Combination of BRAF and MEK Inhibitors Paves Way for Phase III Studies in BRAF-mutated Metastatic Melanoma


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Two late-breaking studies presented at the 2012 European Society for Medical Oncology (ESMO) Congress highlight the promising potential of combining dual BRAF and MEK inhibitors for the treatment of BRAF-mutated metastatic melanoma. A phase II study showed that combining full doses of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved outcomes. A phase Ib study demonstrated noteworthy preliminary responses for the combination of the BRAF inhibitor vemurafenib (Zelboraf) plus the investigational MEK inhibitor GDC-0973.

Dabrafenib plus Trametinib

The phase II study was presented by Georgina Long, MD, of Westmead Hospital and the Melanoma Institute of Australia in Sydney.1 In that trial, the combination of full-dose ­dabrafenib plus full-dose trametinib achieved superior progression-free survival, overall response rate, and duration of response in patients with V600 BRAF mutation–positive metastatic melanoma vs full-dose dabrafenib plus half-dose trametinib vs dabrafenib monotherapy. Simultaneously with the ESMO presentation, the findings were published online in The New England Journal of Medicine.2 ­Dabrafenib and trametinib are under development by GlaxoSmithKline.

About 50% of patients with metastatic melanoma harbor a BRAF V600 mutation. Patients who respond to BRAF inhibitors eventually develop resistance. Trametinib, an investigational MEK1 inhibitor, blocks the “escape route” downstream in the same pathway, and this was the rationale for combining both drugs, explained Dr. Long. As has been shown in earlier studies, the combination of both drugs reduced the incidence of secondary skin cancers found with BRAF inhibitor monotherapy.

“Using dabrafenib as one road block and then adding trametinib as an exit block improves response and duration of response,” Dr. Long told listeners at an ESMO press conference.

Study Data

The investigators randomly assigned 162 patients with BRAF V600E/K –positive metastatic melanoma to monotherapy with dabrafenib at 150 mg twice daily vs the combination of dabrafenib at 150 mg plus trametinib at 1 mg vs full doses of both drugs (ie, dabrafenib, 150 mg twice daily; trametinib, 2 mg).

Median follow-up was 14 months. Median progression-free survival was 9.4 months for the full-dose combination vs 5.8 months for the monotherapy arm (P < .0001), representing a 61% reduction in risk of disease progression. Median progression-free survival was 9.2 months for the arm using half-dose trametinib, which was also significantly better than monotherapy (P = .006). For every subgroup analyzed (based on age, sex, baseline disease stage, baseline LDH, and presence of brain metastasis), the full-dose combination extended progression-free survival vs monotherapy:

Confirmed response rate was 76% for the full-dose combination arm vs 54% for dabrafenib monotherapy (P = .026). Confirmed response was observed in 50% of those assigned to full-dose dabrafenib and half-dose trametinib.

Median duration of response was 5.6 months for monotherapy, 9.5 months for the combination of full-dose dabrafenib and half-dose trametinib, and 10.5 months for the full-dose combination of both drugs.

Median overall survival had not been reached in any of the three arms at the time of the ESMO meeting. According to Dr. Long, 12-month survival for 79% of patients in the full-dose combination arm is unprecedented in metastatic melanoma.

Adverse Events

Pyrexia and chills were the most common adverse events in the combination arms: 71% and 58% for both combinations, respectively. Pyrexia can be prevented with corticosteroids, Dr. Long said.

Cutaneous toxicities (ie, alopecia hyperkeratosis, skin papilloma, and squamous cell carcinoma) associated with BRAF inhibition were reduced in both combination arms compared with dabrafenib monotherapy. Squamous cell carcinoma was found in 10 patients on monotherapy, 1 with the combination that included half-dose trametinib, and 4 in the full-dose combination arm. The distribution of other adverse events was similar in the three treatment arms, except those related specifically to trametinib occurred more frequently in the combination arms (yet not at any greater rate than seen with single-agent trametinib studies).

Ongoing phase III trials are exploring the full-dose combination used in this study vs dabrafenib alone and trametinib alone, respectively.

Phase Ib Trial

The phase Ib dose-escalation trial treated 44 BRAF mutation–positive patients with locally advanced unresectable or metastatic melanoma using vemurafenib, 720 or 960 mg twice per day continuously and GDC-0973 at doses of 60, 80, or 100 mg every day in varying schedules of 14 days on and 14 days off; 21 days on and 7 days off; and continuously.3

This preliminary study demonstrated the safety of the combination and was not designed to evaluate efficacy. Nevertheless, the range of tumor shrinkage from baseline was 25% to 60%.

“Every patient had some degree of response,” said lead author Rene Gonzalez, MD, University of Colorado at Denver, Aurora, Colorado. “But it is premature to comment on efficacy at this time, and further research is needed.”

Adverse effects included diarrhea (54.5%), rash (50%), nausea (38.6%), fatigue/asthenia (34.1%), liver function abnormality (25%), and photosensitivity (25%). Cutaneous squamous cell cancer was observed in one patient who, upon pharmacokinetic analysis, was found to have low levels of the MEK inhibitor.

Genentech and Roche are planning a phase III trial to study this combination in previously untreated BRAF mutation–positive metastatic melanoma. ■

Disclosure: Dr. Long is a consultant advisor to Roche, GlaxoSmithKline, Amgen, and Bristol-Meyers Squibb. She also receives travel and research support (to institution) from Roche. Dr. Gonzalez is a consultant and speaker, is on the advisory board, and receives research support from Roche/Genentech; he is also a consultant to and receives research support from GlaxoSmithKline, and is DSMB Chair for the METRIC study.

References

1. Long GV, Sosman JA, Daud AI, et al: Phase II three-arm randomised study of the BRAF inhibitor dabrafenib alone vs combination with MEK1/2 inhibitor trametinib in patients with BRAF V600 mutation-positive metastatic melanoma. 2012 ESMO Congress. Abstract LBA27. Presented September 29, 2012.

2. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. September 29, 2012 (early release online).

3. Gonzalez R, Ribas A, Daud A, et al: Phase IB study of vemurafenib in combination with the MEK inhibitor GDC-0973 in patients with unresectable or metastatic melanoma. 2012 ESMO Congress. Abstract LBA28. Presented September 29, 2012.


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