Efficacy and safety of regorafenib compared to placebo and to post-cross-over regorafenib in advanced non-adipocytic soft tissue sarcoma.
INTRODUCTION
The placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over.


METHODS
From June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm.


RESULTS
PFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35-0.71; p < .0001). OS was not statistically significant different (HR = 0.78; 0.54-1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45-71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84-1.73; p = .30) without impact on OS.


CONCLUSIONS
Observed PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.
['Brodowicz|Thomas|T|', 'Mir|Olivier|O|', 'Wallet|Jennifer|J|', 'Italiano|Antoine|A|', 'Blay|Jean-Yves|JY|', 'Bertucci|François|F|', 'Eisterer|Wolfgang|W|', 'Chevreau|Christine|C|', 'Piperno-Neumann|Sophie|S|', 'Bompas|Emmanuelle|E|', 'Ryckewaert|Thomas|T|', 'Liegl-Antzwager|Bernadette|B|', 'Thery|Julien|J|', 'Penel|Nicolas|N|', 'Le Cesne|Axel|A|', 'Le Deley|Marie-Cécile|MC|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000970:Antineoplastic Agents D018592:Cross-Over Studies D018450:Disease Progression D004311:Double-Blind Method D005260:Female D005500:Follow-Up Studies D006801:Humans D053208:Kaplan-Meier Estimate D008297:Male D008875:Middle Aged D010671:Phenylurea Compounds D010919:Placebos D000077982:Progression-Free Survival D011725:Pyridines D012509:Sarcoma D055815:Young Adult
Regorafenib Placebo Sarcoma Cross-over Growth modulation index