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)

Source: Flaherty K et al. ASCO 2009; Abstract 9000.

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)

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50

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-25

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-75

-100Patients (n = 15)*

(RECIST cutoff for PR, 30%)

Source: With permission from Flaherty K et al. ASCO 2009; Abstract 9000.

Results Patients with BRAFV600E Melanoma Treated with

PLX4032 > 240 mg BID

* One patient with M1c had 55% reduction in target lesions, but PD in non-target lesions; died before end C2 (not included above)

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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: 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 V600E-

negative disease 3 patients with V600E+ papillary thyroid carcinoma: 1 PR, 2 SD Additional trials planned in melanoma, colorectal cancer and

papillary thyroid carcinoma