Health-related quality of life in patients with KRASG12C-mutated chemorefractory metastatic colorectal cancer treated with sotorasib plus panitumumab or standard of care (CodeBreaK 300): results from a phase 3, randomised clinical trial.

This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints.

本次分析评估了患者报告的结果（PROs）作为次要和探索性终点。

Methods

In this open-label, randomised clinical trial, adult (aged ≥18 years) patients from 67 centres in 13 countries in Asia, Australia, Europe, and North America with KRASG12C-mutated chemorefractory metastatic colorectal cancer (as assessed by central molecular testing of tumour biopsy specimens) who were KRASG12C inhibitor-naive, had progressed to recurrence after previous therapy with fluoropyrimidine, oxaliplatin, and irinotecan, with measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, were enrolled.

在这项开放标签、随机临床试验中，来自亚洲、澳大利亚、欧洲和北美的67个中心的成年（年龄≥18岁）患者，这些患者具有KRASG12C突变的化疗耐药性转移性结直肠癌（通过中心分子检测肿瘤活检标本评估），并且是KRASG12C抑制剂未经治疗的，之前接受过氟尿嘧啶、奥沙利铂和伊立替康治疗后复发，根据实体瘤反应评估标准版本1.1有可测量的疾病，并且东部肿瘤协作组（ECOG）表现状态评分为0、1或2，被纳入研究。

Patients were randomly assigned 1:1:1 using interactive response technology to receive sotorasib 960 mg (daily, orally)-panitumumab (6 mg/kg every 2 weeks, intravenous infusion), sotorasib 240 mg (daily, orally)-panitumumab (6 mg/kg every 2 weeks, intravenous infusion), or investigator's choice of trifluridine-tipiracil (35 mg/m2 [up to 80 mg per dose] on days 1-5 and 8-12 twice a day, orally) or regorafenib (160 mg daily for the first 21 days, orally).

患者使用交互式响应技术以1:1:1的比例随机分配接受sotorasib 960 mg（每日，口服）-panitumumab（每2周6 mg/kg，静脉输注），sotorasib 240 mg（每日，口服）-panitumumab（每2周6 mg/kg，静脉输注），或者研究者选择的trifluridine-tipiracil（第1-5天和第8-12天，每天两次，口服，剂量为35 mg/m2 [每剂最多80 mg]）或regorafenib（前21天每天160 mg，口服）。

Randomisation was stratified by by previous anti-angiogenic therapy, time from initial diagnosis of metastatic disease to randomisation, and ECOG performance status.

随机分组根据先前的抗血管生成治疗、从转移性疾病初诊到随机分组的时间以及ECOG表现状态进行了分层。

The primary endpoint was progression-free survival(reported previously).

主要终点是无进展生存期（先前已报告）。

PROs included fatigue at its worst according to the Brief Fatigue Inventory, pain at its worst according to the Brief Pain Inventory (where lower score is better), and Global Health Status-Quality of Life (GHS-QoL) and physical function subscales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (where higher score is better) assessed via validated PRO questionnaires, administered at baseline, day 1 of each 4-week cycle until disease progression, and safety follow-up.

患者报告结果(PROs)包括根据简短疲劳量表评估的最严重的疲劳程度，根据简短疼痛量表评估的最严重的疼痛程度（得分越低越好），以及通过验证的患者报告结果问卷评估的欧洲癌症研究与治疗组织生活质量核心问卷30的全球健康状况-生活质量（GHS-QoL）和身体功能子量表（得分越高越好），这些评估在基线、每个4周周期的第一天以及疾病进展后进行，直至安全随访期。

Analyses were conducted in a modified intention-to-treatpopulation.

分析是在修改后的意向治疗人群中进行的。

Least squares mean changes from baseline to week 9 were estimated using a mixed effects model for repeated measures.

使用混合效应模型重复测量估计了从基线到第9周的最小二乘平均变化。

Time to deterioration (TTD), change in overall status, and patient-reported tolerability were also evaluated as prespecified exploratory outcomes.

