本帖最后由 shany 于 2014-5-20 23:23 编辑
24楼:
Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
ALK抑制剂AP26113在晚期癌症包括ALK+非小细胞肺癌患者中的疗效和安全性更新
Abstract:
Background: AP26113 is a novel orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested.
背景:AP26113是一种新型有口服活性的酪氨酸激酶抑制剂,临床前数据显示其对ALK及全部9种临床确认的克里唑替尼耐药突变具有抑制活性。
Methods: The Phase (Ph) 2 portion of a Ph1/2 single arm, multicenter study in pts with advanced malignancies is underway. We report updated safety for all treated pts and efficacy data for ALK+ NSCLC pts previously treated with crizotinib. NCT01449461.
方法:一项针对晚期癌症患者的1/2期单臂多中心研究的2期阶段正在进行中。我们在此更新在所有患者中的安全性数据及在曾经接受过克里唑替尼治疗的ALK+非小细胞肺癌患者中的疗效数据。
Results: As of 16 Dec 2013, 114 pts were enrolled: 65 in Ph1 (30-300 mg) and 49 in Ph2 (180 mg). Baseline characteristics: 59% female, median age 57 yr; diagnoses: NSCLC n=106, other n=8. 66 pts remain on study; median follow-up for all pts is 3.6 mo (max= 21.4 mo, ongoing). The most common treatment-emergent AEs (≥20%) were nausea (38%), diarrhea (31%), fatigue (31%), cough (23%), and headache (20%), which were generally grade 1/2 in severity. Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) observed in 6/45 (13%) pts at 180mg QD. These symptoms, requiring immediate medical attention, were not observed at 90mg QD (n=8) or in the lead-in dose cohort (n=19; initiated at 90mg QD, escalated to 180mg QD after 1 wk). Pts continue to be enrolled with this dose escalation scheme, and an additional cohort of 90mg QD without escalation will be added. Among 38 evaluable ALK+ NSCLC pts with prior crizotinib, 24 (63%) responded (23 partial response, 1 complete response). Duration of response was 1.6 - 14.7 mo (ongoing). 15 pts had confirmed responses; 5 await confirmation, 4 are unconfirmed. Among 42 evaluable pts with ALK+ NSCLC, median progression free survival is 47 wk. Independent radiological review conducted on 10 pts enrolled with untreated or progressing brain metastases showed 6/10 pts with response in brain, including 4 with undetectable brain metastases following AP26113; 2 pts had stable disease, 2 pts progressed; 8/10 remain on study (range 5-17 mo).
结果:截止2013年12月16日,共入组114名患者:1期65名(30-300mg),2期49名(180mg)。基线特征:59%女性,中位年龄57岁;诊断:非小细胞肺癌n=106,其他n=8。66名患者仍继续参与研究;中位随访时间3.6个月(最长21.4个月,仍继续随访)。最常见治疗后出现的不良反应(>20%)为恶心(38%),腹泻(31%),疲劳(31%),咳嗽(23%)以及头痛(20%),程度一般为1/2度。在6/45(13%)接受每日四次180mg剂量的患者中观察到前期肺部症状(呼吸困难伴随组织缺氧及/或影像学表现)。这些需要立即处理的症状并未在90mg每日四次(n=8)组或渐进组(n=19,90mg每日四次开始,一周后加量至180mg每日四次)中观察到。此剂量递增组正继续招募患者,并将增加一组无递增的90mg每日四次组。在38名可评估的曾接受克里唑替尼治疗的ALK+非小细胞肺癌患者中,24(63%)名评估为缓解(23名部分缓解,1名完全缓解)。缓解时间为1.6-14.7个月(仍在随访)。15名患者达到确认缓解;5名等待确认,4名未确认。在42名可评估的ALK+非小细胞肺癌患者中,中位PSF为47周。针对10名入组时有未治疗或进展中的脑转移患者进行的独立放射学评估显示6名脑部缓解,包括4名在AP26113治疗后脑肿瘤不可检测;2名稳定,2名进展;8名继续参与研究(时长5-17个月)。
Conclusions: AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized Ph2 trial evaluating 90 mg QD vs. 90mg QD escalating to 180mg QD in crizotinib-resistant ALK+ NSCLC will begin shortly. Clinical trial information: NCT01449461.
结论:AP26113在克里唑替尼耐药的ALK+非小细胞肺癌患者包括脑转移患者中有前景良好的抗肿瘤活性。对比90mg每日四次与90mg每日四次递增至180mg每日四次的2期随机试验将很快在该患者群中开展。
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