Results of the TAPPAS trial: An adaptive enrichment phase III trial of TRC105 and pazopanib (P) versus pazopanib alone in patients with advanced angiosarcoma (AS)

Abstract

Abstract Background Pazopanib (P) is approved for refractory advanced STS refractory. A retrospective study of 40 AS patients treated with P, reported a median progression-free survival (PFS) of 3.1 months and median overall survival (OS) 9.9 months (Kollar et al, Acta Oncol, 2017). Endoglin is an essential angiogenic receptor expressed on AS cells that is upregulated following VEGF inhibition. TRC105, an endoglin antibody, combined with P produced a median PFS of 7.8 months in chemotherapy-refractory and P-naive patients enrolled on a phase I-II trial. Methods TAPPAS was a randomized multicenter trial of TRC105/P vs P that enrolled cutaneous and non-cutaneous AS patients and incorporated an adaptive enrichment design. Key inclusion criteria: 0-2 prior lines of therapy, ECOG ≤ 1. The primary endpoint was PFS by RECIST 1.1 by independent radiographic review (+ cutaneous lesions by photography) (IRR). Secondary endpoints included PFS by investigator review (INV) and OS. An interim analysis to determine the final sample size was conducted following enrollment of 123 patients. Results Of 123 pts (TRC105/P, 62; P, 61), 60% were female, 89% were white; median age was 68 years (range: 24-82); 46% were ECOG PS 0; 50% had cutaneous disease; and 28% had no prior treatment. TRC105/P did not prolong median PFS or OS compared to P (Table). Most common all-grade adverse events (AEs) in TRC105/P vs P: fatigue (61% vs 55%); headache (64% vs 23%), diarrhea (57% vs 51%), nausea (48% vs 49%), vomiting (38% vs 23%), anemia (44% vs 9.4%), epistaxis (56% vs 3.8%) & hypertension (36% vs.55%). Table . 1667O P TRC105/P Median PFS, mo (95% CI), IRR 4.3 (2.9-NE) 4.2 (2.8-8.3) HR (95% CI) 0.98 (0.52-1.8) p-value 0.95 Median PFS, mo (95% CI), Investigator 2.9 (2.6-4.1) 3.9 (2.6-5.5) HR (95% CI) 0.77 (0.46-1.78) p-value 0.31 Median PFS, cutaneous, mo (95% CI), IRR 5.6 (2.6-5.6) 4.2 (2.8-8.3) HR (95% CI) 1.07 (0.43, 2.7) p-value 0.89 Overall Survival, mo (95% CI) 8.7 (7.4, NE) NE (6.8, NE) Odds ratio (95% CI) 0.90 (0.46, 1.74) p-value 0.74 Overall Survival, cutaneous, mo (95% CI) 8.0 (6.7, NE) NE (6.8, NE) Odds ratio (95% CI) 0.68 (0.25, 1.84) p-value 0.45 NE: not estimable; CI: confidence interval; mo: months Conclusions TRC105 did not demonstrate activity when combined with P in angiosarcoma. This was the 1st randomized phase III trial in angiosarcoma. These data provide a benchmark of the activity of P in 1st + 2nd-line setting in AS. A number of patients derived durable benefit from the combination schedule, indicating the heterogeneity of angiosarcomas. Clinical trial identification NCT 02979899. Legal entity responsible for the study Tracon Pharmaceuticals, Inc. Funding Tracon Pharmaceuticals, Inc. Disclosure R.L. Jones: Advisory / Consultancy: Tracon; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Daichii; Advisory / Consultancy: Eisai; Advisory / Consultancy: Epizyme; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck. L. Liu: Full / Part-time employment: Tracon. C. Theuer: Full / Part-time employment: Tracon. All other authors have declared no conflicts of interest.