Article Figures & Data
Figures
- Figure 1.
Dabrafenib treatment duration and best response. A, Duration of exposure to dabrafenib analyzed by best overall response assessed by independent review using the RANO criteria. B, Best reduction in tumor size analyzed by best overall response, assessed by independent review using the RANO criteria, for the subset of patients with measurable disease. Dashed line represents a 50% reduction from baseline, which corresponds to the threshold for partial response per the RANO criteria. aIncludes only patients with measurable disease and ≥1 postbaseline evaluation. Five of these patients had the best overall response as stable disease, with no confirmation from the scan results; 1 patient was not evaluable.
- Figure 2.
MR images of a partial response (ongoing) achieved after 8 weeks of dabrafenib therapy in an 11-year-old male patient with BRAF V600–mutant ganglioglioma determined using coronal T1 postgadolinium contrast sequence. The arrows indicate the location of the tumor.
- Figure 3.
Kaplan–Meier progression-free survival. Kaplan–Meier estimates of progression-free survival. Eleven disease progression events occurred; eight were on-treatment and three were off-treatment. Tumor assessments were by independent review using the RANO criteria.
Tables
- Table 1.
Patient demographics, baseline characteristics, prior treatments, disposition, and dabrafenib exposurea
Part 1 Part 2 Characteristic Dabrafenib 3.75 mg/kg (n = 3) Dabrafenib 4.5 mg/kg (n = 6) Dabrafenib 5.25 mg/kg (n = 6) Dabrafenib RP2D (n = 17) All patients treated with dabrafenib at RP2D (n = 24) All patients with LGG (N = 32) Median age (range), years 8 (4–13) 8.5 (2–16) 7.5 (3–11) 11 (2–17) 9.5 (2–17) 8.5 (2–17) <2 years, n 0 0 0 0 0 0 2–<6 years, n 1 2 2 5 7 10 6–<12 years, n 1 3 4 4 8 12 12–≤18 years, n 1 1 0 8 9 10 Sex, n (%) Male 2 (67) 5 (83) 3 (50) 9 (53) 13 (54) 19 (59) Female 1 (33) 1 (17) 3 (50) 8 (47) 11 (46) 13 (41) Race, n (%) White 3 (100) 5 (83) 6 (100) 13 (76) 19 (79) 27 (84) Black 0 1 (17) 0 2 (12) 3 (13) 3 (9) Asian 0 0 0 2 (12) 2 (8) 2 (6) Performance status, n (%)b 100 2 (67) 3 (50) 3 (50) 9 (53) 12 (50) 17 (53) 80–90 1 (33) 1 (17) 2 (33) 7 (41) 10 (42) 11 (34) <80 0 2 (33) 1 (17) 1 (6) 2 (8) 4 (13) Histology at initial diagnosis, n (%) Pilocytic astrocytoma 1 (33) 3 (50) 1 (17) 8 (47) 10 (42) 13 (41) Ganglioglioma 0 1 (17) 1 (17) 5 (29) 6 (25) 7 (22) Pleomorphic xanthoastrocytoma 0 0 1 (17) 2 (12) 3 (13) 3 (9) Pilomyxoid astrocytoma 1 (33) 0 0 1 (6) 1 (4) 2 (6) Otherc 1 (33) 2 (33) 3 (50) 1 (6) 4 (17) 7 (22) Histologic grade at initial diagnosis, n (%)d Grade I 2 (67) 4 (67) 4 (67) 12 (71) 16 (67) 22 (69) Grade II 1 (33) 2 (33) 2 (33) 4 (24) 7 (29) 9 (28) Median time since initial diagnosis (range), months 36 (32–39) 15 (11–90) 39 (18–83) 26 (6–190) 31 (6–190) 32 (6–190) Prior treatments, n (%)e Chemotherapy 3 (100) 5 (83) 6 (100) 14 (82) 20 (83) 28 (88) Radiotherapy 1 (33) 1 (17) 1 (17) 3 (18) 5 (21) 6 (19) Small-molecule therapy 0 0 1 (17) 1 (6) 2 (8) 2 (6) Immunotherapy 0 0 0 1 (6) 1 (4) 1 (3) Other 0 0 0 3 (18) 3 (13) 3 (9) Median time from last recurrence to dabrafenib start (range), monthsf NA NA 0.8 (0.2–1.3) 1.1 (0.1–81.5) 1.1 (0.1–81.5) 1.1 (0.1–81.5) Median time from last progression to dabrafenib start (range), monthsg 7.6 (0.5–14.7) 0.8 (0.5–1.1) 1.8 (0.2–26.2) 1.6 (0.1–10.3) 1.5 (0.1–26.2) 1.1 (0.1–26.2) Continuing treatment, n (%) 2 (67) 3 (50) 2 (33) 8 (47) 10 (42) 15 (47) Discontinued treatment, n (%) 1 (33) 3 (50) 4 (67) 9 (53) 14 (58) 17 (53) Reasons for discontinuation Investigator discretion 1 (33) 1 (17) 4 (67) 5 (29) 10 (42) 11 (34) Disease progression 0 2 (33) 0 2 (12) 2 (8) 4 (13) Adverse event 0 0 0 2 (12) 2 (8) 2 (6) Median duration of exposure to dabrafenib (range), weeks 157 (62–159) 120 (8–185) 96 (25–152) 105 (<1–149) 104 (<1–152) 108 (<1–185) Patients with dose reductions and/or interruptions, n (%) 1 (33) 3 (50) 1 (17) 5 (29) 6 (25) 10 (31) Abbreviation: NA, not applicable.
