"Major Advance" Declared in Metastatic Melanoma -- And It's Only Phase 1

Nick Mulcahy

September 18, 2010

August 25, 2010 — It is a "major advance in the treatment of metastatic melanoma."

That's how 2 melanoma experts describe newly published data on the investigational agent PLX4032 (Plexxikon/Roche) — even though the data come from a phase 1 trial.

Writing in an editorial in the August 26 issue of the New England Journal of Medicine, which accompanies the results of the phase 1 study, Keiran Smalley, PhD, and Vernon Sondak, MD, from the Moffitt Cancer Center in Tampa, Florida, point out that there is no progression-free survival or overall survival data on the new agent yet.

Nonetheless, the treatment responses to the daily oral agent have been plenty inspiring, they suggest.

"A remarkable 81% of patients whose melanomas had an activating mutation in BRAF had a response to treatment" write the editorialists about the phase 1 dose-escalation trial of PLX4032, the new BRAF kinase inhibitor.

This percentage refers to the 26 of 32 melanoma patients with a BRAF mutation whose tumors shrank 30% or more, and thus had either a partial or complete response, according to the Response Evaluation Criteria in Solid Tumors (RECIST).

The treatment of metastatic melanoma can be individualized for a substantial percentage of patients.

Lead study author Keith Flaherty, MD, from the Massachusetts General Hospital Cancer Center in Boston, and his coauthors are restrained in their description of the study results, calling them "encouraging."

But the editorialists are effusive.

"These results represent a major breakthrough and provide proof of principle that the treatment of metastatic melanoma can be individualized for a substantial percentage of patients," write Drs. Smalley and Sondak.

Not for All Melanoma Patients

Not all melanoma patients will respond to PLX4032. Responses are dependent on the mutation status of patients, note both the editorialists and the study authors.

Only melanoma patients with BRAF mutations — and not those with melanomas carrying the wild-type BRAF — respond to treatment.

About 50% of melanomas harbor an activating mutation in BRAF, Drs. Smalley and Sondak report.

Specific molecular changes such as the BRAF mutation are what drive the proliferation of melanomas, write Dr. Flaherty and his coauthors.

Melanomas can be now "characterized" by those molecular changes, they add.

In addition to BRAF mutations, melanomas can be characterized and driven by mutations in KIT (the v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homologue). Recent phase 2 evidence indicates that imatinib can induce regression in 33% of the relatively "small proportion of melanomas" driven by mutations in KIT, observe Dr. Flaherty and his coauthors.

Some of the newly published data on PLX4032 were first presented at the American Society for Clinical Oncology (ASCO) meeting in 2009, as reported by Medscape Medical News.

At ASCO, another melanoma expert explained how PLX4032 is an advance in therapeutics targeting BRAF.

This agent was designed to specifically block the oncogenic mutated form of BRAF.

"Others have attempted to use kinase inhibitors to block the BRAF gene. This agent was designed to specifically block the oncogenic mutated form of BRAF," said David Fisher, MD, PhD, referring to the V600E mutation.

Dr. Fisher is also from Massachusetts General Hospital Cancer Center but was not involved in the study, which was started when Dr. Flaherty was still at the University of Pennsylvania.

More data on PLX4032 are on the way. A phase 2 study of patients for whom treatment with drugs approved by the US Food and Drug Administration has failed is currently in process. A phase 3 study comparing PLX4032 and dacarbazine is currently enrolling patients.

Adverse Reactions and Resistance

The phase I trial involved dose-escalation and dose-extension cohorts. In each case, patients received twice-daily doses of the agent.

In the dose-escalation cohort, a total of 55 patients (49 had melanoma; 6 had other cancers) were enrolled.

Among the 55 patients, there were 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who received 240 mg or more of PLX4032 twice daily. Ten of the 16 had a partial response, and 1 had a complete response.

In the dose-extension cohort, a recommended dose of PLX4032 was established (960 mg twice daily) for 32 patients. The primary objective was to determine response rate; the rate of 81% is noted above.

Overall, PLX4032 has a "moderate" toxicity, say the editorialists. The major dose-limiting adverse effects were rash (grade 2 or 3), fatigue, and arthralgia.

However, another adverse event occurred "somewhat unexpectedly," note the editorialists. Cutaneous squamous-cell carcinomas, mostly of the keratoacanthoma type, developed in 8 patients in the dose-escalation cohort (15%) and in 10 patients in the dose-extension cohort (31%).

The study authors elaborate on this finding saying: "Usually, squamous-cell carcinoma, keratoacanthoma type, are well-differentiated tumors with very low invasive potential and no metastatic potential."

Drug resistance also appears to be a problem with PLX4032, the editorialists point out.

"The impressive responses seen in the study by Flaherty and colleagues do not necessarily persist for extended periods," they note.

The median duration of progression-free survival is estimated to be 7 months (this has not been finalized), they also note.

"This pattern of initial response and eventual resistance is similar to that seen with targeted therapy in other tumors," write the editorialists.

Nonetheless, the initial response is "very reliable," Dr. Flaherty said at ASCO in 2009, and has repeated again now.

"One of the things that makes these results truly remarkable is that this drug works so reliably," he said in a press statement. "Patients who have been experiencing symptoms like pain and fatigue begin to feel better within a week of starting treatment, giving them a much better quality of life."

The study was sponsored by Plexxikon and Roche Pharmaceuticals, which provided the study drug. Dr. Flaherty reports serving as a consultant to Plexxikon and Hoffman-LaRoche; some of his coauthors are employees of Hoffmann-La Roche and Plexxikon Inc. Dr. Fisher has disclosed no relevant financial relationships.

N Engl J Med. 2010;363:809-819, 876-879.


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