Dual BRAF and MEK Inhibition Is Active in Advanced Melanoma

Minimum skin toxicity with the combination


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In advanced melanoma, combination therapy with two investigational drugs—one targeting BRAF and the other the MEK pathway—achieved a median progression-free survival of 7.4 months, which rose to 10.8 months in patients who were optimally dosed, reported Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at H. Lee Moffitt Cancer Center, Tampa.

Importantly, these outcomes were achieved with far less dermatologic toxicity than is normally observed with either of the investigational agents alone, Dr. ­Weber reported at the 2012 ASCO Annual Meeting.1

100% Disease Control Rate

The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was tested in varying doses in 125 patients with advanced melanoma and the V600E BRAF mutation. The current efficacy analysis focused on 77 patients who had received no prior BRAF-targeted therapy and thus had demonstrated no resistance to BRAF inhibitors.

In the expanded phase Ib trial, investigator-assessed best responses included complete responses in 8%, partial responses in 49%, and stable disease in 39%, for an overall disease control rate of 96% among the 77 patients. However, among the 24 patients receiving dabrafenib, 150 mg twice daily, plus trametinib, 2 mg/d, 100% of patients achieved disease control or better, including complete responses in 8%, partial responses in 54%, and stable disease in 38%, with no patients progressing.

“Certainly this is an impressive record by any assessment,”Dr. Weber suggested, adding that the waterfall plot showing responses was “as good as or better than any I’ve seen in a [melanoma] trial.”

Dermatologic Toxicity Was Rare

The combination was not only very active, but was associated with little skin toxicity. Hyperproliferative skin lesions, including squamous cell carcinoma and actinic keratosis, are well-known side effects of vemurafenib treatment, occurring in up to 25% of patients, Dr. Weber noted.

With dabrafenib/trametinib, however, 13% of the 135 patients in the overall study developed skin toxicity ≥ grade 2; only 3% developed squamous cell carcinoma, 5% developed actinic keratoses, 2% developed skin papillomas, and 22% developed rash, which is a common side effect of MEK inhibitors.

“We did see rashes, but the acneiform rash we often see with MEK inhibitors was almost absent in this study,” he said.

 “It’s fascinating to find such promising effects with this combination regimen,” Dr. Weber said. “Not only are the two drugs causing shrinkage of the cancer, but we’re seeing that a second anticancer therapy may actually suppress the side effects of the first. There is a significant diminution of the dermatologic toxicities, such as just 3% squamous cell carcinoma, which can favorably be compared to the 15% to 25% frequency seen with this drug alone or with other BRAF inhibitors.”

Other Side Effects

On the other hand, 52% of patients had pyrexia, and while just 8% of cases were grade 3 or higher, 23% had doses reduced or delayed because of fever, he added. Fatigue, nausea, and chills occurred at rates similar to those seen with BRAF inhibitors alone.

The phase II randomized portion of the study is currently ongoing, and the phase III testing of the “150/2” dose has begun, he said, adding, “Obviously we must be cautious, but we find these results extremely encouraging.” ■

Disclosure: Dr. Weber has received honoraria from and served on advisory boards for GlaxoSmithKline.

Reference

1. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.


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Expert Point of View: Dual BRAF and MEK Inhibition Is Active in Advanced Melanoma

Commenting on the trial of combined BRAF and MEK inhibition in advanced melanoma, Michael K.K. Wong, MD, PhD, Professor of Medicine at Keck School of Medicine, University of Southern California, Los Angeles, called the findings “nothing short of extraordinary” and a potential “game changer.”


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