↵aAs of data cutoff (September 12, 2017).
↵bUsing Karnofsky (≥16 years of age; n = 28) or Lansky (<16 years of age; n = 4) performance status, as appropriate.
↵cDesmoplastic neuroepithelial neoplasm, cervicomedullary tumor, glioneuronal brain stem tumor, posterior fossa brain tumor, optic pathway glioma, gliomatosis cerebri, and other low-grade glioma.
↵dOne patient had missing data for disease grade at initial diagnosis but was confirmed to have LGG.
↵ePatients may have had multiple therapies and prior therapy type was undetermined in 2 patients; best response to last therapy received included 5 patients with a partial response, 13 patients with stable disease, and 9 patients with progressive disease (response to last therapy was undetermined in 5 patients).
↵fIn 11 patients with recurrence.
↵gIn 25 patients with disease progression.
- Table 2.
Dabrafenib efficacy
Part 1 Part 2 Characteristic Dabrafenib 3.75 mg/kg (n = 3) Dabrafenib 4.5 mg/kg (n = 6) Dabrafenib 5.25 mg/kg (n = 6) Dabrafenib RP2D (n = 17) All patients treated with dabrafenib at RP2D (n = 24) All patients with LGG (N = 32) Independent reviewa Best overall response, n (%) Complete response 0 1 (17) 0 0 0 1 (3) Partial response 2 (67) 2 (33) 2 (33) 7 (41) 9 (38) 13 (41) Stable diseaseb 1 (33) 3 (50) 4 (67) 8 (47) 13 (54) 16 (50) Progressive disease 0 0 0 2 (12) 2 (8) 2 (6) Objective response, n (%) [95% CI] 2 (67) [9–99] 3 (50) [12–88] 2 (33) [4–78] 7 (41) [18–67] 9 (38) [19–59] 14 (44) [26–62] Median duration of response (range), months — — — — 11.0 (3.7–14.5) 11.0 (7.4–14.5) Disease control, n (%) [95% CI] 3 (100) [29–100] 5 (83) [36–100] 5 (83) [36–100] 12 (71) [44–90] 18 (75) [53–90] 25 (78) [60–91] Median progression-free survival (95% CI), monthsc 35 (15–NE) (NE–NE) 13 (13–NE) (NE–NE) 14 (13–NE) 35 (13–NE) 1-year progression-free survival rate (95% CI), %c 100 (100–100) 80 (20–97) 100 (100–100) 78 (46–92) 79 (53–92) 85 (64–94) - Table 3.
Safety summary and treatment-related AEs
All patients with LGG (N = 32) All grade Grade 3/4 Patients with a treatment-related AE, n (%) 29 (91) 9 (28) Treatment-related AEs (in >20% of patients), n (%) Fatigue 11 (34) 0 Rash 10 (31) 0 Dry skin 9 (28) 0 Pyrexia 9 (28) 0 Rash maculopapular 9 (28) 3 (9) Arthralgia 8 (25) 1 (3) Headache 7 (22) 0 Vomiting 7 (22) 0 AEs leading to discontinuation, n (%) 2 (6) 2 (6) Treatment-related deaths, n (%) 0 0 Patients with a treatment-related serious AE, n (%) 5 (16) 3 (9) Treatment-related serious AEs, n (%) Arthralgia 1 (3) 1 (3) Disseminated intravascular coagulation 1 (3) 1 (3) Ejection fraction decreased 1 (3) 0 Febrile neutropenia 1 (3) 0 Hypotension 1 (3) 1 (3) Pyrexia 1 (3) 0 Rash maculopapular 1 (3) 1 (3)
Volume 25, Issue 24
