澳大利亚悉尼大学黑色素瘤研究所Georgina V. Long团队研究了达拉非尼联合曲美替尼辅助治疗III期黑色素瘤的最终效果。2024年6月19日出版的《新英格兰医学杂志》发表了这项研究成果。

一项试验的5年结果表明，在BRAF V600突变的III期黑色素瘤患者中，与安慰剂相比，达拉非尼联合曲美替尼的辅助治疗可获得更长的无复发生存期和无远处转移生存期。但仍需要更长期的数据，包括关于总生存率的数据。

研究组随机分配870名患有BRAF V600突变的III期黑色素瘤切除患者接受为期12个月的达拉非尼（150 mg，每日两次）加曲美替尼（2 mg，每日一次）或两种匹配的安慰剂治疗。他们报告了这项试验的最终结果，包括总生存率、黑色素瘤特异性生存率、无复发生存率和无远处转移生存率的结果。

达拉非尼加曲美替尼的中位随访时间为8.33年，安慰剂为6.87年。Kaplan-Meier对总生存率的估计显示，与安慰剂相比，达拉非尼加曲美替尼的疗效并不显著（死亡风险比为0.80；95%置信区间[CI]为0.62至1.01；分层对数秩检验P=0.06）。在几个预先指定的亚组中观察到了一致的生存益处，包括792名BRAF V600E突变的黑色素瘤患者（死亡风险比为0.75；95%可信区间为0.58至0.96）。与安慰剂相比，无复发生存率更倾向于达拉非尼加曲美替尼（复发或死亡的风险比为0.52；95%可信区间为0.43至0.63），无远处转移生存率亦是如此（无远处转移或死亡的危险比为0.56；95%置信区间为0.44至0.71）。没有新的安全信号报告，这一发现与之前的试验报告一致。

研究结果表明，经过近10年的随访，在切除的III期黑色素瘤患者中，与安慰剂相比，达拉非尼加曲美替尼的辅助治疗具有更好的无复发生存率和无远处转移生存率。对总生存率的分析表明，联合治疗的死亡风险比安慰剂低20%，但益处并不显著。在BRAF V600E突变的黑色素瘤患者中，研究结果表明，联合治疗的死亡风险降低了25%。

附：英文原文

Title: Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma

Author: Georgina V. Long, Axel Hauschild, Mario Santinami, John M. Kirkwood, Victoria Atkinson, Mario Mandala, Barbara Merelli, Vanna Chiarion Sileni, Marta Nyakas, Andrew Haydon, Caroline Dutriaux, Caroline Robert, Laurent Mortier, Jacob Schachter, Dirk Schadendorf, Thierry Lesimple, Ruth Plummer, James Larkin, Monique Tan, Sachin Bajirao Adnaik, Paul Burgess, Tarveen Jandoo, Reinhard Dummer

Issue&Volume: 2024-06-19

Abstract:

BACKGROUND

The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis–free survival than placebo among patients with BRAF V600–mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival.

METHODS

We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis–free survival.

RESULTS

The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan–Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P=0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis–free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports.

CONCLUSIONS

After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis–free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy.

DOI: NJ202406190000001

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2404139