T790M阳性晚期NSCLC患者对奥希替尼CNS应答

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trialsT790M阳性晚期NSCLC患者对奥希替尼CNS应答：两项Ⅱ期试验的汇总数据

Background:背景：

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC).中枢神经系统（CNS）转移在非小细胞肺癌（NSCLC）患者中很常见。

Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS.在CNS转移的患者中已证明奥希替尼的全身疗效，初步临床证据显示在CNS中有效。

To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261).为了进一步评估奥希替尼的活性，我们使用两项Ⅱ期研究AURA扩展（NCT01802632）和AURA2（NCT02094261）的汇总数据，呈现预先指定的CNS应答的亚组分析。

Patients and methods:患者和方法：

Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg qd (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with 1 measurable CNS lesion (perRECIST1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS).接受过表皮生长因子受体酪氨酸激酶抑制剂治疗后进展的T790M阳性晚期NSCLC患者，接受奥希替尼80 mg qd（n=411）。病情稳定、无症状的CNS转移患者符合入组条件；允许既往CNS治疗。在基线脑扫描时经盲法独立中心神经放射学评估（BICR）具有1个可测量CNS病变的患者（perRECIST1.1）纳入可评价CNS应答组（cEFR）。该CNS分析的主要结局是BICR评估的CNS客观有效率（ORR）；次要结局包括CNS应答持续时间、疾病控制率（DCR）和无进展生存期（PFS）。

Results:结果：

Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54%[27/50; 95% confidence interval (CI) 39–68] and 92% (46/50;95%CI81–98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1–15 months); at 9months, 75% (95%CI53–88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95%CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population.在基线脑扫描时，有CNS转移的128例患者中，50例被纳入cEFR。确认的中枢神经系统客观缓解率（CNS ORR）和DCR分别为54％[27/50；95%可信区间（CI）39-68]和92％（46/50； 95％CI 81-98）。无论先前是否进行过脑放疗，均观察到CNS应答。尚未达到中位CNS应答持续时间（22％到期）（范围1-15个月）；在9个月时，估计有75％（95％CI 53-88）的患者仍然处于应答状态。中枢神经系统无进展生存期（CNS PFS）中位随访时间为11个月；尚未达到中位CNS PFS（95％CI，7-不可计算）。在cEFR中观察到的安全性特征与总患者群一致。

Conclusions:结论：

Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously.证明奥希替尼对CNS转移具有临床意义的疗效、较高的DCR、令人鼓舞的ORR，而安全性与之前报道的一致。

ClinicalTrials.gov number: NCT01802632; NCT02094261

Key words: osimertinib, NSCLC, CNS, brain metastases关键词：奥希替尼，NSCLC，CNS，脑转移瘤

Discussion讨论

In this pooled analysis of two single-arm phase II studies, osimertinib demonstrated clinically meaningful activity in patients with T790M-positive NSCLC and CNS metastases. Osimertinib demonstrated an encouraging CNS ORR of 54% with a rapid onset of response and CNS DCR of 92%. Systemic ORR and safety were consistent with that reported for the overall patient population.在这个两项单臂Ⅱ期研究的汇总分析中，奥希替尼在T790M阳性NSCLC和CNS转移患者中表现出有临床意义的活性。奥希替尼显示令人鼓舞的54％的中枢神经系统总有效率（CNS ORR）、起效迅速，中枢神经系统疾病控制率（CNS DCR）为92％。全身ORR和安全性与报告的总患者群一致。

The results of this pooled analysis support previous results, which demonstrated the efficacy of osimertinib in patients with CNS metastases. CNS PFS with osimertinib is encouraging; however, mature CNS PFS data are not available, as patients did not continue to receive brain scans following disease progression (irrespective of site of progression) or discontinuation from study. Assuch, one limitation of the CNS PFS analysis is that the observed treatment benefit may be overestimated; however, results of the CNS PFS analysis of the overall population were consistent with the analysis of the cEFR. Osimertinib activity in seven patients with suspected LM based on radiologic features was encouraging. The role of osimertinib (160 mg qd) in patients with LM from NSCLC is further being investigated in the BLOOM study (NCT02228369); preliminary results indicate promising activity and manageable tolerability.汇总分析的结果支持以前的结果，证明了奥希替尼在CNS转移患者中的疗效。奥希替尼的CNS PFS令人鼓舞；然而，不能得到成熟的CNS PFS数据，因为患者在疾病进展（不论进展部位）或中止研究后不再继续接受脑扫描。因此，CNS PFS分析的一个局限性是可能高估了观察到的治疗获益；然而，总人群的CNS PFS分析结果与cEFR分析结果一致。基于放射学特征疑似软脑膜转移的7名患者中奥希替尼的活性令人鼓舞。BLOOM研究（NCT02228369）进一步调查奥希替尼（160 mg qd）在NSCLC软脑膜转移患者中的作用；初步结果显示有希望的活性和可管理的耐受性。

