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2 Drugs Beat 1 for Metastatic Melanoma
Sep 30, 12 Clinical UpdatesA two-drug combination bested monotherapy for metastatic melanoma, resulting in a 60% reduction in the odds of progression, according to a study reported here.
Patients treated with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib had a median progression-free survival (PFS) of 9.4 months compared with 5.8 months for patients who received only dabrafenib.
The combination led to significant improvement in objective response and was associated with less treatment-associated skin cancer than observed with the BRAF inhibitor alone, as reported here at the European Society for Medical Oncology meeting and published simultaneously online in the New England Journal of Medicine.
“This is the first kinase-kinase combination to show enhanced antitumor activity and to reduce a specific oncogenic adverse event with a biological rationale behind it,” Georgina Long, MD, of Westmead Hospital in North Sydney, Australia, said during an ESMO press briefing.
“Combined treatment prolonged progression-free survival and improved the response rate compared to single-agent dabrafenib. The toxicity was tolerable and manageable, particularly a decrease in cutaneous squamous-cell carcinoma.” The findings were consistent with data from the same study reported earlier this year at the American Society of Clinical Oncology meeting. The study involved patients with metastatic melanoma harboring the V600E or V600K mutation, which occurs in about half of all melanomas. The BRAF inhibitors vemurafenib (Zelboraf) and dabrafenib have prolonged survival and PFS in patients with V600E-positive melanoma, but are associated with an increased risk of squamous-cell skin cancer (keratoacanthoma). Additionally, resistance to BRAF inhibition is associated with reactivation of the MEK pathway, typically after about 6 to 7 months of treatment. Recognition of the limitations of BRAF inhibition in melanoma led to investigation of the selective MEK inhibitor trametinib. In the current presentation, the researchers reported findings from a phase II study that randomized patients with V600-positive melanoma to receive dabrafenib alone or in combination with trametinib. The primary endpoints were incidence of squamous-cell skin cancer, PFS, and objective response. The final analysis included 247 patients, of whom 85 were included in an open-label assessment of the safety and pharmacokinetics of various doses of dabrafenib and trametinib. The remaining 162 patients were randomized to receive dabrafenib alone or with one of two doses the MEK inhibitor. In the randomized phase of the trial, median PFS was 9.4 months with higher-dose trametinib versus 5.8 months with dabrafenib alone (HR 0.39, P<0.001). The lower-dose combination resulted in a median PFS of 9.2 months, also superior to dabrafenib alone (P=0.005). The higher dose of trametinib led to objective responses in 76% of patients compared with 54% for monotherapy (P=0.03). Though survival was not a primary endpoint, the results established a landmark in the treatment of metastatic melanoma. "The 12-month survival in the full-combination group was 79%. We have never, ever seen a 12-month survival of that level in metastatic melanoma," said Long. The high-dose combination was associated with a lower incidence of squamous-cell skin cancer (7% versus 19%), but the difference did not achieve statistical significance (P=0.09). Patients who received the lower-dose combination had an incidence of 2%, which was significantly lower than with dabrafenib alone (P=0.004). "Never, ever in the history of drug development have we combined two drugs and seen a reduction in toxicity," Long said of the safety results. Rash occurred in 20% and 27% of the trametinib groups versus 36% of patients randomized to dabrafenib alone. Alopecia occurred in substantially more patients in the monotherapy arm (34% versus 9% and 5%). The most common adverse event was pyrexia, which affected 71% of patients in the full-dose dabraftrametinib arm, including grade 3 severity in 5%. Chills occurred in 58% of the group and was grade 3 severity in 2% of patients. Pyrexia requiring hospitalization occurred in 19% and 25% of the half-dose and full-dose combination arms, respectively, versus 2% of the monotherapy group). Other adverse events that occurred more often in the combination therapy included fatigue , nausea, vomiting , and diarrhea. Few patients had grade 3/4-severity events. The most common grade 3/4 adverse event in the full-dose combination group was neutropenia (11%); one patient developed febrile neutropenia. ###The study was supported by GlaxoSmithKline, and investigators included GlaxoSmithKline employees. Long disclosed relationships with GlaxoSmithKline, Roche, Merck, and Bristol-Myers Squibb. Co-investigators disclosed relationships with GlaxoSmithKline, Roche, Pfizer, Merck, Bristol-Myers Squibb, Oncosec, Oncoprime, Merck-Serrono, Novartis, sanofi-aventis, and Genentech.### Primary source: New England Journal of Medicine Source reference: Flaherty KT, et al “Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations” N Engl J Med 2012; DOI: 10.1056/NEJMoa1210093. Additional source: European Society for Medical Oncology Source reference: Long GV et al. “Phase II three-arm randomized study of the BRAF inhibitor (BRAFi) dabrafenib alone vs combination with MEK1/2 inhibitor (MEKi) trametinib in pts with BRAF V600 mutation-positive metastatic melanoma (MM)” ESMO 2012; Abstract LBA27.Also in this section:
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