联合使用BRAF+MEK抑制剂已被FDA批准用于BRAF V600E突变实体肿瘤，但在结直肠癌方面除外。然而，除了MAPK介导的耐药机制外，还存在其他多种抵抗机制，如激活CRAF、ARAF、MET、P13K/AKT/mTOR途径等复杂途径。在VEM-PLUS研究中，我们对四个一期研究进行了汇总分析，评估了贝伐单抗单药和贝伐单抗联合靶向治疗（索拉非尼、克唑替尼或依维莫司）或卡铂加紫杉醇治疗携带BRAF V600突变的晚期实体肿瘤的安全性和疗效。当比较贝伐单抗单药和联合方案时，除了缺乏显著的OS或PFS持续时间外，在贝伐单抗和紫杉醇卡铂试验及交叉患者中存在劣质OS（P = 0.011；HR，2.4；95% CI，1.22-4.7）。与BRAF治疗难治组相比，先前没有接受BRAF抑制剂治疗的患者在12.6个月时的OS明显改善，而难治组仅为10.4个月（P = 0.024；HR，1.69；95% CI 1.07-2.68）。原发性PFS在两组之间也具有统计学意义，BRAF治疗初次使用组为7个月，而BRAF治疗难治组为4.7个月（P = 0.016；HR，1.80；95% CI 1.11-2.91）。贝伐单抗单药试验中的确证ORR（28%）高于联合试验。我们的研究表明，与贝伐单抗单药相比，贝伐单抗与细胞毒性化疗或RAF-或mTOR靶向药物的联合治疗并不能显著延长患有BRAF V600E突变实体肿瘤的患者的OS或PFS。有必要更好地了解BRAF抑制剂耐药的分子机制，并平衡毒性和疗效，采用新的试验设计。 © 2023. The Author(s)。

Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or PFS durations were noted, except for inferior OS in the vemurafenib and paclitaxel and carboplatin trial (P = 0.011; HR, 2.4; 95% CI, 1.22-4.7) and in crossover patients (P = 0.0025; HR, 2.089; 95% CI, 1.2-3.4). Patients naïve to prior BRAF inhibitors had statistically significantly improved OS at 12.6 months compared to 10.4 months in the BRAF therapy refractory group (P = 0.024; HR, 1.69; 95% CI 1.07-2.68). The median PFS was statistically significant between both groups, with 7 months in the BRAF therapy naïve group compared to 4.7 months in the BRAF therapy refractory group (P = 0.016; HR, 1.80; 95% CI 1.11-2.91). The confirmed ORR in the vemurafenib monotherapy trial (28%) was higher than that in the combination trials. Our findings suggest that, compared with vemurafenib monotherapy, combinations of vemurafenib with cytotoxic chemotherapy or with RAF- or mTOR-targeting agents do not significantly extend the OS or PFS of patients who have solid tumors with BRAF V600E mutations. Gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance, balancing toxicity and efficacy with novel trial designs are warranted.© 2023. The Author(s).