50% CA19-9 reduction in 36% versus 12% (p = 0.0009)
CA19-9肿瘤指标降低达50%的由12%增加到36%
“The Forest plot sensitivity analyses also favored the MM-398 combination
over 5-FU/leucovorin across all the prognostic subanalyses,” Dr. Chen said.
Variables evaluated included the stratification factors (ethnicity, Karnofsky
performance status, and baseline albumin), as well as tumor location, liver
metastases, disease stage at diagnosis, time since initial histological
diagnosis, number of prior lines of therapy, time since last prior therapy,
and CA19-9 levels.
陈博士指出：“在森林图的敏感性分析也偏好MM-398结合5-FU
/leucovorin的疗法。”，在各种变量分析和病情如肿瘤位置
与肝功能和病情分期与病史，之前的治疗史与肿瘤指标。
New support for the ITT data comes from an analysis of the per-protocol (PP)
population, defined as patients who received at least 80% of the target dose
of chemotherapy in the first 6 weeks of the study and who did not violate any
inclusion/exclusion criteria. The PP group for the MM-398 and control arms
represents approximately 60% of patients originally assigned to these arms.
Although early progression, clinical deterioration, death, and consent
withdrawal accounted for some attrition, dose reductions or interruptions
stemming from adverse events primarily accounted for why patients failed to
make the PP group.
新的数据来自按照计划接受分派的治疗 (per-protocol, PP)
分析结果，疗程定义为六周内至少施用 80%的目标剂量，没有
违反任何相容不相容的标准。MM-398和控制组，在排除之前阶
段中临床恶化或死亡等原因退出，或剂量有减少或中断，接受
分派的治疗尚包含 60%成员。
The more recent PP analysis of MM-398 plus 5-FU/leucovorin versus
5-FU/leucovorin alone showed a greater survival difference between groups
than the original ITT analysis. Median OS in the PP subset extended to 8.9
months with MM-398 versus 5.1 months without (stratified HR 0.47; 95% CI
[0.29, 0.77]; p = 0.0018).
近期的按照计划接受分派的治疗的分析显示，MM-398结合5-FU
/leucovorin复合疗法相较5-FU/leucovorin单独疗法的结果比
意向分析预期还好，在有结合使用MM-398，总存活期中位数由
5.1个月增加到 8.9个月。
The toxicity profile of MM-398 when added to 5-FU/leucovorin appeared
manageable. In the safety population, the most frequent adverse events of
grade 3 or higher occurring more often with versus without addition of MM-398
included neutropenia (20% vs. 2%), fatigue (14% vs. 4%), diarrhea (13% vs.
5%), vomiting (11% vs. 3%), and nausea (8% vs. 3%).
MM-398在药物毒性部分，与 5-FU/leucovorin并用时是能够控
制的。安全分析群体中最常见的三级以上不良反应结合MM-398
是较常发生，嗜中性白血球低下( neutropenia) 由2%增为20%
，疲倦 ( fatigue) 由4%增为 14%，腹泻 ( diarrhea) 由 5%
增为 13%，呕吐 (vomiting) 由3%增为 11%，反胃 (nausea)
由3%增为8%。
Discussant Laura Williams Goff, MD, of Vanderbilt University Medical Center,
who reviewed the NAPOLI-1 findings, noted that MM-398 yielded “a provocative
partial response rate in the second-line patient population of 16% in the
combination arm,” which stacks up favorably compared with 8% partial
response rates previously reported with FOLFIRI in second-line pancreatic
cancer. In accord, Dr. Goff believes that MM-398 represents an exciting new
option for further development in pancreas cancer.
评论家Laura Williams Goff 对NAPOLI-1结果关注到“第二线
用药的患者在结合MM-398疗法 16%有强烈的反应。”相较于之
前的 FOLFIRI只有8%有更好的结果。Goff博士相信MM-398能成
为未来胰脏癌治疗研发选择。
MM-398 has received a Fast Track designation with the U.S. Food and Drug
Administration based on its activity in combination with 5-FU/leucovorin in
pancreatic cancer previously treated with gemcitabine-based therapy.
MM-398由于结合 5-FU/leucovorin的疗效，已经被美国食品药
物管理局 (USFDA) 批准新药快速审查资格。