BEACON CRC撞线：BRAF V600E mCRC或将因此获批首个靶向治疗

ARRAY前几天公告，在先前接受过1-2轮治疗的BRAF V600E mCRC患者中，BRAFTOVI Triplet(即BRAF抑制剂BRAFTOVI® (encorafenib)+MEk抑制剂MEKTOVI® (binimetinib)+anti-EGFR单抗ERBITUX® (cetuximab))相比cetuximab+化疗(FORFIRI or Irinotecan)显著提升ORR(26.1% vs. 1.9%, p<0.0001, per BICR) 和OS (median 9.0 months vs. 5.4 months, [HR 0.52, 95% CI (0.39-0.70), p<0.0001])，降低了48%的死亡风险，达到预设的主要终点，既有可能成为首个Chemo-free的BRAFm的mCRC的靶向治疗方案，计划19年下半年提交上市申报。

美、欧、日大约5、15和2万人死于CRC，中国大约每年19-20万人死于CRC

BRAF突变占整个CRC的15%，有着极差的预后：个位数的ORR，4-6 mo的OS，目前FDA还未批准任何针对性的疗法

BRAF突变中最主要的是V600E，自从BRAF V600E靶向治疗抑制剂在黑色素瘤中取得成功后，也开展了单独或联合方案针对BRAF V600E mCRC的研究，结果小结如下，具体细节可以参阅先前推送：BRAFi+MEKi+anti-EGFR三联获NCCN推荐治疗BRAF V600E+ CRC。anti-EGFR+化疗一般是4-8%的ORR和4-6 mo的OS，在此基础上加BRAFi可以将ORR和OS提升至～20%和～9 mo。BEACON CRC trial开始前进行的Safety Lead-in中BRAFi+MEKi+anti-EGFR的chemo-free三联将ORR和OS提升至48%和15mo。

BEACON CRC trial中入组615名先前接受2-3轮治疗患者(分别>65%和<35%属于2线和3线治疗)，按照1:1:1随机分至BRAFTOVI Triplet(encorafenib + binimetinib + cetuximab)、BRAFTOVI  Doublet(encorafenib + cetuximab)和对照组(FOLFIRI + cetuximab or Irinotecan + cetuximab)。主要终点是三联组 vs 对照组相比的OS，次要终点三联组 vs 对照组、三联组 vs 二组的疗效对比，其他次要终点PFS、ORR、DOR、安全性和可耐受性，还包括生活质量数据。

这次公告的结果，之前提到虽然达到主要终点，但是还是有些不足，一个是样本扩大后ORR和OS都打了6折，这也为直接从早期单臂外推到三期临床破了点冷水，另外一个就是三联组相比二连组只有临床获益的趋势，但是没有统计学意义。但无论如何，总体上瑕不掩瑜，BRAFTOVI Triplet(encorafenib + binimetinib + cetuximab)应该会获批成为首个针对BRAF V600E突变的mCRC后线Chemo-free疗法。

其他正在开展的基于encorafenib + binimetinib 针对BRAF V600E突变肿瘤的临床研究

最后是原文ARRAY BIOPHARMA ANNOUNCES BRAFTOVI + MEKTOVI + CETUXIMAB MEET PRIMARY ENDPOINTS OF ORR AND OS IN PHASE 3 BEACON CRC TRIAL INTERIM ANALYSIS FOR THE TREATMENT OF BRAF(V600E)-MUTANT METASTATIC COLORECTAL CANCER- BRAFTOVI combinations showed statistically significant improvement in ORR and OS versus control -- BRAFTOVI + MEKTOVI + cetuximab reduced the risk of death by 48% versus control -- Potential to be the first chemotherapy-free, targeted regimen for metastatic CRC patients -- Array intends to submit these data for marketing approval in 2H19 -- Array will host a conference call today, Tuesday, May 21, 2019, at 9:00 am Eastern Time -BOULDER, Colo., May 21, 2019 /PRNewswire/ -- Array BioPharma Inc. (Nasdaq: ARRY) today announced positive results from the interim analysis of the Phase 3 BEACON CRC trial evaluating the combination of BRAFTOVI®(encorafenib), a BRAF inhibitor, MEKTOVI® (binimetinib), a MEK inhibitor, and ERBITUX® (cetuximab), an anti-EGFR antibody (BRAFTOVI Triplet), in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), following one or two prior lines of therapy. The trial met both primary endpoints of confirmed objective response rate (ORR), as assessed by Blinded Independent Central Review (BICR), and overall survival (OS). Array intends to submit these results of the BEACON CRC trial for marketing approval in the second half of 2019.Results from the trial showed that BRAF-mutant mCRC patients treated with the BRAFTOVI Triplet demonstrated a statistically significant improvement in ORR (26.1% vs. 1.9%, p<0.0001, per BICR) and OS (median 9.0 months vs. 5.4 months, [HR 0.52, 95% CI (0.39-0.70), p<0.0001]) compared to cetuximab plus irinotecan-containing regimens (Control)."The BEACON CRC trial is the first Phase 3 trial in patients with BRAFV600E-mutant mCRC and these results show a significant improvement compared to available standard of care options for this patient population," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Given that there are no therapies currently FDA-approved for this patient population, I believe the results of the BEACON CRC trial will be practice-changing."The analysis of ORR was based on the first 331 randomized patients, while the interim analysis of OS included all 665 randomized patients, and was based on a data cutoff date in February of 2019, approximately two weeks after the last patient was enrolled. Future analyses will assess ORR on the total population and OS with longer follow up.Results from the secondary endpoint analysis showed that patients treated with the combination of BRAFTOVI and cetuximab (BRAFTOVI Doublet) demonstrated a statistically significant improvement in ORR (20.4% vs. 1.9%, p<0.0001, per BICR) and OS (median 8.4 months vs. 5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003]) compared to Control.A descriptive comparison of the BRAFTOVI Triplet to the BRAFTOVI Doublet demonstrated a positive trend across endpoints including ORR and OS [HR 0.79, 95% CI (0.59-1.06), nominal p=0.1164].In patients receiving one prior line of therapy, ORR as assessed by BICR was 34.3% with the BRAFTOVI Triplet and 22.4% with the BRAFTOVI Doublet, while at this time the OS for both arms is consistent with that seen in the overall population."We are pleased to announce positive results from the BEACON CRC trial, including that the BRAFTOVI Triplet reduced the risk of death by 48% versus control," said Ron Squarer, CEO, Array BioPharma. "We are deeply grateful to the patients and investigators whose participation has helped bring us one step closer to delivering a new standard of care for patients with BRAF-mutant mCRC. This has the potential to be the first chemotherapy-free, targeted regimen for mCRC patients, a population with a very high unmet need for effective treatments."As demonstrated in the control arm of the BEACON CRC trial and consistent with historical data, patients with BRAF-mutant mCRC generally have a poor prognosis with currently available treatments and currently there are no FDA-approved therapies specifically indicated for this high unmet need population. [1-12,14] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and V600E is the most common mutation. [1-3,12-14]The BRAFTOVI Triplet and Doublet were generally well-tolerated with no unexpected toxicities. The safety profiles of the BRAFTOVI Triplet and Doublet were consistent with prior reported experience with each regimen and with effects of MEK, RAF and EGFR therapies.In March 2019, the National Comprehensive Cancer Network® (NCCN®) updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and an anti-EGFR antibody as a Category 2A treatment for patients with BRAFV600E-mutant mCRC, after failure of one or two prior lines of therapy for metastatic disease. The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial.On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.