西班牙马德里大学医院Luis Paz-Ares团队比较了索托拉西布与多西他赛用于先前治疗的KRASG12C突变非小细胞肺癌的疗效与安全性。2023年2月7日出版的《柳叶刀》杂志发表了这项成果。

索托拉西布是GTPase蛋白KRASG12C的特异性不可逆抑制剂。研究组比较了非小细胞癌症（NSCLC）患者（KRASG12C突变，此前曾用其他抗癌药物治疗）使用索托拉西布与标准治疗的疗效和安全性。

研究组在22个国家的148个中心进行了一项随机、开放标签的3期临床试验，招募至少18岁的KRASG12C突变晚期NSCLC患者，他们在之前的铂基化疗和PD-1或PD-L1抑制剂后进展。关键排除标准包括新发或进展中的未经治疗的脑损伤或有症状的脑损伤、先前发现的除KRASG12C以外的致癌驱动突变（如EGFR或ALK）、先前用多西他赛治疗（如果肿瘤在治疗终止后6个月内未进展，则允许使用新辅助或辅助多西他赛）、先前使用直接KRASG12C抑制剂进行治疗，在研究第1天起28天内进行全身性抗癌治疗，并在治疗开始后2周内进行治疗性或姑息性放疗。

研究组采用互动反应技术，以开放标签方式将患者随机分配（1:1）给口服索托拉西布（960 mg，每天一次）或静脉注射多西他赛（75 mg/m²，每3周一次）。根据既往晚期疾病治疗线数（1 vs 2 vs>2）、种族（亚洲人vs非亚洲人）和中枢神经系统转移史（有或无）对随机分组进行分层。治疗持续到疾病进展、不耐受、开始另一种抗癌治疗、撤回同意或死亡（以先发生者为准）的独立中心确认。主要终点是无进展生存期，这是在意向治疗人群中通过盲、独立的中心审查进行评估的。对所有接受治疗的患者进行了安全性评估。

在2020年6月4日至2021年4月26日期间，345名患者被随机分配接受索托拉西布（171例[50%]）或多西他赛（174例[50%]）治疗。索托拉西布组169名（99%）患者和多西他赛组151名（87%）患者接受了至少一剂治疗。中位随访17.7个月后，与多西他赛组相比，索托拉西布组的无进展生存期达到了统计学显著增加的主要终点（中位无进展生存期分别为5.6个月与4.5个月；危险比为0.66）。

索托拉西布组耐受性良好，3级或更差（n=56[33%]vs n=61[40%]）和严重的治疗相关不良事件（n=18[11%]vs n=34[23%]）发生率均低于多西他赛组。对于索托拉西布，最常见的3级或更严重的治疗相关不良事件是腹泻（n=20[12%]）、丙氨酸氨基转移酶升高（n=13[8%]）和天冬氨酸氨基转移酶增高（n=9[5%]）。对于多西他赛为中性粒细胞减少症（n=13[9%]）、疲劳（n=9[6%]）和发热性中性粒细胞降低症（n=8[5%]）。

研究结果表明，与多西他赛相比，索托拉西布显著提高了KRASG12C突变晚期NSCLC患者的无进展生存率，并具有更有利的安全性。

附：英文原文

Title: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial

Author: Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Bjrn Stollenwerk, David Waterhouse, Luis Paz-Ares

Issue&Volume: 2023-02-07

Abstract:

Background

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs.

Methods

We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.

Findings

Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4–20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3–7·8] vs 4·5 months [3·0–5·7]; hazard ratio 0·66 [0·51–0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).

Interpretation

Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.

DOI: 10.1016/S0140-6736(23)00221-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00221-0/fulltext