1549P - Pazopanib exposure in advanced soft tissue and bone sarcoma: A pharmacokinetic/pharmacodynamic analysis

Background

Pazopanib (PAZ) is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). A relationship was reported between PAZ trough concentration (C_min) and progression free survival (PFS) in RCC (Suttle A.B. 2015; Verheijen R.B. 2017). However, information on the exposure-efficacy relationship in sarcoma remains sparse. A PAZ C_min threshold of 27 mg/L was determined in an exploratory study (Bellesoeur A. 2017).

Methods

In this prospective observational study, PAZ C_min was monitored in metastatic sarcoma from 2014 to 2020, thus 529 blood samples were analyzed by liquid chromatography. For the primary endpoint, PFS of STS patients with a mean C_min above or below the pharmacokinetic threshold of 27 mg/L was analyzed in Kaplan–Meier analysis plus log-rank test. Secondary, we performed exposure–overall survival in STS and exposure-toxicity analyses in both STS and bone sarcoma (BS).

Results

A total of 118 patients, including 95 STS and 23 BS patients (median age 52 yrs; 53% male), had at least one PAZ plasma concentration available at steady state (after Day 15) and were eligible for PK/PD assessment. The most common subtypes included leiomyosarcoma (n = 28) and synovial sarcoma (n = 14). The starting dose of PAZ was 800mg in 66 patients (56%). The threshold of 27 mg/L at the first sample was not reached for 46% of patients. A C_min≥ 27 mg/L was significantly correlated with a better 3-month PFS in comparison with a C_min < 27 mg/L (67% vs 40% of patients without progression at 3 months, OR 0.32, IC95 [0.14-0.76], p = 0.0099). C_min≥ 27 mg/L showed a tendency to improve overall survival, although the result was not significant (HR 0.64, IC95 [0.38-1.06], p = 0.08), and a higher level of C_min first sample was significantly correlated with more grade 3-4 toxicities (34.9 vs 28.7 mg/L, p = 0.03).

Conclusions

We confirmed that PAZ C_min≥ 27 mg/L was significantly related to improved 3-month PFS in a large cohort of STS patients. About half of the patients did not reach this threshold and were thus at risk of decreased efficacy. PAZ concentration monitoring appears as a new approach to improve clinical outcome in metastatic soft-tissue sarcoma patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

P. Boudou-Rouquette.

Funding

Has not received any funding.

Disclosure

P. Boudou Rouquette: Financial Interests, Invited Speaker: Takeda. F. Goldwasser: Financial Interests, Invited Speaker: Fresenius Kabi. J. Alexandre: Financial Interests, Invited Speaker: Roche/Genentech; Financial Interests, Invited Speaker: AstraZeneca; Financial Interests, Invited Speaker: Novartis; Financial Interests, Invited Speaker: Sanofi/Aventis; Financial Interests, Invited Speaker: Ipsen; Financial Interests, Invited Speaker: MSD Oncology; Financial Interests, Invited Speaker: GlaxoSmithKline. All other authors have declared no conflicts of interest.