Piha-Paul Sarina A, Dumbrava Ecaterina E, Nair Binoj C, Xiong Wendy, Xu Li, Mostorino Rosa, Subbiah Vivek, Tannir Nizar, Fu Siqing, Naing Aung, Janku Filip, Karp Daniel D, Patel Shreyaskumar, Daw Najat C, Hong David, Meric-Bernstam Funda, Zinner Ralph
Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Onco Targets Ther. 2021 May 7;14:3037-3049. doi: 10.2147/OTT.S291801. eCollection 2021.
Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.
We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib.
Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR).
Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.
克唑替尼可抑制ALK、MET和ROS1酪氨酸激酶，但单药治疗出现耐药是一个问题。帕唑帕尼的抗血管生成特性可能克服克唑替尼耐药。此外，克唑替尼的抗血管生成特性可能增强帕唑帕尼的临床疗效。
我们评估了克唑替尼和帕唑帕尼治疗晚期实体瘤患者的安全性和反应。
入组82例患者（中位年龄53岁，范围18 - 78岁）。既往全身治疗的中位次数为3次（范围0 - 8次）。我们能够将剂量逐步增加至8级剂量（克唑替尼250 mg每日两次，帕唑帕尼800 mg每日一次），未确定最大耐受剂量（MTD）。32%的患者出现3级或4级毒性，最常见的是疲劳（n = 9，11%）、腹泻（n = 6，7%）、呕吐（n = 3，4%）、贫血（n = 2，2%）和谷丙转氨酶升高（n = 2，2%）。82例患者中，61例（74%）根据RECISTv1.1有可测量病灶并进行了首次重新分期（6周）。6/61例（10%）患者观察到部分缓解（PR），10/61例（16%）患者观察到持续≥6个月的疾病稳定（SD）（SD≥6个月/PR的患者总计16/61例（26%））。
6级剂量（克唑替尼200 mg每日两次，帕唑帕尼600 mg每日一次）是联合用药中最可耐受的剂量，可用于未来研究。我们还观察到在接受过多次既往治疗的晚期实体瘤患者中有适度的临床活性。
