Abstract：
BACKGROUND: BRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen.
METHODS: Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold.
RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS.
CONCLUSIONS: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.
METHODS: Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold.
RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS.
CONCLUSIONS: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.
摘要：
背景：BRAF+MEK抑制剂可延长BRAFV600突变晚期黑色素瘤患者的预期寿命。获得性抵抗限制了受益的持续时间，但临床前和病例研究表明,间歇性给药可以克服这一局限性.INTERIM是一项评估间歇性给药方案的2期试验。
方法：由于开始dabrafenib+trametinib而导致的BRAFV600突变晚期黑色素瘤患者随机接受连续（CONT），或间歇（INT;dabrafenibd1-21，曲美替尼d1-14每28天）给药。复合主要终点包括无进展生存期（PFS）和生活质量（QoL）。次要终点包括反应率（ORR），总生存期（OS）和不良事件（AE）。通过液滴数字PCR（ddPCR）测量突变体BRAFV600EctDNA，使用>1%的突变等位基因频率作为检测阈值。
结果：79例患者（39INT，40CONT)被招募；中位年龄67岁，65%AJCC(第7版)IV期M1c，29%有脑转移。中位随访19个月，所有疗效指标的INT均较差：中位PFS8.5vs10.7mo（HR1.39，95CI0.79-2.45，p=0.255）；中位OS18.1movs未达到（HR1.69，95CI0.87-3.28，p=0.121），ORR57%vs77%。INT患者经历了较少的治疗相关的AE（76％vs88％），但更多的是>3级不良事件（53%对42%）。QoL赞成CONT。治疗前BRAFV600EctDNA的检测与两组的OS较差(HR2.55,95CI1.25-5.21,p=0.01)相关。治疗期间未检测到的变化并不能显着预测更好的OS。
结论：INTERIM的发现与其他最近的临床试验一致，该临床试验报告称间歇给药不能提高BRAF+MEK抑制剂的疗效。
方法：由于开始dabrafenib+trametinib而导致的BRAFV600突变晚期黑色素瘤患者随机接受连续（CONT），或间歇（INT;dabrafenibd1-21，曲美替尼d1-14每28天）给药。复合主要终点包括无进展生存期（PFS）和生活质量（QoL）。次要终点包括反应率（ORR），总生存期（OS）和不良事件（AE）。通过液滴数字PCR（ddPCR）测量突变体BRAFV600EctDNA，使用>1%的突变等位基因频率作为检测阈值。
结果：79例患者（39INT，40CONT)被招募；中位年龄67岁，65%AJCC(第7版)IV期M1c，29%有脑转移。中位随访19个月，所有疗效指标的INT均较差：中位PFS8.5vs10.7mo（HR1.39，95CI0.79-2.45，p=0.255）；中位OS18.1movs未达到（HR1.69，95CI0.87-3.28，p=0.121），ORR57%vs77%。INT患者经历了较少的治疗相关的AE（76％vs88％），但更多的是>3级不良事件（53%对42%）。QoL赞成CONT。治疗前BRAFV600EctDNA的检测与两组的OS较差(HR2.55,95CI1.25-5.21,p=0.01)相关。治疗期间未检测到的变化并不能显着预测更好的OS。
结论：INTERIM的发现与其他最近的临床试验一致，该临床试验报告称间歇给药不能提高BRAF+MEK抑制剂的疗效。
