MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with Advanced Melanoma Resistant to PD-(L)1 Inhibition.

patients_and_methods

In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral, or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 7, every 28 days.

在这项II期研究中，对于无法切除或转移性黑色素瘤（皮肤型、肢端型或粘膜型）患者，并且在抗PD-(L)1治疗期间（无论是否联合抗CTLA-4治疗）确认疾病进展的患者，按2:1的比例随机分配接受ceralasertib 240 mg每日两次，连续服用7天，然后在第8天静脉注射durvalumab 1,500 mg，每28天一次；或仅接受ceralasertib 240 mg每日两次，连续服用7天，每28天一次。

The primary endpoint was objective response rate(ORR).

主要终点是客观缓解率（ORR）。

Key secondary endpoints included progression-free survival(PFS), overall survival(OS), and safety.

关键次要终点包括无进展生存期（PFS）、总生存（OS）和安全性。

Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted.

对基线（肿瘤和循环）和治疗期间（仅循环）生物标志物进行了探索性分析。

Results

ORR was 9.3% [95% confidence interval(CI), 4.3-16.9] for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95% CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95% CI, 1.9-3.5) versus 1.9 months [95% CI, 1.9-3.1; hazard ratio(HR), 0.80; 95% CI, 0.54-1.18]; and median OS was 16.0 months [95% CI, 10.5-not calculated (NC)] versus 12.3 months (95% CI, 9.5-NC; HR, 0.81; 95% CI, 0.49-1.37).

ceralasertib联合durvalumab的客观缓解率(ORR)为9.3%（95%置信区间[CI]，4.3-16.9），低于预设的最小阈值，ceralasertib单药治疗的ORR为5.8%（95% CI, 1.2-15.9）；中位无进展生存期（PFS）分别为2.0个月（95% CI, 1.9-3.5）和1.9个月（95% CI, 1.9-3.1；风险比[HR], 0.80；95% CI, 0.54-1.18）；中位总生存（OS）分别为16.0个月（95% CI, 10.5-未计算[NC]）和12.3个月（95% CI, 9.5-NC；HR, 0.81；95% CI, 0.49-1.37）。

Both regimens were well tolerated.

两种治疗方案均耐受性良好。

Exploratory analyses indicated a possible link between higher baseline pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels.

探索性分析表明，较高的基线治疗前肿瘤CD8+ T细胞计数与两组的总生存改善可能存在关联，并暗示ceralasertib治疗可能会引起循环CD14+单核细胞和GDF-15血浆水平的短暂、周期性变化。

Conclusions

Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.

在抗PD-(L)1耐药的晚期黑色素瘤中，ceralasertib联合durvalumab治疗和ceralasertib单药治疗均显示出较低的反应率。