GSK BRAF Inhibitor With Early But Impressive Results


Presented by Rick Kefford, MD, from Melanoma Institute of Australia.

This was a Phase I/II trial of this agent (colloquially called “436″) in melanoma. 112 patients were treated in a dose escalation construct, all with mutant BRAF melanomas.

The second part was a Dose Expansion phase started in March 2010 V600 BRAF mutant melanomas: 20 patients with melanoma and 10 patients with melanoma metastatic to brain. All these patients got the same dose. This DATA HAS NOT BEEN PRESENTED BEFORE.

Dose selected was 150 mg bid (twice a day). This showed acceptable inhibition of target enzymes on tumor biopsies. However, MTD (max tolerated dose) has not technically been reached and some cohorts still being observed. Some DLTs seen, and typical BRAF skin keratoacanthomas and non-malignant hyperkeratoses, although somewhat less than PLX4032 in this small sample.

In Phase I trial, 18 patients treated at chosen dose of 150 mg bid. Side effects seen not unexpected: fatigue, fevers, rash, arthritis and others. SCCs seen in about 7%, compared to incidence about 30% for PLX4032. Hair curls (hahaha). Improves hangovers (he said it!).  Median PFS was 8.3 months with 70% PR.

In expanded trial, OR 77%, 1 CR, rest are PR. 73% of patients still on study. Pictures shown of regressing lung, soft tissue and liver mets. This was inV660E mutants.

In V600k mutants, lower response rate in much smaller group but still some responses.

Quality of Life discussed: no data, but anecdotal rapid improvement in pain and other problems within days of initiating therapy. Patients apparently feel remarkably better, which was also seen with PLX4032 drug.

Brain metastases: some of this was presented at ESMO(?which parts). In 10 patients with asymptomatic  brain mets, 8/10 PR+ (3 CR). No patients had increase in brain mets, ie no progressive disease seen. Extracranial responses in parallel to brain met response.

Future plans: Phase III trial planned to start inDec 2010, randomized vs DTIC with crossover. Phase II for melanoma patients with brain mets planned for early 2011.

Nothing extraordinary in Discussion period.

However, this was the highlight of the entire meeting from my perspective.

Eric D. Whitman, MD

Senior Editor

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