For patients diagnosed in the late stages of BRAF-mutated melanomas, one of the most common and deadly forms of skin cancer, treatment with a combination of immunotherapy options improves survival and lowers the risk of life-threatening events, found McMaster University researchers.
“This is the first analysis to draw comparison between targeted and immune therapies for BRAF-mutated melanomas,” said Dr Feng Xie, an associate professor in the department of clinical epidemiology and biostatistics at McMaster’s Michael G DeGroote School of Medicine and principal investigator of the study. “Our results will help patients and clinicians choose treatments.”
Cutaneous melanoma is an aggressive and deadly form of skin cancer. According to the Canadian Cancer Society, the disease accounts for 3.3% of new cancer cases each year in Canada, and it has a 15% death rate.
In its early stages, melanoma is often cured with surgery alone, however most patients who are diagnosed in the late stages of disease are not candidates for surgery and drug therapy is the main course of treatment.
Tahira Devji, the first author of the paper and a PhD student of McMaster’s Health Research Methodology Programme, said that around 40% to 60% of melanomas have a mutation in the BRAF protein.
A number of effective treatment options are available for patients with advanced BRAF-mutated melanoma, which fall under two classes of drug therapies: targeted therapy, like chemotherapy, which stops cancer from growing and spreading; and immunotherapy, which works by stimulating the immune system to attack tumour cells.
It has been unclear which is the optimal initial treatment.
The goal of the study was to estimate the relative efficacy and safety of systemic therapies for those who have been diagnosed with advanced BRAF-mutated melanoma but not yet received any treatment.
The team evaluated 15 randomised controlled trials published between 2011 and 2015, assessing the benefits and harms of targeted or immune checkpoint inhibitors in 6,662 patients with cancer that had spread to the lymph nodes and surgery was not an option, or distant metastatic melanoma.
They found that combined BRAF and MEK targeted therapy and PD-1 immunotherapy were both equally effective in improving overall survival. Combined BRAF and MEK inhibition was most effective in improving progression-free survival. PD-1 inhibition was associated with the lowest risk of life-threatening events.
They concluded that the safety of PD-1 inhibitors supports using this treatment option as first-line therapy in circumstances where quick action is not a priority.
“While the data in our study represents best available evidence, using more than one kind of immunotherapy shows promise in early outcomes in clinical trials and could change the treatment landscape once longer-term results are published,” said Feng Xie.
Importance: Multiple effective first-line systemic treatment options are available for patients with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment.
Objective: To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive, BRAF-mutated melanoma.
Data Sources: We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016.
Study Selection: We included RCTs in which at least 1 intervention was a targeted (BRAF or MEK) or an immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor.
Data Extraction and Synthesis: Two reviewers performed study selection, data abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis using a fixed-effect model to combine direct comparisons with indirect evidence. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (OR) for objective response rate (ORR) and serious adverse events.
Results: Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10 treatment strategies were included. Both BRAF/MEK and PD-1 were associated with improved OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor. There was no significant difference in OS between BRAF/MEK and PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a significant advantage of BRAF/MEK compared with all other treatment strategies for PFS. BRAF/MEK was associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared with BRAF alone, with both being superior in achieving ORR compared with other treatments. Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There was no significant difference in the risk of serious adverse events between chemotherapy and PD-1 (OR, 1.00; 95% CrI, 0.74-1.34).
Conclusions and Relevance: Compared with other treatments, BRAF/MEK and PD-1 inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports using this option as first-line therapy in circumstances where rapid response is not a priority.
Tahira Devji; Oren Levine; Binod Neupane; Joseph Beyene; Feng Xie