Nikanjam Mina, Tinajero Jose, McGann Mary, Li Jerry, Yang Jincheng, Shen Felicity, Sicklick Jason K, Kato Shumei, Capparelli Edmund, Kurzrock Razelle
Division of Hematology and Oncology, Moores Cancer Center, University of California San Diego (UCSD).
Department of Pharmacy, UCSD Health.
J Hematol Oncol Pharm. 2023 Feb;13(1):19-25.
The diversity in the genomic landscape of advanced and metastatic tumors calls for combination therapies based on the genomic signature associated with each tumor. Determining safe and tolerable doses for novel combinations of oncology drugs is essential for a precision medicine approach, but can also require dose reductions. Trametinib, palbociclib, and everolimus are among the targeted therapies most often used in novel combinations at our precision medicine clinic.
To evaluate the safe, tolerable dosing of trametinib, palbociclib, and everolimus when used as part of novel combinations with other agents for the treatment of advanced or metastatic solid tumors.
This retrospective study included adult patients with advanced or metastatic solid tumors who received trametinib, everolimus, or palbociclib plus other therapies as a part of novel combinations between December 2011 and July 2018 at the University of California San Diego. Patients were excluded if they received trametinib, everolimus, or palbociclib in standard combinations, such as dabrafenib plus trametinib, everolimus plus fulvestrant, everolimus plus letrozole, and palbociclib plus letrozole. Dosing and adverse events were determined through a review of the electronic medical records. A safe, tolerable drug combination dose was defined as being tolerated for at least 1 month, with no clinically significant serious adverse events.
A safe, tolerable dose was determined for 76% of the 71 patients who received trametinib, 88% of the 48 patients who received everolimus, and 73% of the 41 patients receiving palbociclib when used in combination with other therapies. For patients with clinically significant adverse events, dose reductions were attempted in 30% of the trametinib recipients, in 17% of everolimus recipients, and in 45% of palbociclib recipients. When used in combination with other therapies, the optimal dosing of trametinib, palbociclib, and everolimus was lower than the standard single-agent dosing: it was 1 mg daily for trametinib; 5 mg daily for everolimus; and 75 mg daily, for 3 weeks on and 1 week off for palbociclib. Of note, everolimus could not be given concomitantly with trametinib at these doses.
Safe and tolerable dosing of novel combination therapies that includes trametinib, everolimus, or palbociclib is feasible for a precision medicine approach. However, neither results from this study nor results from previous studies could support the use of everolimus in combination with trametinib, even at reduced doses.
晚期和转移性肿瘤基因组格局的多样性要求基于与每种肿瘤相关的基因组特征进行联合治疗。确定肿瘤学药物新组合的安全且可耐受剂量对于精准医疗方法至关重要，但也可能需要降低剂量。曲美替尼、哌柏西利和依维莫司是我们精准医疗诊所最常用于新组合的靶向治疗药物。
评估曲美替尼、哌柏西利和依维莫司与其他药物联合用于治疗晚期或转移性实体瘤时的安全、可耐受剂量。
这项回顾性研究纳入了2011年12月至2018年7月在加利福尼亚大学圣地亚哥分校接受曲美替尼、依维莫司或哌柏西利加其他疗法作为新组合一部分的晚期或转移性实体瘤成年患者。如果患者接受曲美替尼、依维莫司或哌柏西利的标准组合，如达拉非尼加曲美替尼、依维莫司加氟维司群、依维莫司加来曲唑以及哌柏西利加来曲唑，则被排除。通过查阅电子病历确定给药剂量和不良事件。安全、可耐受的药物组合剂量定义为至少耐受1个月，且无临床显著的严重不良事件。
71例接受曲美替尼治疗的患者中，76%确定了安全、可耐受剂量；48例接受依维莫司治疗的患者中，88%确定了安全、可耐受剂量；41例接受哌柏西利治疗的患者中，73%确定了安全、可耐受剂量，这些药物均与其他疗法联合使用。对于有临床显著不良事件的患者，30%接受曲美替尼治疗的患者、17%接受依维莫司治疗的患者以及45%接受哌柏西利治疗的患者尝试了降低剂量。与其他疗法联合使用时，曲美替尼、哌柏西利和依维莫司的最佳给药剂量低于标准单药给药剂量：曲美替尼为每日1毫克；依维莫司为每日5毫克；哌柏西利为每日75毫克，服用3周，停药1周。值得注意的是，依维莫司不能与曲美替尼同时以这些剂量给药。
对于精准医疗方法而言，包括曲美替尼、依维莫司或哌柏西利的新联合疗法的安全且可耐受给药是可行的。然而，本研究结果和既往研究结果均不支持依维莫司与曲美替尼联合使用，即使是降低剂量。
