Starks David, Rojas-Espaillat Luis, Meissner Tobias, Elsey Rachel, Xu Bing, Koenen Maria, Feng Shelley, VanOosbree Annika, Slunecka John, Lee John, Williams Casey B
Avera Cancer Institute, Sioux Falls, South Dakota, USA.
University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA.
Cancer Med. 2023 Sep;12(18):18654-18665. doi: 10.1002/cam4.6475. Epub 2023 Aug 30.
Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies.
Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff.
The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.
开展1期试验，以确定依维莫司和尼拉帕利在晚期卵巢癌和乳腺癌患者中的安全性和耐受性。
纳入了14例经过多次治疗的患者（12例高级别浆液性卵巢癌、1例透明细胞卵巢癌和1例三阴性乳腺癌）。所有患者既往未接受过PARP治疗，在入组前接受了全面的基因组分析。队列2（尼拉帕利每日200mg，依维莫司每周3天，每次5mg）出现了2例剂量限制毒性，1例患者出现血小板减少持续时间延长，另1例患者出现严重高血压。剂量降低后又纳入了4例患者，其中1例患者再次出现严重高血压，导致研究结束。最常见的3级或以上不良事件为血小板减少、高血压、贫血、疲劳、中性粒细胞减少和碱性磷酸酶升高。2例患者达到部分缓解（PR），5例患者疾病稳定（SD）。11例可评估患者的客观缓解率（ORR）为18%，临床获益率（CBR）为45%。中位无进展生存期（PFS）为6个月，中位总生存期（OS）约为18个月，数据截止时仍有3例患者存活。
依维莫司和尼拉帕利联合使用在较低剂量时即显示出显著毒性，且由于高血压迅速发作和严重程度，该联合方案不可行。这一局限性可能削弱了联合方案的疗效，因为PFS一般，但由于3例铂类难治性卵巢癌患者仍存活，OS令人惊讶地延长。有必要进一步研究PI3K通路多靶点阻断联合PARP的治疗方案。
