(JCO: pleural mesothelioma治療) 北極星cisplatin (75 mg/m2)+ pemetrexed (500 mg/m2)+.ADI-PEG20

北極星肺間皮癌聯合用藥 臨床結果佳（中央社記者韓婷婷台北2017年5月3日電）國際權威雜誌「臨床腫瘤學雜誌」(Journal of Clinical Oncology) 近日刊登北極星藥業-KY（6550）以ADI-PEG20聯合肺間皮癌及非小細胞肺癌目前標準治療方法的臨床試驗數據，給予高度評價。北極星藥業-KY表示，此次的臨床試驗是以ADI-PEG20聯合Cisplatin+Pemetrexed 治療5名肺間皮癌與4名非小細胞肺癌未經化療治療病患的一期臨床試驗。結果顯示疾病控制率100%、腫瘤反應率（PR）78%。這樣的結果獲長期報導癌症相關臨床試驗數據的「臨床腫瘤學雜誌」重視，並邀請國際癌症相關領域權威專文評論給予高度評價。其中，肺間皮癌有腫瘤反應率的病人包括最難治療的非上皮狀肺間皮癌病患，所有病患在整個18週的聯合治療過程中血內精氨酸濃度均維持明顯下降，而且不良反應非常輕微，安全性極高。若與目前治療癌症的Bevacizumab聯合Cisplatin+Pemetrexed治療肺間皮癌二期臨床試驗數據相比較，同樣是以5位最嚴重兩種態樣的病患來做臨床，Bevacizumab腫瘤反應率為0，ADI-PEG 20則有60%，結果令人震奮，這結果未來也可望在大規模隨機對照試驗中進行證實。針對此篇報導，「臨床腫瘤學雜誌」也邀請到國際癌症相關權威香港大學教授JAMES Chung-Man給予評論，評論中表示：目前晚期肺間皮癌的治療方式有限，Cisplatin+Pemetrexed聯合療法是當前唯一治療方式。但近年來有資料顯示，Bevacizumab和免疫療法對惡性肺間皮癌的治療雖然可能具有潛在功效，然而並未被完全證實；因此，各大藥廠仍持續投入研究，希望能有更多元且有效的晚期肺癌和肺間皮癌治療藥物。北極星藥業在2012年完成的二期臨床試驗顯示，ADI-PEG 20單一用藥治療肺間皮癌已有相當明顯的療效，使用ADI-PEG20治療的病人其無惡化存活期已經較對照組延長68%，值得直接進入三期臨床試驗，但由於中和ADI活性的抗體在2個月後開始出現，導致血中精氨酸低濃度時間較短，北極星藥業決定探討聯合用藥是否可進一步增加療效。

[Epub ahead of print]

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers.  J Clin Oncol. 2017 Apr 7:JCO2016713230. doi: 10.1200/JCO.2016.71.3230.

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.