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ORIC-101 pharmacodynamics in PBMCs and tumor specimens. A, Pharmacodynamic (PD) modulation (average expression of GR target genes FKBP5, GILZ, and PER1) on day 1 of cycle 1 as observed in 40 dose expansion patients with PBMC sample collection and cortisol assessment at C1D1 (pre-dose and 6 hours post-dose), and with pre-dose cortisol levels >200 nmol/L. Samples are colored by cohort. B, PD suppression from cycle 1 day 1 (pre-dose) to day 15 (pre-dose) as observed in 26 patients with PBMC sample collection and cortisol assessment at C1D1 pre-dose and C1D15 pre-dose, and with C1D1 pre-dose cortisol levels >200 nmol/L. C, PD suppression from cycle 1 day 1 (pre-dose) to cycle 2 day 1 (pre-dose) as observed in 28 patients with PBMC sample collection and cortisol assessment at C1D1 pre-dose and C2D1 pre-dose, and with C1D1 pre-dose cortisol levels >200 nmol/L. D, PD modulation on day 1 of cycle 2 as observed in 30 dose expansion patients with PBMC sample collection and cortisol assessment at C2D1 (pre-dose and 6 hours post-dose) and with pre-dose cortisol levels >200 nmol/L. E, On-treatment change in GR activation signaling in 10 patients (four dose escalation, six dose expansion) with paired tumor biopsies. The horizontal arrows indicate directionality of observed changes in GR activation as indicated by GR Signature Score (average expression of FKBP5, GILZ, PER1, and KLF9) from screening to end of cycle 2 or end of treatment, in the 10 patients. The solid line shows the expected distribution of GR activation from a reference cohort of archival and fresh tumor biopsies collected during this ORIC-101 trial. Patients with decreased GR signaling are highlighted in the boxed area. F, Association of on-treatment decrease in GR activation signaling with longer time on treatment.
Chen et al. (Fri,) studied this question.