Nikanjam Mina, Liu Sariah, Yang Jincheng, Kurzrock Razelle
Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California, USA
Department of Hematology-Oncology, Kaiser Permanente San Diego Medical Center, San Diego, California, USA.
Oncologist. 2017 May;22(5):576-584. doi: 10.1634/theoncologist.2016-0357. Epub 2017 Apr 19.
Combining targeted and cytotoxic agents has the potential to improve efficacy and attenuate resistance for metastatic cancer. Information regarding safe starting doses for clinical trials of novel three-drug combinations is lacking.
Published phase I-III adult oncology clinical trials of three-drug combinations involving a targeted agent were identified by PubMed search (January 1, 2010 to December 31, 2013). A dose percentage was calculated to compare the dose used in combination to the single agent recommended dose: (U.S. Food and Drug Administration-approved/recommended phase II dose/maximum tolerated dose). The additive dose percentage was the sum of the dose percentages for each drug in the combination.
A total of 37,763 subjects and 243 drug combinations were included. Only 28% of studies could give each of the three agents at 100%. For combinations involving two targeted agents and a cytotoxic agent, the lowest starting additive dose percentage was 133%, which increased to 250% if two antibodies were included. For combinations of one targeted agent and two cytotoxic agents, the lowest additive safe dose percentage was 137%. When both cytotoxic agents were held at 100%, as occurred in 56% of studies (which generally used cytotoxic doublets with known combination safety dosing), the lowest safe dose percentage was 225% (providing that a histone deacetylase inhibitor was not the targeted agent).
These findings serve as a safe starting point for dosing novel three-drug combinations involving a targeted agent in clinical trials and practice. 2017;22:576-584 IMPLICATIONS FOR PRACTICE: Targeted and cytotoxic drug combinations can improve efficacy and overcome resistance. More knowledge of safe starting doses would facilitate use of combinations in clinical trials and practice. Analysis of 37,763 subjects (243 combinations) showed three drugs could be safely administered, but less than 30% of combinations could include all three drugs at full dose. Dose reductions to 45% of the dose of each single agent may be required. Combinations involving two antibodies required fewer dose reductions, and the use of established cytotoxic doublets made initial dose assignment easier.
联合使用靶向药物和细胞毒性药物有可能提高转移性癌症的疗效并减弱耐药性。目前缺乏关于新型三联药物组合临床试验安全起始剂量的信息。
通过PubMed检索（2010年1月1日至2013年12月31日）确定已发表的涉及靶向药物的三联药物组合的I - III期成人肿瘤学临床试验。计算剂量百分比以比较联合用药剂量与单药推荐剂量：（美国食品药品监督管理局批准的/推荐的II期剂量/最大耐受剂量）。相加剂量百分比是联合用药中每种药物剂量百分比的总和。
共纳入37763名受试者和243种药物组合。只有28%的研究能够给予三种药物中的每种药物100%的剂量。对于涉及两种靶向药物和一种细胞毒性药物的组合，最低起始相加剂量百分比为133%，如果包含两种抗体则增加到250%。对于一种靶向药物和两种细胞毒性药物的组合，最低相加安全剂量百分比为137%。当两种细胞毒性药物均维持在100%时（56%的研究中出现这种情况，这些研究通常使用已知联合安全给药剂量的细胞毒性双联疗法），最低安全剂量百分比为225%（前提是组蛋白去乙酰化酶抑制剂不是靶向药物）。
这些发现为在临床试验和实践中对涉及靶向药物的新型三联药物组合给药提供了一个安全的起始点。2017年；22:576 - 584 对实践的启示：靶向药物和细胞毒性药物联合使用可提高疗效并克服耐药性。更多关于安全起始剂量的知识将有助于在临床试验和实践中使用联合用药。对37763名受试者（243种组合）的分析表明三种药物可以安全给药，但不到30%的组合能够给予全部三种药物的全剂量。可能需要将每种单药剂量降低至45%。涉及两种抗体的组合所需剂量降低较少，并且使用既定的细胞毒性双联疗法使初始剂量分配更容易。
