背景:目前批准的ROS1重排非小细胞肺癌(NSCLC)的靶向治疗具有颅内活性不足或中枢神经系统相关毒性。我们评估了福立替尼的疗效和安全性,一种新型ALK和ROS1抑制剂,在晚期ROS1重排的NSCLC患者中。
方法:这两部分(阶段2a和2b),多中心,单臂,开放标签,第二阶段研究在中国29个中心进行。符合条件的参与者是经组织学或细胞学证实ROS1重排的成年人(年龄≥18岁)。局部晚期或转移性IIIB-IV期非小细胞肺癌,东部肿瘤协作组的表现状态为2或更低。以前没有接受或接受过一种ROS1抑制剂的患者被纳入2a期,未接受ROS1抑制剂治疗的患者被纳入2b期队列1。2a期参与者在21天的周期内每天一次口服80、120、160或210mg琥珀酸福立替尼(福立替尼);2b期患者接受推荐的2期剂量160mg。主要终点是客观反应率,由独立审查委员会在完整分析集中评估(即,所有接受至少一剂研究治疗的参与者)。安全性分析集包括接受至少一个剂量的研究治疗并且具有可用安全性评估的所有参与者。这项研究正在进行中,并在ClinicalTrials.gov注册,NCT04237805。
结果:在2020年3月26日至2022年12月29日之间,有104例患者入选并接受治疗。在方案修订之前,有六名先前接受过一种以上ROS1抑制剂的患者进入2a期,说明该阶段的患者应接受不超过一种ROS1抑制剂;这些患者被纳入安全性分析,但被排除在ROS1抑制剂预处理队列的疗效分析之外。因此,疗效分析集(n=98)包括42例2a期患者(17例未接受ROS1抑制剂治疗,25例之前接受过ROS1抑制剂治疗)和56例2b期队列1患者.在阶段2a,未接受ROS1抑制剂治疗的患者的客观缓解率为94%(95%CI71~100;17例患者中的16例),之前接受过ROS1抑制剂治疗的患者的客观缓解率为40%(21~61例;25例患者中的10例).在第2阶段队列1中,客观缓解率为88%(95%CI76-95;56例患者中有49例)。在基线时41例中枢神经系统转移患者的预设探索性分析中,2a期ROS1抑制剂初治患者的客观缓解率为100%(95%CI48-100;5例患者中有5例),在2a期患者中,40%(16-68;15人中的6人)以前接受过ROS1抑制剂,和90%(70-99;21人中的19人)在2b期队列1的患者中。104例患者中有33例(32%)发生3-4级治疗相关不良事件;最常见的是高血糖症(12例[12%]患者)和心电图延长QT间期(6例[6%])。11例(11%)患者发生严重治疗相关不良事件,高血糖症(六[6%])最常见。无治疗相关不良事件导致死亡。
结论:福立替尼在ROS1抑制剂初治的ROS1重排NSCLC患者中显示出全身和颅内抗肿瘤活性和良好的耐受性。福立替尼代表了对这些患者的一种有希望的治疗方法,尤其是中枢神经系统转移的患者。
背景:复星制药,万邦生物制药,广东省肺癌转化医学重点实验室.
BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC.
METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in
China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805.
RESULTS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death.
CONCLUSIONS: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases.
BACKGROUND: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.