Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.

Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases.

RAS通路的异常激活是胰管腺癌（PDAC）的主要驱动因素，超过90%的病例中存在致癌性RAS突变。

Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS.

达拉克索拉西布是一种口服的RAS(ON)多选择性、三复合抑制剂，针对突变型和野生型RAS的活性鸟苷三磷酸结合状态。

Methods

In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice.

在这项 III 期、国际性、开放标签、随机试验中，我们随机分配了先前接受过治疗的转移性胰腺导管腺癌（mPDAC）患者，以接受达拉克索拉西布或研究者选择的化疗方案。

The dual primary end points were overall survivaland progression-free survivalin the subpopulation of patients with RAS G12 mutations (the RAS G12 population).

双重主要终点是RAS G12突变患者亚组（RAS G12人群）的总生存和无进展生存。

Key secondary end points included overall survivaland progression-free survivalin the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations.

关键次要终点包括总体人群（包括RAS G12、G13或Q61突变患者或未发现RAS突变的患者）的总生存和无进展生存，以及RAS G12和总体人群中的客观反应和患者报告的生活质量。

Safety was also assessed.

安全性也得到了评估。

Results

A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients).

共有500名患者参与了研究，其中91.8%的患者携带RAS G12突变，他们被随机分配接受达拉非尼西布（248名患者）或化疗（252名患者）。

The median overall survivalin the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survivalin the overall population was 13.2 months and 6.7 months, respectively; the hazard ratiowas 0.40 in both populations (P<0.001).

RAS G12人群中位总生存期为13.2个月使用达拉非尼，6.6个月使用化疗；总体人群中位总生存期分别为13.2个月和6.7个月；两组的危险比为0.40（P<0.001）。

The median progression-free survivalin the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons).

RAS G12人群中位无进展生存期为7.3个月使用达拉非尼，3.5个月使用化疗；总体人群中位无进展生存期分别为7.2个月和3.6个月；两组的危险比分别为0.45和0.49（两者比较P<0.001）。

Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidenceof adverse events of grade 3 or higher was 61.8% and 69.6%, respectively.

治疗开始后发生的不良事件在所有达拉克索拉西布组患者中报告，以及在化疗组患者中的97.7%中报告；3级或更高级别的不良事件发生率分别为61.8%和69.6%。

Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group.

导致治疗中断的治疗相关不良事件在达拉克索拉西布组患者中的发生率为1.2%，而在化疗组患者中为11.2%。

Conclusions

Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survivaland progression-free survivalthan chemotherapy.

在先前接受过治疗的转移性胰腺导管腺癌（mPDAC）患者中，与化疗相比，达拉西那西布治疗显著延长了总生存期和无进展生存期。

(Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).

(该研究由Revolution Medicines资助；RASolute 302临床试验注册号为NCT06625320。)