Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer.
Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-20-3089
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发表时间：
2021-02-15
期刊：
影响因子：
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通讯作者：
Tolaney SM
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作者：
Keenan TE;Li T;Vallius T;Guerriero JL;Tayob N;Kochupurakkal B;Davis J;Pastorello R;Tahara RK;Anderson L;Conway J;He MX;Shannon E;Godin RE;Sorger PK;D'Andrea A;Overmoyer B;Winer EP;Mittendorf EA;Van Allen EM;Shapiro GI;Tolaney SM
我们报告了一项II期研究的结果，该研究评估了WEE 1抑制剂adavosertib与顺铂联合治疗转移性三阴性乳腺癌（mTNBC）的疗效。既往接受过0 - 1线化疗的mTNBC患者接受顺铂75 mg/m2 IV治疗，21天后接受顺铂+adavosertib 200 mg口服，每日两次，每21天给药5次。该研究有90%的把握度检测无效（20%）和替代（40%）客观缓解率（ORR）之间的差异，单侧I型错误为0.1：ORR> 30%被预先定义为值得进一步研究的方案。adavosertib治疗前后肿瘤活检的RNA测序和多重循环免疫荧光以及存档组织的靶向下一代测序与临床获益相关，定义为疾病稳定≥ 6个月或完全或部分缓解。34例患者开始方案治疗;中位年龄为56岁，2例患者（6%）有BRCA 2突变，14例（41%）既往接受过一次化疗。ORR为26%（95%CI 13 - 44），中位无进展生存期为4.9个月（95%CI 2.3 - 5.7）。治疗相关的3 - 5级不良事件发生在53%的患者中，最常见的是21%的腹泻。1例死亡是由于败血症，可能与研究治疗相关。来自具有临床益处的患者的肿瘤表现出富集的免疫基因表达和T细胞浸润。在既往接受过0 - 1线治疗的mTNBC患者中，adavosertib联合顺铂错过了预先规定的ORR临界值> 30%。在具有临床获益的患者中发现免疫浸润肿瘤值得验证。这项II期临床试验评估了WEE 1抑制剂adavosertib联合顺铂是否改善了转移性三阴性乳腺癌（mTNBC）患者的临床结局，并研究了对该疗法反应的分子相关性。共有34例患者接受adavosertib和顺铂作为mTNBC的一线或二线治疗。未达到终点，但客观缓解率为26%，中位无进展生存期为4.9个月。转录组学和免疫荧光分析显示，adavosertib治疗和临床获益可能与肿瘤内免疫基因表达和T细胞浸润相关。这些研究结果表明，阿达沃塞替可能会增强抗肿瘤免疫力，并值得在未来的研究中进行验证，包括正在进行的阿达沃塞替与PD-L1抑制剂durvalumab联合试验。
We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC treated with 0–1 prior lines of chemotherapy received cisplatin 75 mg/m2 IV followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for 5 doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORRs) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response. 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% (95%CI 13–44), and median progression-free survival was 4.9 months (95%CI 2.3–5.7). Treatment-related grade 3–5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred due to sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T cell infiltration. Among patients with mTNBC treated with 0–1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation. This phase II clinical trial evaluated whether the WEE1 inhibitor adavosertib combined with cisplatin improved clinical outcomes for patients with metastatic triple-negative breast cancer (mTNBC) and investigated molecular correlates of response to this therapy. A total of 34 patients were treated with adavosertib and cisplatin as first or second-line therapy for mTNBC. The endpoint was not met but objective response rate was 26% and median progression-free survival was 4.9 months. Transcriptomic and immunofluorescence analyses revealed that adavosertib treatment and clinical benefit may correlate with intratumoral immune gene expression and T cell infiltration. These findings suggest that adavosertib may augment antitumor immunity and warrant validation in future studies, including an ongoing trial of adavosertib with the PD-L1 inhibitor durvalumab.