Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201.

Methods

In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog (KRAS) mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mg two times per week in combination with oral defactinib 200 mg two times per day.

在这项II期、开放标签的研究中，经过≥1线铂类化疗后复发且可测量的LGSOC患者根据肿瘤Kirsten大鼠肉瘤病毒同源物(KRAS)突变状态进行分层，并随机分配接受口服阿武托美4.0 mg每周两次单药治疗或与口服德法替尼200 mg每日两次联合使用。

The combination was selected as the go-forward regimen for expansion.

该联合方案被选为扩展阶段的前进方案。

The primary end point was objective response rate(ORR) by blinded independent central review.

主要终点是通过盲法独立中央审查的客观缓解率（ORR）。

Results

A total of 115 patients received the go-forward combination regimen.

共有115名患者接受了前进方案的联合治疗。

Patients had a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%), bevacizumab (51%), and MEK inhibitor (22%).

患者先前接受的治疗线数中位数为3（范围，1-9），包括激素治疗（86%）、贝伐单抗（51%）和MEK抑制剂（22%）。

Confirmed ORR was 31% (95% CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI, 14.8 to 31.1).

确认的客观缓解率(ORR)为31%（95%置信区间，23%至41%），缓解的中位持续时间为31.1个月（95%置信区间，14.8至31.1个月）。

ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts.

KRAS突变型队列的ORR为44%，而KRAS野生型队列的ORR为17%。

The median progression-free survivalwas 12.9 months (95% CI, 10.9 to 20.2) overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to 18.4) in KRAS-mutant and wild-type cohorts, respectively.

整体中位无进展生存期为12.9个月（95%置信区间，10.9至20.2个月），KRAS突变型队列和野生型队列的中位无进展生存期分别为22.0个月（95%置信区间，11.1至36.6个月）和12.8个月（95%置信区间，7.4至18.4个月）。

The most frequent grade ≥3 treatment-related adverse events (AEs) were elevated creatine phosphokinase (24%), diarrhea (8%), and anemia (5%).

最常发生的3级或以上治疗相关不良事件（AEs）是肌酸激酶升高（24%）、腹泻（8%）和贫血（5%）。

Ten percent of patients discontinued because of AEs.

10%的患者因不良事件(AEs)而停药。

Conclusions

The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC.

阿武托美替尼与德法替尼联合使用的疗效和安全性支持将这种组合作为复发性低级别浆液性卵巢癌(LGSOC)潜在的治疗标准。

A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781).

一项随机III期研究，比较avutometinib和defactinib与研究者选择的治疗方案对于复发性低级别浆液性卵巢癌（LGSOC）女性患者的疗效，目前正在招募中（RAMP301；ClinicalTrials.gov注册号：NCT06072781）。