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Phase I Study of PLX4032: Proof
of Concept for V600E BRAF
Mutation as a Therapeutic Target
in Human Cancer
Flaherty K et al.
American Society of Clinical Oncology 2009;
Abstract 9000. (Clinical Science Symposium
Presentation)
Introduction


V600E BRAF kinase activating mutation
– Point mutation that constitutively activates
map-kinase pathway
– Observed in 6-8% of all cancers, including melanoma
(60%) colorectal cancer (10%), anaplastic and
papillary thyroid carcinomas, low-grade serous ovarian
carcinomas
Phase I, sequential dose-escalation study of PLX4032
(oral agent — the most selective BRAF inhibitor to have
entered clinical development — N = 55: 49 melanoma,
3 thyroid, 1 rectal, 1 ovarian, 1 germ cell)
Source: Flaherty K et al. ASCO 2009; Abstract 9000.
Results
Patients with BRAFV600E Melanoma Treated with
PLX4032 > 240 mg BID
% change from baseline
(sum of lesion size)
100
75
50
25
0
-25
-50
(RECIST cutoff for PR, 30%)
-75
-100
Patients (n = 15)*
* One patient with M1c had 55% reduction in target lesions, but PD in non-target lesions;
died before end C2 (not included above)
Source: With permission from Flaherty K et al. ASCO 2009; Abstract 9000.
Results
Patient with BRAFV600E Melanoma PET Scan at
Baseline and Day +15 Treatment at 320 mg BID
A patient with response in extensive “intransit” metastases on the leg and
more distant skin and lymph node sites
Source: With permission from Flaherty K et al. ASCO 2009; Abstract 9000.
Summary and Conclusions
Nearly all AEs were mild and transient, mostly rash, fatigue,
photosensitivity but also cutaneous squamous cell cancer
following chronic dosing (n = 6)
 Responses to PLX4032 with V600E+ melanoma
– 9 PRs in 15 patients
– Regression of liver, lung and bone metastases
– Symptom improvement in many patients
– Premature to define PFS, but it appears to be ~6 months,
with many patients still on therapy
– No evidence of tumor regression in 5 patients with V600Enegative disease
 3 patients with V600E+ papillary thyroid carcinoma: 1 PR, 2 SD
 Additional trials planned in melanoma, colorectal cancer and
papillary thyroid carcinoma

Source: Flaherty K et al. ASCO 2009; Abstract 9000.