Second-Line nal-IRI (MM-398) Shows Consistent Improvement in Clinical
Outcomes in Metastatic Pancreatic Cancer
移轉性胰臟癌第二線用藥，奈米化微脂體修飾抗癌妥 (nal-IRI:nanoliposomal
irinotecan) MM-398在臨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.
抗藥性 ( gemcitabine, 中文商品名健擇，抗腫瘤作用之核苷
酸類似物) 移轉性胰臟癌三期臨床實驗，在深入分析控制組與
對照組數據之後，5-fluorouracil(5-fluorouracil, 5-FU 服
樂癌注射劑) 與 leucovorin(若克瘤注射液，可保護正常細胞
並防止葉酸拮抗劑引起嚴重之毒性) 化學療法與增加MM-398的
合併療法相比，在前六週至少 80%使用本研究規畫的處方，在
增加使用MM-398一組存活期應加 3.8個月，數據來自於陳立宗
領導的國家衛生研究院與癌症研究所研究計畫。
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是由微脂體包覆抗癌藥irinotecan的球體結構，如此能
夠延長藥物週期，並能夠增加癌細胞對藥物的吸收有效轉成活
化型態的 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.
之前的研究畫NAPOLI-1，收納了接受過移轉性胰臟癌一線療法
(gemcitabine)，來在於14國76個點的 417位病人，透過總族
和體能表現指標分類，與分析了血蛋白基線，分成MM-398單獨
療法，5-FU/leucovorin療法 (控制組) 和5-FU/leucovorin結
合MM-398三組。
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單獨療法因為比常用 5-FU/leucovorin療法沒有顯著的
療效優勢，且比和 5-FU/leucovorin療法合併使用毒性高而未
被偏愛。但 5-FU/leucovorin療法結合MM-398後的療效和安全
性引起高度興趣。
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 研究結果指出在意向分析之下 (intent-to-treat,
ITT)， 5-FU/leucovorin療法結合MM-398後，在總存活期
(overall survival, OS) 與無惡化存活期 (progression-
free survival, PFS) 和整體療效 (overall response rate
, ORR)都有顯著改善 (significantly)，此外並降大大地低了
CA19-9腫瘤指標。達到下述成果：
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)
總存活期中位數由 4.2個月改善到6.1個月
Median PFS of 3.1 months versus 1.5 months (p = 0.0001)
ORR of 16% versus 1% (p < 0.001)
無惡化存活期中位數由1.5個月改善至3.1個月
At least 50% CA19-9 reduction in 36% versus 12% (p = 0.0009)
CA19-9腫瘤指標降低達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.
陳博士指出：「在森林圖的敏感性分析也偏好MM-398結合5-FU
/leucovorin的療法。」，在各種變數分析和病情如腫瘤位置
與肝功能和病情分期與病史，之前的治療史與腫瘤指標。
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.
新的數據來自按照計劃接受分派的治療 (per-protocol, PP)
分析結果，療程定義為六週內至少施用 80%的目標劑量，沒有
違反任何相容不相容的標準。MM-398和控制組，在排除之前階
段中臨床惡化或死亡等原因退出，或劑量有減少或中斷，接受
分派的治療尚包含 60%成員。
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).
近期的按照計劃接受分派的治療的分析顯示，MM-398結合5-FU
/leucovorin複合療法相較5-FU/leucovorin單獨療法的結果比
意向分析預期還好，在有結合使用MM-398，總存活期中位數由
5.1個月增加到 8.9個月。
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在藥物毒性部分，與 5-FU/leucovorin並用時是能夠控
制的。安全分析群體中最常見的三級以上不良反應結合MM-398
是較常發生，嗜中性白血球低下( neutropenia) 由2%增為20%
，疲倦 ( fatigue) 由4%增為 14%，腹瀉 ( diarrhea) 由 5%
增為 13%，嘔吐 (vomiting) 由3%增為 11%，反胃 (nausea)
由3%增為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.
評論家Laura Williams Goff 對NAPOLI-1結果關注到「第二線
用藥的患者在結合MM-398療法 16%有強烈的反應。」相較於之
前的 FOLFIRI只有8%有更好的結果。Goff博士相信MM-398能成
為未來胰臟癌治療研發選擇。
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由於結合 5-FU/leucovorin的療效，已經被美國食品藥
物管理局 (USFDA) 批准新藥快速審查資格。