Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial

Abstract

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.

Patients and methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.

Results: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.

Conclusions: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549.

Figure 1.. Waterfall plot of best change in tumor size from baseline (central review, all cohorts, intention-to-treat population, n=52).

Included are data for 50 evaluable patients with measurable disease and a tumor assessment at baseline and 2 additional patients with measurable disease and a tumor assessment at baseline who were deemed not evaluable for response. The plot summarizes data from patients with measurable disease and a tumor assessment at baseline and at least one post-baseline tumor assessment.

Figure 2.. Gene expression profiles of 29 tumors with centrally confirmed FGFR fusions.

Gene expression percentiles were calculated within the corresponding tumor types. T cell-inflamed gene expression signature assessments were based on the method described by Cristescu et al, 2018 (24). Immune cell fraction was calculated by quanTIseq (25). For gene expression, the maximum percentile is set to red, fading to white for the minimum percentile. For the T cell-inflamed GEP score, a three-color scheme is used: red represents the maximum score, blue represents the minimum score, and the median score is depicted by white, with a gradient in place between these values. For TME, the maximum cell fraction is set to green, transitioning to white for the minimum cell fraction CRC, colorectal cancer; GEP, gene expression profile; NE, not evaluable; NK, natural killer; NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease; TME, tumor microenvironment..