A phase II study of adding the multikinase sorafenib to existing endocrine therapy in patients with metastatic ER-positive breast cancer

Growth factor signaling and angiogenesis may promote endocrine-resistance in breast cancer and blocking these pathways can overcome resistance in preclinical models. We conducted a phase-II study of adding the VEGFR/Ras/Raf/MAPK inhibitor sorafenib to endocrine therapy in metastatic ER-positive breast cancer, either upon progression or after maximal response with measurable residual disease. Tumor biopsies and serum were collected on days 1 and 28. Primary endpoint was response by RECIST after 3 months and secondary endpoints included safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 patients but the study closed after 11 patients because of slow accrual. 8 patients had progressive disease (PD) on entry and 3 had stable disease (SD). One patient with SD discontinued sorafenib after 2-weeks because of grade 3 rash. Of the 10 remaining patients after adding sorafenib, 7 had SD (70%), 3 had PD (30%) and median TTP was 6.1-months. Of the 8 patients who entered the study with PD on endocrine therapy, 5 converted to SD (62%) with a median TTP of 6.4-months. Notably, patients on tamoxifen had a median TTP of 8.4-months. The most common adverse events were hypophosphatemia, hypokalemia, and rash, and the majority were grade 1&2 with no grade 4 toxicities. There was a significant reduction in serum VEGFR2 and PDGFR-α on day-28 (p-values 0.0035 and 0.017, respectively). Both serum VEGF and sVEGFR-1 were increased on day-28, but the differences were not statistically significant (p-values 0.3223 and 0.084, respectively). Microarray analysis identified 32 suppressed genes with an FDR of <0.20 and at least a 2-fold change with no induced genes and 29 KEGG pathways were enriched on day-28. Our study suggests that sorafenib can restore endocrine sensitivity, particularly tamoxifen, and this strategy of adding novel agents in patients progressing on endocrine therapy should be examined in future trials. This was a single-institution, phase II study of adding sorafenib to existing endocrine therapy. On study entry, eligible patients underwent serum sample collection and core biopsy of accessible disease (if applicable) on endocrine therapy and prior to starting sorafenib. Serum and a second biopsy were then collected on day 28. Sorafenib dose was 400mg orally twice daily along with continuing the same endocrine agent. Patients were followed monthly for clinical and toxicity evaluation. Disease response by RECIST criteria was assessed after 3 months by appropriate scans and these were obtained every 2 months thereafter until progression. Sorafenib and the endocrine agent were continued until disease progression or unacceptable toxicity

生长因子信号通路与血管生成可促进乳腺癌内分泌治疗耐药，临床前模型证实阻断此类通路可克服耐药。我们开展了一项II期临床试验，针对转移性ER阳性乳腺癌（ER-positive breast cancer）患者，在其内分泌治疗进展或经最大程度应答后仍存在可测量残留病灶的情况下，联合VEGFR/Ras/Raf/MAPK抑制剂索拉非尼（sorafenib）与内分泌治疗。研究分别于第1天和第28天采集肿瘤活检样本与血清样本。主要终点为3个月后基于实体瘤疗效评价标准（RECIST）评估的应答情况，次要终点包括安全性、疾病进展时间（TTP）及生物标志物检测。原计划入组43例患者，但因入组速度缓慢，该研究在入组11例患者后提前终止。入组时，8例患者存在疾病进展（PD），3例患者为疾病稳定（SD）。1例SD患者在用药2周后因出现3级皮疹停用索拉非尼。在剩余10例接受联合治疗的患者中，7例达到SD（占比70%），3例出现PD（占比30%），中位TTP为6.1个月。其中，8例入组时在内分泌治疗期间出现PD的患者中，5例转为SD（占比62%），中位TTP为6.4个月。值得注意的是，接受他莫昔芬（tamoxifen）治疗的患者中位TTP达8.4个月。最常见的不良事件为低磷血症、低钾血症与皮疹，多数为1~2级不良反应，未出现4级毒性事件。第28天时，血清血管内皮生长因子受体2（VEGFR2）与血小板衍生生长因子受体α（PDGFR-α）水平显著降低（对应p值分别为0.0035与0.017）。而血清血管内皮生长因子（VEGF）与可溶性血管内皮生长因子受体1（sVEGFR-1）水平在第28天时有所升高，但差异无统计学意义（对应p值分别为0.3223与0.084）。基因芯片分析显示，第28天时共有32个基因表达受到抑制，错误发现率（FDR）<0.20且至少存在2倍表达变化，未发现上调基因；同时富集得到29条京都基因与基因组百科全书（KEGG）通路。本研究提示，索拉非尼可恢复内分泌治疗敏感性，尤其是针对他莫昔芬的耐药情况，未来的临床试验应进一步探索在内分泌治疗进展患者中联合新型药物的治疗策略。本研究为单中心II期临床试验，将索拉非尼联合现有内分泌治疗方案。入组时，符合入组标准的患者需在内分泌治疗期间、开始索拉非尼治疗前，采集血清样本并对可及病灶进行核心活检（如适用）；并于第28天再次采集血清样本与第二次活检样本。索拉非尼给药剂量为400mg，口服，每日两次，同时维持原内分泌治疗方案。患者每月接受一次临床随访与毒性评估。3个月后通过影像学检查基于RECIST标准评估疾病应答情况，此后每2个月复查一次直至疾病进展。索拉非尼与内分泌治疗药物可持续使用至疾病进展或出现不可耐受的毒性反应。