PLX4032 IS COMING

September 10, 2010 — The investigational targeted therapy for metastatic melanoma, PLX4032 (Plexxicon/Roche), has repeatedly drawn praise from oncologists and generated enthusiasm.

In 2009, when early data were presented to a palpably excited audience at the American Society of Clinical Oncology annual meeting, the session moderator suggested that PLX4032 was part of "a decisive step toward personalized medicine" in melanoma.

In February 2010, the New York Times published a 3-part series on metastatic melanoma, starring PLX4032 and its lead investigator, who said the agent was his patients' "best shot."

More recently, a pair of melanoma experts described PLX4032 as a "breakthrough" and a "major advance" in an editorial that accompanied phase 1 study data on the agent (N Engl J Med. 2010;363:876-878).

Now, in a quieter moment, a letter published online September 7 in Nature reveals more of the science behind PLX4032, including the fact that its clinical efficacy requires "broad target blockade."

Complete Inhibition Needed

PLX4032 is "a potent inhibitor of oncogenic B-RAF kinase activity" write the authors, led by Gideon Bollag, PhD, from Plexxicon, which discovered the investigational agent and is based in Berkeley, California.

B-RAF is the most frequently mutated protein kinase in human cancers, the authors point out.

"The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumors are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients," they write.

That hoped-for benefit is now on its way to being known, suggest the authors.

Median progression-free survival, although not yet established, is estimated to be about 7 months — which compares favorably with the less than 2 months that other experimental agents for advanced melanoma have shown, they note.

PLX4032 only works in melanoma patients with BRAF mutations — not those with melanomas carrying the wild-type BRAF. About 50% of melanomas harbor an activating mutation in BRAF.

In the extension component of the phase 1 study, 81% (26 of 32) of melanoma patients with a BRAF mutation had tumors shrink 30% or more, and thus had either a partial or complete response, according to the Response Evaluation Criteria in Solid Tumors (RECIST). The high response rate was called "remarkable" by experts who were not associated with the study.

The authors of the new paper offer insight into what is required for a patient to have a significant tumor response.

To understand that, the authors, who are both Plexxicon staff and academics, focused on the part of the RAF/MEK/ERK pathway that PLX4032 selectively inhibits — namely, the ERK pathway.

The researchers wanted to monitor activity in this pathway in treated patients and, as a result, measured phosphorylated-ERK levels, using immunohistochemistry, in biopsied tumor cells, both in the nucleus and cytoplasm.

The data, which are published as supplementary information to the letter, "indicate that the near-complete inhibition of ERK signaling may be needed for significant tumor response." This need for broad target blockade was unexpected, said Dr. Bollag.

"This surprised us," he told Medscape Medical News, "since you might expect that 50% to 60% would be enough to shut down the tumor, but that level of inhibition barely slowed them down."

This level of inhibition required "rather high levels of drug exposure; those high levels required good tolerability of the compound," added Dr. Bollag.

However, for all of its exciting results, PLX4032 is not a miracle.

"Tumor regrowth occurs in many of the patients," Dr. Bollag and his colleagues write in their letter. Drug resistance occurs and is not understood. "The durability of response to PLX4032 is still under evaluation," the authors summarize.

Still, the fact that PLX4032 caused tumor regression in a large proportion of patients with BRAF-mutant advanced-stage melanoma provides "strong support for the hypothesis that the oncogenic B-RAF protein is a dominant driver of tumor growth and maintenance," they state.

Dr. Bollag is an employee of Plexxicon.

Nature. Published online September 7, 2010. Abstract