Barlesi Fabrice, Yao Wenxiu, Duruisseaux Michaël, Doucet Ludovic, Martínez Aitor Azkárate, Gregorc Vanesa, Juan-Vidal Oscar, Lu Shun, De Bondt Charlotte, de Marinis Filippo, Linardou Helena, Kim Young-Chul, Jotte Robert, Felip Enriqueta, Lo Russo Giuseppe, Reck Martin, Michenzie Mary F, Yang Wenjing, Meade Julie N, Korytowsky Beata, Mok Tony S K
Gustave Roussy, Villejuif, France; Paris Saclay University, Le Kremlin-Bicêtre, France.
Sichuan Cancer Hospital & Institute, Chengdu, China.
Lancet. 2025 Aug 9;406(10503):615-626. doi: 10.1016/S0140-6736(25)00866-9.
Adagrasib is a KRAS inhibitor that demonstrated promising activity against KRAS-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRAS-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy.
KRYSTAL-12 is a randomised, multicentre, open-label, phase 3 trial conducted at 230 centres in 22 countries. Patients with Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutated locally advanced or metastatic NSCLC, who had previously received both platinum-based chemotherapy and anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy, were randomly allocated in a 2:1 ratio to receive 600 mg adagrasib (twice a day orally) or 75 mg/m docetaxel (every 3 weeks intravenously) using a centralised interactive web response system. Randomisation was stratified by region (non-Asia-Pacific vs Asia-Pacific) and previous treatment (sequential vs concurrent chemotherapy or immunotherapy). Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomised patients (intention-to-treat [ITT] population). Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov (NCT04685135), and is active but no longer recruiting.
Between Feb 23, 2021, and Nov 16, 2023, 453 patients were randomly allocated to receive adagrasib (301 [66%]) or docetaxel (152 [34%]). In each group, 298 (99%) patients received adagrasib and 140 (92%) received docetaxel. In the ITT population (median follow-up 7·2 months [95% CI 5·8-8·7]), median progression-free survival was 5·5 months (95% CI 4·5-6·7) with adagrasib and 3·8 months (95% CI 2·7-4·7) with docetaxel (hazard ratio 0·58 [95% CI 0·45-0·76]; p<0·0001). Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with docetaxel. There were four (1%) treatment-related deaths in the adagrasib group and one (1%) treatment-related death in the docetaxel group.
Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRAS-mutated NSCLC, without new safety signals.
Mirati Therapeutics, a Bristol Myers Squibb company.
阿达格拉西布是一种KRAS抑制剂，在一项2期试验中显示出对KRAS突变的晚期非小细胞肺癌（NSCLC）具有有前景的活性。在此，我们旨在比较阿达格拉西布与多西他赛在先前接受过化疗和免疫治疗的KRAS突变晚期NSCLC患者中的疗效和安全性。
KRYSTAL-12是一项在22个国家的230个中心进行的随机、多中心、开放标签的3期试验。既往接受过铂类化疗和抗程序性细胞死亡蛋白1或抗程序性死亡配体1治疗的 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变的局部晚期或转移性NSCLC患者，使用集中交互式网络响应系统以2:1的比例随机分配接受600mg阿达格拉西布（每日口服两次）或75mg/m²多西他赛（每3周静脉注射一次）。随机分组按地区（非亚太地区与亚太地区）和既往治疗（序贯与同步化疗或免疫治疗）进行分层。治疗持续至疾病进展、出现不可接受的毒性、研究者或患者决定停药或死亡。主要终点是在所有随机分组患者（意向性治疗[ITT]人群）中通过盲法独立中央审查评估的无进展生存期。在所有接受治疗的患者中评估安全性。该试验已在ClinicalTrials.gov注册（NCT04685135），目前正在进行但不再招募患者。
在2021年2月23日至2023年11月16日期间，453例患者被随机分配接受阿达格拉西布（301例[66%]）或多西他赛（152例[34%]）。在每组中，298例（99%）患者接受了阿达格拉西布治疗，140例（92%）患者接受了多西他赛治疗。在ITT人群中（中位随访7.2个月[95%CI 5.8 - 8.7]），阿达格拉西布组的中位无进展生存期为5.5个月（95%CI 4.5 - 6.7），多西他赛组为3.8个月（95%CI 2.7 - 4.7）（风险比0.58[95%CI 0.45 - 0.76]；p<0.0001）。在接受阿达格拉西布治疗的298例患者中，140例（47%）发生3级及以上治疗相关不良事件，在接受多西他赛治疗的140例患者中，64例（46%）发生此类事件。阿达格拉西布组有4例（1%）治疗相关死亡，多西他赛组有1例（1%）治疗相关死亡。
在先前接受治疗的KRAS突变NSCLC患者中，阿达格拉西布在无进展生存期方面比多西他赛有统计学意义的改善，且无新的安全信号。
百时美施贵宝公司旗下的Mirati Therapeutics公司。
