Activity of regorafenib in patients with non-adipocytic soft tissue sarcoma (NASTS): Evaluation of heterogeneity of treatment effect on the updated analysis of pooled cohorts.
Authors: Le Deley Marie-Cecile , Blay Jean-Yves , Wallet Jennifer , Bertucci Francois , Bompas Emmanuelle , Brodowicz Thomas , Chaigneau Loic , Chevreau Christine , Decoupigny Emilie , Italiano Antoine , Lieg-Atzwanger Bernadette , Mir Olivier , Piperno-Neumann Sophie , Thery Julien , Le Cesne Axel , Penel Nicolas 
Published: June 2022

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Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p < 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p < 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.