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Final results of the multicenter randomized phase II PAZOGIST trial evaluating the efficacy of pazopanib (P) plus best supportive care (BSC) vs BSC alone in resistant unresectable metastatic and/or locally advanced gastrointestinal stromal tumors (GIST).
Background: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. Imatinib followed by sunitinib then regorafenib is the usual sequence in advanced setting. P is effective in soft tissue sarcomas; it has never been evaluated in a randomized setting in GIST. Methods: Eligible patients (pts) were randomized (1:1; stratification on number of prior drugs (2 vs ≥3)) to receive P+BSC or BSC. Primary endpoint was Progression-Free Survival (PFS). 80 pts were planned to detect an improvement in the 4-month PFS rate (PFS-4m) from 15% (BSC) to 45% (P+BSC) with 5% two-sided α and 80% power. Secondary objectives included Best Overall Response (BOR), Overall Survival (OS), safety and trough plasma P concentrations (Ct). Results: From Apr 11 to Dec 13, 81 pts (P+BSC: 40, BSC: 41) were randomized. Arms were well balanced; median age: 63y (27-85), 70% males and 54% with ≥ 3 prior drugs. The intent-to-treat analysis based on investigator-assessed progressive disease (PD) showed an improved PFS with PFS-4m of 45.2% (95% CI 29.1-60.0) for P+BSC vs 17.6% (95% CI 7.8-30.8) for BSC (HR: 0.59, 95% CI 0.37-0.96; p = 0.03). 36 pts out of 41 switched to P following investigator-assessed PD (median P duration: 3.5 months (0.1-19), main reasons for discontinuation: PD (52.8%) and toxicity (22.3%)). Centrally-assessed BOR showed stable disease in 84.2% vs 70.7% and PD in 15.8% vs 26.8% of pts in P+BSC and BSC arms. Among all pts treated with P (n = 76), 72.4% experienced grade ≥ 3 related adverse events (AE) (hypertension: 36.8%), including 25% of related serious AE (pulmonary embolism, 9.2%). At the time of analysis, 29 vs 31 pts had died in the P+BSC and BSC arms (OS HR: 0.94, 0.56-1.56). 1 toxic death occurred (hepatic cytolysis). Preliminary results showed a higher median Ct at steady state in pts progression-free at 4 months vs progressive: 25 (2-63) vs 17 (8-35) µg/ml (n = 43; p = 0.08). Conclusions: P combined to BSC improves PFS in advanced GIST resistant to imatinib and sunitinib. In the context of a high switch rate, no difference in OS was found. Further PK analyses are ongoing. Clinical trial information: NCT01323400
Abstracts by Jean-Yves Blay:
- Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 536
Final overall survival (OS) analysis with modeling of crossover impact in the phase III GRID trial of regorafenib vs placebo in advanced gastrointestinal stromal tumors (GIST).Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: 156
Biomarker-driven access to vemurafenib in BRAF-positive cancers: Second study of the French National AcSé Program.Meeting: 2016 ASCO Annual Meeting | Abstract No: TPS11620Category: Tumor Biology - Tumor-Based Biomarkers