PDF(Pubmed)
Abstract：
UNASSIGNED: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases.
UNASSIGNED: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined.
UNASSIGNED: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data.
UNASSIGNED: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.
UNASSIGNED: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined.
UNASSIGNED: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data.
UNASSIGNED: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.
摘要：
■POLARIS（第2期[ph2]；NCT03911869）评估了恩科非尼（BRAF抑制剂）与比尼美替尼（MEK1/2抑制剂）联合治疗BRAF/MEK抑制剂初治的BRAFV600突变型黑色素瘤无症状脑转移患者。
■安全导入（SLI）评估了高剂量恩科拉非尼300mg每日两次（BID）加比尼45mgBID的耐受性。如果高剂量在ph2中是可耐受的，患者将被随机分配接受高剂量或标准剂量（恩科拉菲尼450mg，每日一次[QD]加比米替尼45mgBID）。否则,标准剂量评估为推荐的ph2剂量(RP2D).在第1周期期间耐受标准剂量的患者可以在第2周期中剂量递增至恩可拉非尼600mgQD加比米替尼45mgBID。安全,功效,和药代动力学进行了检查。
■RP2D是恩科拉非尼的标准剂量，>33%的可评估SLI患者（3/9）存在剂量限制性毒性。总的来说,在13名安全性可评估的患者中(10名SLI，3ph2),9人曾接受过免疫疗法。SLI中有9个治疗相关的不良事件，ph2中有3个。在可评估SLI疗效的患者中（n=10），1例达到完全反应，5例达到部分反应（PR）；脑转移反应率（BMRR）为60％（95％CI：26.2，87.8）。在ph2中，3例患者中有2例达到PR（BMRR，67%[95%CI：9.4，99.2]）。与历史450mgQD数据相比，反复服用300mg恩科非尼BID剂量并未增加稳态暴露。
■尽管由于提前终止试验而导致的患者人数很少，BMRR在SLI和ph2之间似乎相似，并且ph2的安全性与以前的标准剂量恩科拉非尼联合比尼的报道一致。
■安全导入（SLI）评估了高剂量恩科拉非尼300mg每日两次（BID）加比尼45mgBID的耐受性。如果高剂量在ph2中是可耐受的，患者将被随机分配接受高剂量或标准剂量（恩科拉菲尼450mg，每日一次[QD]加比米替尼45mgBID）。否则,标准剂量评估为推荐的ph2剂量(RP2D).在第1周期期间耐受标准剂量的患者可以在第2周期中剂量递增至恩可拉非尼600mgQD加比米替尼45mgBID。安全,功效,和药代动力学进行了检查。
■RP2D是恩科拉非尼的标准剂量，>33%的可评估SLI患者（3/9）存在剂量限制性毒性。总的来说,在13名安全性可评估的患者中(10名SLI，3ph2),9人曾接受过免疫疗法。SLI中有9个治疗相关的不良事件，ph2中有3个。在可评估SLI疗效的患者中（n=10），1例达到完全反应，5例达到部分反应（PR）；脑转移反应率（BMRR）为60％（95％CI：26.2，87.8）。在ph2中，3例患者中有2例达到PR（BMRR，67%[95%CI：9.4，99.2]）。与历史450mgQD数据相比，反复服用300mg恩科非尼BID剂量并未增加稳态暴露。
■尽管由于提前终止试验而导致的患者人数很少，BMRR在SLI和ph2之间似乎相似，并且ph2的安全性与以前的标准剂量恩科拉非尼联合比尼的报道一致。
