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PMID (33994796)
Authors Piha-Paul SA, Dumbrava EE, Nair BC, Xiong W, Xu L, Mostorino R, Subbiah V, Tannir N, Fu S, Naing A, Janku F, Karp DD, Patel S, Daw NC, Hong D, Meric-Bernstam F, Zinner R
Title A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies.
Journal Vol Issue Date Pages Journal Short Title
OncoTargets and therapy 14 2021 3037-3049 Onco Targets Ther
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK R1209Q colon cancer predicted - sensitive Crizotinib + Pazopanib Case Reports/Case Series Actionable In a Phase I trial, Xalkori (crizotinib) and Votrient (pazopanib) combination treatment resulted in a partial response in a patient with colon cancer harboring ALK R1209Q (PMID: 33994796; NCT01548144). 33994796