Complete response to dabrafenib-trametinib combo improves survival outcomes in advanced melanoma
A complete response to dabrafenib and trametinib treatment in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations leads to greater survival outcomes at 5 years, according to an analysis of data from the COMBI-d* and COMBI-v** trials.
“Dabrafenib plus trametinib led to 5-year disease control in approximately one-fifth of patients and 5-year survival in approximately one-third,” said study author Dr Paul Nathan from the Mount Vernon Cancer Centre in Northwood, UK.
The subjects in this analysis were the 563 treatment-naïve adults (median age 55 years, 57 percent male) with unresectable or metastatic melanoma and BRAF V600E or V600K mutations who had received the BRAF inhibitor dabrafenib (150 mg BID) plus the MEK inhibitor trametinib (2 mg QD) in the phase III COMBI-d and COMBI-v trials. The patients received treatment until disease progression or intolerable toxicity. The median follow-up period was 22 months.
At 5 years, the progression-free survival (PFS) rate was 19 percent (median PFS 11.1 months), from 31, 24, and 21 percent at 2, 3, and 4 years respectively. The 5-year overall survival (OS) rate was 34 percent (median OS 25.9 months) from 52, 44, and 37 percent at 2, 3, and 4 years, respectively. [ASCO 2019, abstract 9507; N Engl J Med 2019;doi:10.1056/NEJMoa1904059]
The objective response rate (ORR) was 68 percent, with 19 and 49 percent of patients having a complete and partial response, respectively, and 23 and 6 percent having stable and progressive disease, respectively.
Five-year PFS and OS rates were especially good among patients with complete response, at 49 and 71 percent, respectively.
“Complete response appears to strongly predict long-term benefit,” said Nathan.
Baseline lactate dehydrogenase (LDH) levels also appeared to affect survival outcomes with patients with normal or below the upper limit of normal (ULN) range having better 5-year PFS and OS rates than those with elevated LDH levels (25 percent vs 8 percent [PFS] and 43 percent vs 16 percent [OS]). Patients with normal LDH levels and <3 sites of metastasis at baseline had 5-year PFS and OS rates of 31 and 55 percent, respectively.
Other factors affecting survival outcomes were older age (with every 10-year increase associated with a reduced risk of PFS or OS events; hazard ratio [HR], 0.92; p=0.02 [PFS] and HR, 0.92; p=0.04 [OS]), female (HR, 0.74; p=0.003 [PFS] and HR, 0.68; p<0.001 [OS]), ECOG score 0 vs ≥1 (HR, 0.68 [PFS] and HR, 0.49 [OS]; p<0.001 for both), a normal vs elevated LDH level (HR, 0.50 [PFS] and HR, 0.47 [OS]; p<0.001 for both), and <3 vs ≥3 sites of metastasis (HR, 0.72; p=0.005 [PFS] and HR, 0.58; p<0.001 [OS]).
Eighteen percent of patients permanently discontinued treatment due to adverse events (AEs), the most common of which were pyrexia, decreased ejection fraction (4 percent each), and increased alanine aminotransferase levels (1 percent).
According to Nathan, the results point to improved outcomes among patients with “lower baseline tumour burden and less aggressive tumour biology”. Conversely, patients with elevated baseline LDH levels appear to have worse outcomes and as such, require different treatment, said Nathan and co-authors.