Nick Mulcahy

June 08, 2012

June 8, 2012 (Chicago, Illinois) — An investigational oral therapy, dabrafenib (GlaxoSmithKline), might be even better than the BRAF-targeted drug vemurafenib (Zelboraf, Roche), which is already available for the treatment of BRAF-mutated melanoma.

Vemurafenib is the first therapy approved by the US Food and Drug Administration and the current standard of care for patients with metastatic melanoma and BRAF mutations.

However, new data suggest dabrafenib is better tolerated than vemurafenib.

In the BREAK-3 study, presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO), "squamous cell carcinomas and keratoacanthomas were seen in only 7% of the patients," lead author Axel Hauschild, MD, from the University Hospital in Kiel, Germany, explained during a meeting press conference.

A recent phase 3 trial of vemurafenib (the BRIM-3 study) showed that cutaneous squamous cell carcinoma, keratoacanthoma, or both developed in 18% of patients (N Engl J Med. 2011;364:2507-2516).

Overall, treatment with dabrafenib In BREAK-3 resulted in fewer cases of serious skin toxicities, including squamous cell carcinomas, than were reported with vemurafenib in the BRIM-3 study.

Loss of Efficacy

However, a clinical issue even bigger than secondary skin cancer looms for BRAF inhibition, said press conference moderator Sylvia Adams, MD, from the New York University School of Medicine in New York City.

Researchers await mature results from studies of combination therapies for metastatic melanoma to see if that strategy "can push off the onset of resistance," she said.

Dr. Adams was referring to the fact that BRAF inhibition as monotherapy has dramatic initial response rates, but the effectiveness is not sustained.

Trials exploring combination therapies include a study of dabrafenib and the MEK inhibitor trametinib (GlaxoSmithKline); earliy results from that study were presented here at the ASCO meeting.

Secondary skin cancers caused by BRAF inhibition are important, but they need to be kept in perspective, a melanoma expert recently told Medscape Medical News. They are relatively benign and are not a reason to stop treatment with a BRAF inhibitor, said Ashani T. Weeraratna, PhD, from the Wistar Institute in Philadelphia, Pennsylvania.

Jury Still Out on Overall Survival

Whether or not BRAF inhibition with dabrafenib is more effective than that with vemurafenib in prolonging the life of patients with metastatic melanoma remains to be seen.

Overall survival data from the BREAK-3 study, comparing dabrafenib with dacarbazine in 250 patients, were not reported; they are "very immature," Dr. Hauschild explained.

However, the overall response rates are comparable, with both agents providing either a partial or complete response in about 50% of patients in their respective phase 3 clinical trials.

In BREAK-3, a 3:1 randomization ratio allowed more patients to be treated with dabrafenib. All the patients had previously untreated unresectable stage III/IV metastatic melanoma with mutations in the BRAF gene.

Dr. Hauschild reported that dabrafenib (150 mg twice daily) reduced the risk for disease progression by 70%, compared with standard dacarbazine chemotherapy (1000 mg/m² intravenously every 3 weeks). The difference in this progression-free survival was statistically significant (hazard ratio 0.30; P < .0001), reported Dr. Hauschild.

Overall, median progression-free survival was 5.1 months with dabrafenib and 2.7 months with dacarbazine.

The overall response rate, assessed by the investigators, was 53% with dabrafenib and 19% with dacarbazine. An independent review found similar numbers.

The investigators reported stable disease in 40% of the dabrafenib group and in 30% of the dacarbazine group.

The numbers mean that more than 90% of dabrafenib-treated patients benefited from treatment, said Dr. Hauschild.

Both treatments were generally well tolerated. Dr. Hauschild noted that "there were very few serious adverse events." More patients in the dacarbazine group experienced hematologic adverse events, as would be expected with chemotherapy; more patients in the dabrafenib group experienced moderate skin reactions, arthralgia, and pyrexia.

Discontinuation was 3% in both groups, which is "very low," said Dr. Hauschild.

The trial was funded by GlaxoSmithKline. Dr. Hauschild and Dr. Adams report financial ties to GlaxoSmithKline. Some coauthors report financial ties to GlaxoSmithKline, and some are employees of the company.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract LBA8500. Presented June 4, 2012.

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