Patients with CNS metastases are frequently excluded from clinical trials; therefore, there is limited evidence regarding the efficacy of first- and second-generation EGFR-TKIs in the CNS. In a retrospective review of patients with brain metastases from EGFR/anaplastic lymphoma kinase-driven NSCLC, median time to intracranial progression with TKIs was similar to that achieved with SRS (15 versus 12months, respectively), but shorter than with WBRT (50.5months); there was no difference in overall survival. As the cerebrospinal fluid penetration of erlotinib and gefitinib is limited, high-dose administration is sometimes used in an attempt to increase levels in the cerebrospinal fluid.临床试验经常把CNS转移的患者排除在外；因此，关于第一和第二代EGFR-TKIs在CNS中疗效的证据有限。在EGFR/间变性淋巴瘤激酶驱动的NSCLC脑转移患者的一项回顾性综述中，颅内进展的中位时间TKIs与SRS相似（分别为15个月和12个月），但短于WBRT（50.5个月） ；总生存没有差异。由于厄洛替尼和吉非替尼的脑脊液渗透有限，有时高剂量给药试图增加脑脊液中的水平。

Previous research has suggested that radiotherapy may facilitate the CNS penetration of systemic therapies by altering BBB permeability. However, CNS responses to osimertinib were observed regardless of prior radiotherapy status. While the observed ORR was higher in patients who had no prior brain radiotherapy or radiotherapy 6 months before osimertinib, compared with patients who received radiotherapy 6 months before osimertinib, these data should be interpreted with caution given the overlapping CIs and the low number of patients in each subgroup.既往研究表明放疗可以通过改变血脑屏障通透性促进全身治疗的CNS渗透。然而，无论先前的放疗情况如何，均观察到CNS对奥希替尼应答。虽然观察到的ORR在未进行过脑放疗或奥希替尼前6个月放疗的患者中较高，但与在奥希替尼前6个月接受放疗的患者相比，这些数据应谨慎解释，因为CIs重叠而且每个亚组患者数量少。

Osimertinib treatment is now recommended for patients with brain metastases from T790M-positive NSCLC. Before this, the recommended treatment options for patients with CNS metastases from NSCLC were limited to surgery and SRS or WBRT. Osimertinib offers patients with CNS metastases an additional line of treatment and may allow patients to avoid the adverse effects associated with WBRT. While all patients in this study had T790M-positive NSCLC, the T790M status of patients’ CNS disease was not assessed. Published data suggest that T790M may occur less frequently in CNS metastases than in the primary tumour; therefore, some patients in our study may have had T790M-negative CNS metastases. In such patients, osimertinib would be acting against EGFR-TKI sensitising mutations rather than the T790M resistance mutation. In the recent FLAURA (NCT02296125) study, osimertinib demonstrated superior efficacy versus standard-of-care EGFR-TKI as first-line therapy in patients with advanced EGFRm NSCLC, including those patients with known or treated CNS metastases at study entry.对于T790M阳性NSCLC脑转移患者目前推荐奥希替尼治疗。在此之前，对于CNS转移的NSCLC患者推荐的治疗方案仅限于手术和SRS或WBRT。奥希替尼为CNS转移患者提供了额外的治疗方案，并可能使患者免于WBRT相关的不利影响。虽然本研究中的所有患者均为T790M阳性NSCLC，但并未评估患者CNS病变的T790M状态。已公布的数据表明T790M出现频率在CNS转移瘤中可能低于原发肿瘤；因此，我们研究中的某些患者可能是T790M阴性CNS转移。在这类患者中，奥希替尼可能会作用于EGFR-TKI敏感突变而不是T790M耐药突变。在最近的FLAURA（NCT02296125）研究中，对于晚期EGFRm NSCLC患者、包括那些在研究入组时已知或治疗过的CNS转移的患者，奥希替尼显示出优于EGFR-TKI作为一线标准治疗的效果。

In summary, osimertinib demonstrated clinically meaningful efficacy in patients with CNS metastases, with a high CNS DCR and encouraging CNS ORR, consistent with the systemic response to osimertinib. Osimertinib offers an additional line of treatment of patients with T790M-positive NSCLC and CNS metastases.总之，奥希替尼对CNS转移患者证明有临床意义的疗效，具有高CNS DCR和令人鼓舞的CNS ORR，与奥希替尼的全身应答一致。奥希替尼为T790M阳性NSCLC和CNS转移患者提供了额外的治疗方案。