Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer.
Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-21-3045
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发表时间：
2022-04-14
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我们之前曾在一项1b期试验（NCT 01623349）中报告了奥拉帕尼联合PI 3 K α特异性抑制剂alpelisib治疗高级别浆液性卵巢癌患者的安全性和推荐II期剂量（RP 2D）。在这里，我们报告了来自该研究的乳腺癌队列。符合条件的患者患有复发性三阴性乳腺癌（TNBC）或具有生殖系BRCA突变的任何亚型的复发性乳腺癌，并入选剂量递增或扩展队列。定义RP 2D后，次要终点包括安全性和客观缓解率（ORR）。使用循环游离DNA（cfDNA）进行探索性分析。入组了17例TNBC患者，中位既往接受过3线化疗。最常见的治疗相关3-4级不良事件是高血糖（18%）和皮疹（12%）。ORR为18%（RP 2D治疗患者为23%），59%的患者疾病得到控制。中位缓解持续时间为7.4个月。cfDNA肿瘤分数（TFx）的分析显示，TFx患者<15% after completion of the first cycle had a longer progression-free survival compared to those with TFx>15%（6.0个月vs 0.9个月，p=0.0001）。Alpelisib联合奥拉帕尼在预治疗的TNBC患者中可耐受，在非BRCA携带者中有活性证据。CfDNA提供了重要的预后信息。结果突出了PI 3 Ki的潜在协同使用，以使HR-熟练（BRCA野生型）TNBC对PARPi敏感，并表明PARPi的使用扩展到BRCA-突变型肿瘤之外的潜力。
We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here we report on the breast cancer cohort from that study. Eligible patients had recurrent triple-negative breast cancer (TNBC), or recurrent breast cancer of any subtype with a germline BRCA mutation and were enrolled to a dose escalation or expansion cohort. After definition of the RP2D, secondary end points included safety and objective response rate (ORR). Exploratory analyses were performed using circulating free DNA (cfDNA). 17 patients with TNBC were enrolled with a median of 3 prior lines of chemotherapy. The most common treatment-related grade 3–4 adverse events were hyperglycemia (18%) and rash (12%). The ORR was 18% (23% for patients treated at the RP2D) and 59% had disease control. The median duration of response was 7.4 months. Analysis of cfDNA tumor fractions (TFx) revealed that patients with TFx<15% after completion of the first cycle had a longer progression-free survival compared to those with TFx>15% (6.0 months vs 0.9 months, p=0.0001). Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA carriers. CfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3Ki to sensitize HR-proficient (BRCA wild-type) TNBC to PARPi and suggest the potential to expand the use of PARPi beyond BRCA-mutant tumors.