Previous studies have shown the clinical benefit of rechallenging the RAF pathway in melanoma patients previously treated with BRAF inhibitors. 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor, either as monotherapy or in combination with other therapies, after prior therapy with a first RAF inhibitor. This retrospective observational study results showed that rechallenging with RAFi(s) led to an overall response rate of 18.1% [PR in thyroid (1 anaplastic; 3 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma, and 1 anaplastic astrocytoma]. The clinical benefit rate was 54.5%; more than 30% of patients had durable responses with PR and SD lasting > 6 months. The median progression-free survival on therapy with second RAF inhibitor in the rechallenge setting either as monotherapy or combination was shorter at 2.7 months (0.9-30.1 m) compared to 8.6 months (6.5-11.5 m) with RAF-1i. However, the median PFS with RAF-2i responders (PFS-2) improved at 12.8 months compared to 11.4 months with RAF-1i responders. The median OS from retreatment with RAF-2i was 15.5 months (11.1-30.8 m). Further prospective studies are needed to validate these results and expand targeted therapy options for RAF-aberrant cancers.

中文翻译：

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BRAF 异常泛癌中的 RAF 抑制剂再激发疗法：RE-RAFFLE 研究

先前的研究表明，对先前接受 BRAF 抑制剂治疗的黑色素瘤患者重新挑战 RAF 通路具有临床益处。 44 名携带 RAF 改变的多发性肿瘤患者在先前使用第一种 RAF 抑制剂治疗后，再次使用第二种 RAF 抑制剂作为单一疗法或与其他疗法联合治疗。这项回顾性观察研究结果表明，用 RAFi 再次挑战的总体缓解率为 18.1% [甲状腺 PR（1 例间变性；3 例乳头状细胞瘤）、1 例卵巢癌、2 例黑色素瘤、1 例胆管癌和 1 例间变性星形细胞瘤]。临床受益率为54.5%；超过 30% 的患者获得持久缓解，PR 和 SD 持续 > 6 个月。在再激发试验中，第二种 RAF 抑制剂单药或联合治疗的中位无进展生存期较短，为 2.7 个月（0.9-30.1 m），而 RAF-1i 的中位无进展生存期为 8.6 个月（6.5-11.5 m）。然而，RAF-2i 应答者 (PFS-2) 的中位 PFS 改善为 12.8 个月，而 RAF-1i 应答者的中位 PFS 为 11.4 个月。 RAF-2i 再治疗的中位 OS 为 15.5 个月 (11.1-30.8 m)。需要进一步的前瞻性研究来验证这些结果并扩大 RAF 异常癌症的靶向治疗选择。