麻豆传媒

Targeted combination therapy following surgery in BRAF-mutated stage III melanoma led to longer relapse-free survival, researchers reported.

In a 5-year follow-up of a phase III trial, adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist) cut the risk of relapse in half compared with placebo (hazard ratio for relapse or death 0.51, 95% CI 0.42-0.61), said Reinhard Dummer, MD, of the University of Zurich Hospital in Switzerland, and colleagues.

Of the patients receiving dabrafenib plus trametinib, 52% (95% CI 48-58%) were alive without experiencing a relapse after 5 years versus only 36% (95% CI 32-41%) of patients on placebo, they reported in the .

Additionally, 65% of those on this adjuvant combination were alive without a distant metastasis after 5 years versus 54% of those on placebo. This equated to a 45% reduced risk for distant metastasis or death (HR 0.55, 95% CI 0.44-0.70).

During the follow-up period, there were no significant differences in the rate of serious adverse events between the groups.

Underpinning these findings are that demonstrated a median relapse-free survival not reached in the dabrafenib/trametinib arm compared to 16.6 months with surgery alone. At 3 years, the relapse-free survival rate was 58% versus 39%, respectively.

The 870-person trial included adults who had undergone a complete resection of histologically confirmed stage IIIA melanoma with a lymph node metastasis of at least 1 mm, stage IIIB melanoma, or stage IIIC melanoma. All patients were positive for BRAF V600E or V600K mutations, which were confirmed in primary tumor or lymph node tissue by a central reference laboratory.

Twelve weeks prior to randomization, all patients were also required to undergo a completion lymphadenectomy. After randomization, half of patients received 150-mg dabrafenib twice daily plus 2-mg trametinib once daily or two matched placebos for 12 months or until disease relapse.

"When this clinical trial was designed, all patients had to undergo aggressive surgery with lymph node dissection removing multiple lymph nodes," Dummer explained to 麻豆传媒, pointing out that nowadays, "based on the lack of improvement in progression-free survival and overall survival, the surgical procedures are less aggressive."

"Therefore today we do not recommend aggressive lymph node dissection in patients that qualify for adjuvant therapy," he noted, adding that "in patients that do not have the BRAF mutation, there is the possibility to apply immunotherapy."

He pointed out that targeted therapy has been considered to be very efficient for a limited period of time, but questions lingered on limitations regarding their long-term benefit. But because these findings saw a consistent long-term improvement in overall survival even long after treatment discontinuation, Dummer said this "suggests that a low tumor burden might be associated with an improved long-term outcome if targeted therapy is used for BRAF-mutated melanoma."

"There is an urgent need for biomarkers that identify the early progressers during adjuvant therapy. Potentially these patients would profit from immunotherapy alone or from combination using targeted therapy and immunotherapy," he added.

Some questions still remain, however, including whether or not 12 months is the optimal duration of treatment for these patients.

"Early biomarker results suggest that in a subgroup, longer treatment durations might be necessary. In other patients a shorter treatment could be sufficient," he suggested.

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