Overview of three recent Phase III randomised studies
About 50% of metastatic cutaneous melanomas harbour a BRAF mutation, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, a critically important signalling pathway in melanoma. The BRAF inhibitors vemurafenib and dabrafenib have shown improved response rates and significantly longer progression-free-survival (PFS) and overall survival (OS) when compared to chemotherapy in patients with a BRAF-activating mutation suffering from metastatic cutaneous melanoma. However tumours become resistant to the treatment after a period of time, with a median time to progression of about six months. The most common resistance mechanisms reactivate the MAPK pathway. MEK is a downstream effector of BRAF in the MAPK pathway; therefore blocking both BRAF and MEK at the same time delays the development of drug resistance and prolongs PFS. Furthermore, combined BRAF and MEK inhibition prevents paradoxical activation of the MAPK pathway and reduces the incidence of secondary cutaneous squamous-cell carcinomas and keratoacanthomas, which are seen with BRAF inhibitors.
Three large Phase III randomised studies evaluating the superiority of combined BRAF and MEK inhibition versus BRAF inhibition alone have recently been published.
The combination of the BRAF inhibitor dabrafenib (Teniflar, GSK) and the MEK inhibitor trametinib (Mekinist, GSK) has been compared to dabrafenib plus placebo in 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation (COMBI-D study, Ref. 1). PFS was the primary end point of the study, in which 211 patients received dabrafenib plus trametinib and 212 dabrafenib plus placebo. Baseline characteristics were similar in the two arms. The median follow-up was nine months. The main findings were:
- The combination of dabrafenib plus trametinib significantly extended PFS when compared to single use of dabrafenib (9.3 months vs. 8.8 months). This benefit resulted in a 25% relative reduction in the risk of disease progression.
- The overall response rate was significantly higher in the dabrafenib plus trametinib group (67% vs. 51%).
- The combination therapy was associated with a 37% relative reduction in the risk of death compared to the monotherapy at the interim survival analysis performed at 6 months.
- Pyrexia was the most common grade 3-4 adverse event and it occurred more frequently in the group of patients receiving the combination (6% vs. 2%). Fewer patients in the dabrafenib–trametinib group than in the dabrafenib-only group developed cutaneous squamous-cell carcinomas (2% vs. 9%) or cutaneous hyperkeratoses (3% vs. 32%).
A second study evaluated dabrafenib and trametinib, this time compared to vemurafenib alone. The trial was open label, with 704 previously untreated patients having a BRAF activating mutation (either V600E or V600K) randomised to receive dabrafenib plus trametinib or vemurafenib (COMBI-V study, Ref. 2). 352 patients were enrolled in each group.
The primary end point in this case was OS. At the pre-planned interim analysis, performed after 77% of the total number of expected events, the overall survival rate at 12 months was 72% in the combination-therapy group and 65% in the vemurafenib group. Since the primary end point was met, the study was stopped in July 2014 for efficacy. Median PFS was longer in the combination-therapy group than in the vemurafenib group (11.4 months vs. 7.3 months); similarly, the response rate was higher in the combination arm (64% vs. 51%). Pyrexia was the most common adverse event with the combined treatment, whereas skin rash most often occurred in patients receiving vemurafenib. Development of cutaneous squamous-cell carcinoma was significantly reduced in patients receiving the combination.
In a study of a similar design, single agent BRAF inhibitor vemurafenib (Zelboraf, Roche) was compared to the combination of vemurafenib plus the MEK inhibitor cobimetinib (Ref 3). A total of 495 treatment-naïve advanced disease patients with a BRAF-V600E were treated. The primary end point was again PFS. At a median follow-up of 7.3 months, the main findings were:
- Patients receiving the combination had a significantly longer PFS compared to single agent vemurafenib (9.9 months vs. 6.2 months). This benefit resulted in a 50% relative reduction in the risk of disease progression.
- 68% of patients in the combination group had an objective response, compared with 45% in the single-agent group.
- The combination therapy was associated with a 35% relative reduction in the risk of death compared to monotherapy at the interim survival analysis performed at 9 months.
- Skin rash and increased liver enzyme were the most common grade 3-4 side effects, the latter occurring more often in patients receiving the combination. Secondary skin cancers were significantly higher in patients on single agent therapy (20% vs. 3%).
Taken together, the findings of these three studies provide clear evidence of the benefit of combined BRAF and MEK inhibition. As well as the development of secondary skin cancers, toxicities of any grade were most commonly seen in patients on combination treatment. Toxicities were manageable by means of dose reduction or temporary treatment interruption.
The combination dabrafenib plus trametinib has been approved by the FDA for the treatment of patients with advanced or metastatic melanoma with a BRAF activating mutation, but has not yet been approved by the EMA. NICE have scheduled an appraisal of the combination for August 2016.
The combination of dabrafenib and trametinib is licensed in the US and Australia but not yet in the UK. Until recently British patients were able to access this combination through a company-sponsored ‘Compassionate Use Programme’. NHS England has decided that the dabrafenib-trametinib combination will no longer be available to patients.
- Long GV, Stroyakovskiy D, Gogas H et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014; 371:1877-88
- Robert C, Karaszewska R, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372: 30-9.
- Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371:1867-76.