Article Figures & Data
Figures
- Figure 1.
Study schema. An accelerated dose-escalation study design was used to investigate doses from 10 to 900 mg, twice daily (b.i.d.), followed by expansion cohorts initially receiving the preliminary recommended phase II dose (RP2D) of 600 mg, twice daily.
- Figure 2.
Pharmacokinetics and pharmacodynamics of ulixertinib. Plasma concentrations of ulixertinib as a function of time and dose level following dosing on day 1 (A) and at steady state (B). AUC as a function of dose level following dosing on day 1 (C) and at steady state (D). The data for dose levels 10 to 150 mg twice daily (b.i.d.) represent a single patient at each dose level. Plasma levels and pharmacodynamic effects of ulixertinib are shown as a function of the dose level (E). Ulixertinib plasma levels from patients dosed with 600 mg/kg, twice daily, are shown at day 1 and steady state (F).
- Figure 3.
Dose-escalation patient response. Individual patient's target lesion response (A) and time on study (B) are shown as a function of initial dose level. C, A representative sustained partial tumor response in a melanoma patient that was refractory to prior BRAF inhibitor therapy. Horizontal red line in A depicts RECIST v1.1 partial response threshold. b.i.d., twice daily.
- Figure 4.
Cohort expansion patient response. Target lesion responses (A) and time on study (B), grouped by cohort, are shown for each evaluable patient initially dosed with 600 mg of ulixertinib twice daily in the expansion phase of the study. Specific genetic mutations are also indicated (A, B). C, Tumor response data for patients with atypical (non-V600) BRAF mutations, with specific mutations indicated. Data are further discriminated by color based on the literature-reported MAPK pathway activity, as indicated by pERK levels. CRC, colorectal cancer; NSCLC, non–small cell lung cancer.
- Figure 5.
Representative patient responses to ulixertinib. Longitudinal radiographic scans from a subset of patients who responded to ulixertinib are shown. A, A patient with gallbladder adenocarcinoma with a BRAF L485W mutation who experienced partial response in two lesions (green circles) over 12 weeks. B, A patient with glioblastoma multiforme with a BRAF V600E mutation who experienced a 64% reduction of their tumor (green circles) after 10 cycles of treatment with ulixertinib.
Tables
- Table 1.
Clinical characteristics of patients at baseline, including cancer types, prior therapies, and enrollment
Baseline characteristic All patients (N = 135) Age Median (range), years 62 (21–85) ≥65 year 63 (47) Sex, n (%) Male 83 (61) Female 52 (39) ECOG performance status, n (%) 0 45 (33) 1 90 (67) Prior immune therapy, n (%) Yes 69 (51) No 66 (49) Prior BRAFi/MEKi therapy, n (%) Yes 32 (24) No 103 (76) Pretreatment LDH, n (%) Elevated 43 (32) Not elevated 50 (37) Not done 42 (31) Body mass index Median (range), kg/m2 26.83 (14.6–148.2) Primary cancer type, n (%) Melanoma 53 (39) Colorectal 26 (19) Non–small cell lung 19 (14) Papillary thyroid 6 (4) Glioblastoma 4 (3) Prostate 3 (2) Small intestine 3 (2) Othera 21 (16) Enrollment, n (%) Dose escalation 27 (20) BRAF colorectal cohort 17 (13) BRAF non–small cell lung cohort 16 (12) BRAF melanoma cohort 21 (16) BRAF other cancer cohort 24 (18) NRAS melanoma cohort 22 (16) MEK cancer cohort 8 (6) NOTE. Data are presented as N (%) unless indicated otherwise.
aIncludes adenoid cystic, angiosarcoma, appendiceal, cecum, cholangiocarcinoma, gallbladder, gastrointestinal stromal tumor, mediastinal non-seminomatous germ cell tumor, mesothelioma, ovarian, pancreatic, salivary duct, small cell lung, squamous cell, thyroid, urachal, and vaginal.
- Table 2.
Patients with AEs that occurred in ≥10% (possibly related or related) including combined rash events and combined ocular events
<300 mg b.i.d. (n = 5) 300 mg b.i.d. (n = 4) 600 mg (n = 115) >600 mg b.i.d. (n = 11) Adverse event, n (%) Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3 Total (N = 135) Combined rasha 3 (60) 0 (0) 3 (75) 0 (0) 65 (56) 22 (19) 8 (72) 1 (9) 102 (76) Diarrhea 5 (100) 0 (0) 1 (25) 0 (0) 44 (38) 7 (6) 5 (45) 3 (27) 65 (48) Fatigue 3 (60) 0 (0) 1 (25) 0 (0) 43 (37) 3 (3) 5 (45) 2 (18) 57 (42) Nausea 3 (60) 0 (0) 2 (50) 0 (0) 44 (38) 2 (2) 6 (54) 0 (0) 57 (42) Decreased appetite 0 (0) 0 (0) 0 (0) 0 (0) 28 (24) 0 (0) 6 (54) 0 (0) 34 (25) Pruritus 0 (0) 0 (0) 1 (25) 0 (0) 27 (23) 1 (<1) 4 (36) 0 (0) 33 (24) Vomiting 0 (0) 0 (0) 2 (50) 0 (0) 18 (16) 1 (<1) 4 (36) 1 (9) 26 (19) Combined ocular eventsb 1 (20) 0 (0) 0 (0) 0 (0) 14 (12) 1 (<1) 2 (18) 0 (0) 18 (13) Edema peripheral 1 (20) 0 (0) 0 (0) 0 (0) 12 (10) 1 (<1) 1 (9) 0 (0) 15 (11) Anemia 0 (0) 1 (20) 0 (0) 0 (0) 6 (5) 5 (4) 0 (0) 3 (27) 15 (11) Dehydration 0 (0) 0 (0) 0 (0) 0 (0) 9 (8) 1 (<1) 1 (9) 2 (18) 13 (10) Alopecia 1 (20) 0 (0) 0 (0) 0 (0) 10 (9) 0 (0) 2 (18) 0 (0) 13 (10) Abbreviation: b.i.d., twice daily.
↵a“Combined rash” includes preferred terms of dermatitis acneiform (42), acne (1), skin exfoliation (2), and any term containing rash (81).
↵b“Combined ocular events” includes preferred terms of halo vision (1), photophobia (2), retinal detachment (1), retinal vein occlusion (1), retinopathy (1), vision blurred (6), visual impairment (10), and vitreous floaters (1). Note that retinal vein occlusion event (grade 3) occurred after >10 months on study and resolved with drug cessation.
Supplementary Data
- Table S1 - Tumor types and molecular alterations of enrolled patients
- Table S2 - Dose levels enrolled in dose escalation with number and description of dose limiting toxicities at each dose level.
- Table S3 - Pharmacokinetic data expressed in Cmax at each dose level in the dose escalation portion of the study.
Volume 8, Issue 2