时间至恶化（TTD）、总体状态的变化以及患者报告的耐受性也被评估为预先设定的探索性结果。

TTD was summarised using a stratified Cox proportional hazards model and Kaplan-Meier curve.

使用分层Cox比例风险模型和Kaplan-Meier曲线总结了TTD。

Change in overall status and patient-reported tolerability were also summarised descriptively over time.

总体状况的变化和患者报告的耐受性也随时间进行了描述性总结。

The study is registered with ClinicalTrials.gov, NCT05198934, and prespecified analyses are completed.

该研究已在ClinicalTrials.gov上注册，注册号为NCT05198934，预先设定的分析已完成。

Results

Between April 19, 2022, and March 14, 2023, 160 patients were enrolled and randomly assigned to receive sotorasib 960 mg-panitumumab (n=53), sotorasib 240 mg-panitumumab (n=53), and investigator's choice (n=54).

2022年4月19日至2023年3月14日期间，共有160名患者被纳入研究并随机分配接受sotorasib 960 mg-panitumumab（n=53），sotorasib 240 mg-panitumumab（n=53）和研究者选择（n=54）。

Median duration of treatment was 6·0 months (IQR 3·7-7·0), 4·6 months (3·3-6·2), and 2·2 months (1·8-4·2) in these groups, respectively. 81 (51%) patients in the study were female; 109 (68%) patients were White, 40 (25%) were Asian, one (1%) was Black, and ten (6%) were of another race or not reported; 12 (8%) were Hispanic or Latino and three (2%) were of unknown ethnicity.

治疗持续时间的中位数分别为6.0个月（四分位数间距3.7-7.0）、4.6个月（3.3-6.2）和2.2个月（1.8-4.2）。研究中有81名（51%）患者为女性；109名（68%）患者为白人，40名（25%）为亚洲人，1名（1%）为黑人，10名（6%）为其他种族或未报告；12名（8%）为西班牙裔或拉丁裔，3名（2%）为未知种族。

Compliance rates for PRO assessments at week 9 were high (approximately 80%) and similar across treatment groups.

第9周患者报告结果(PRO)评估的依从率高（约80%），且各治疗组之间相似。

Least squares mean changes in PROs at week 9 favoured the two sotorasib groups.

第9周的患者报告结果(PROs)的最小二乘均值变化倾向于两个索托拉西布组。

Differences in changes from baseline for sotorasib 960 mg-panitumumab and sotorasib 240 mg-panitumumab (both vs investigator's choice), respectively were: -0·89 (95% CI -1·80 to 0·01) and -0·58 (-1·47 to 0·30) for fatigue at its worst, -1·45 (-2·32 to -0·58) and -1·14 (-2·00 to -0·28) for pain at its worst, 9·43 (2·31 to 16·56) and 6·49 (-0·43 to 13·41) for GHS-QoL, and 5·38 (-0·01 to 10·78) and 6·34 (1·07 to 11·62) for physical function.

基线变化的差异，对于索托拉西布960 mg-帕尼单抗和索托拉西布240 mg-帕尼单抗（均与研究者选择的方案比较），分别为：疲劳最严重时的-0·89（95%置信区间-1·80到0·01）和-0·58（-1·47到0·30），疼痛最严重时的-1·45（-2·32到-0·58）和-1·14（-2·00到-0·28），GHS-QoL的9·43（2·31到16·56）和6·49（-0·43到13·41），以及身体功能的5·38（-0·01到10·78）和6·34（1·07到11·62）。

interpretation

Along with improved clinical outcomes, these analyses suggest that sotorasib plus panitumumab could represent a valuable new treatment in patients with KRASG12C-mutated chemorefractory metastatic colorectal cancer.

随着临床结果的改善，这些分析表明，sotorasib联合panitumumab可能代表了一种有价值的新型治疗方法，适用于携带KRASG12C突变的化疗耐药性转移性结直肠癌患者。

funding

Amgen.

安进公司。