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非鳞NSCLC:TKI+培美曲塞可能有助于延缓TKI耐药

发表者:张品良 793人已读

Gefitinib with pemetrexed as first-line therapy in patients with advanced nonsquamous non-small cell lung cancer with activating epidermal growth factor receptor mutations吉非替尼联合培美曲塞作为具有活化表皮生长因子受体突变的晚期非鳞非小细胞肺癌患者的一线治疗山东省肿瘤医院呼吸内科张品良

While lung cancer is the most common cause of cancer death worldwide, epidermal growth factor receptor (EGFR) is the most common type of actionable mutation. Improved outcome with EGFR tyrosine kinase inhibitor (TKI) compared with conventional chemotherapy was the beginning of precision medicine for non-small cell lung cancer (NSCLC). And the testing of EGFR became routine especially in adenocarcinoma of the lung. However, most patients will develop disease progression following successful treatment with EGFR TKIs. In the pooled analysis of 54 studies, gefitinib produced 9.4 months (95% CI, 9.0–9.8) of progression-free survival (PFS). The most common mechanism of resistance is secondary mutation of T790M. So, improving PFS of patients with EGFR mutated tumor treated with EGFR TKI remains a critical therapeutic challenge.肺癌是全世界癌症死亡最常见的原因,表皮生长因子受体(EGFR)是最常见的能够采取行动的突变。与常规化疗相比,表皮生长因子受体酪氨酸激酶抑制剂(TKI)作为非小细胞肺癌(NSCLC)初始精准给药改善预后。而表皮生长因子受体的检测已成为常规尤其是肺腺癌。不过,在表皮生长因子受体酪氨酸激酶抑制剂成功治疗后,大多数患者会出现疾病进展。在54项研究的汇集分析中,吉非替尼获得的无进展生存期(PFS)为9.4个月(95% CI,9.0-9.8)。最常见的耐药机制是T790M的继发性突变。因此,改善表皮生长因子受体酪氨酸激酶抑制剂治疗的表皮生长因子受体突变肿瘤患者的无进展生存期仍然是一个紧要的治疗难题。

There would be two strategies to improve the efficacy of the first generation EGFR TKI alone. One is employing more efficacious drug and another strategy would be EGFR TKI plus other drugs to delay the appearance of resistance clones. The Iressa follow up measures study (IFUM) showed objective response rate of 50% by central review and 70% by investigator assessment. Afatinib, a second generation irreversible EGFR TKI produced superior objective response rate with 70% compared with 56% in gefitinib arm (P=0.0083) and showed a longer median duration of response (10.1 vs. 8.4 months respectively). Osimertinib which is a third generation EGFR TKI designed to target patients with T790M mutated tumor, which might enable patients to achieve more prolonged PFS than first generation EGFR TKI. Osimertinib also seems to have a higher central nervous system activity than other EGFR TKIs and it would further support the front-line treatment. Currently ongoing phase III FLAURA trial is exploring the osimertinib in the front-line treatment compared with gefitinib or erlotinib.有两种策略来提高第一代表皮生长因子受体酪氨酸激酶抑制剂单药的疗效。一是使用更有效的药物,另一个策略是表皮生长因子受体酪氨酸激酶抑制剂+其他药物以推迟耐药克隆的出现。易瑞沙随访措施研究(IFUM)显示,客观缓解率中心审查为50%而调查者评估为70%。阿法替尼是一个二代不可逆表皮生长因子受体酪氨酸激酶抑制剂,客观缓解率70%,优于吉非替尼组的56%(P=0.0083),呈现更长的中位疗效持续时间(分别为10.1个月对8.4个月)。奥希替尼是一个第三代表皮生长因子受体酪氨酸激酶抑制剂,设计成能靶向治疗T790M突变的肿瘤患者,可能会使患者达到比第一代表皮生长因子受体酪氨酸激酶抑制剂持续更久的无进展生存期。奥希替尼似乎还比其他表皮生长因子受体酪氨酸激酶抑制剂有更高的中枢神经系统活性,因此可能进一步支持一线治疗。目前正在进行的Ⅲ期FLAURA试验探索奥希替尼一线治疗并与吉非替尼或厄洛替尼相比较。

Because the mechanism is different, the combination of EGFR TKI and conventional chemotherapy is an attractive strategy to improve the efficacy of chemotherapy or EGFR TKI alone. There have been many trials of the combination treatment against chemotherapy alone in all-comers, but those were not such successful. FASTACT-II showed benefit of intercalated combination of chemotherapy [platinum (day 1), gemcitabine (day 1 and 8)] and erlotinib (day 15–28 of a 28-day cycle). But the benefit was contained mainly in the patients with EGFR mutated tumor and partially interpreted as due to erlotinib maintenance. Mean PFS was 16.8 months. In the second-line setting, pemetrexed (day 1) plus intercalated erlotinib (day 2–14 of a 21-day cycle) could improve its PFS in non-smoking and nonsquamous cell carcinoma patients compared with either erlotinib or pemetrexed alone. In the randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel (up to six cycles), the addition of chemotherapy could not prolong PFS (5.0 vs. 6.6 months, P=0.1988) in patients who were never or light former smoker with advanced lung adenocarcinoma (CALGB 30406 trial).因为机制不同,表皮生长因子受体酪氨酸激酶抑制剂联合传统化疗是提高化疗或表皮生长因子受体酪氨酸激酶抑制剂单药疗效一个诱人的策略。已有很多对所有参与者联合治疗对比单纯化疗的试验,但未获得上述的成功。FASTACT-II显示联合化疗[铂(第1天)、吉西他滨(第1、8天)]和厄洛替尼(28天为1周期的第15-28天)穿插治疗获益。但获益主要发生在具有表皮生长因子受体突变的肿瘤患者中,因此,部分解释是由于厄洛替尼维持治疗。平均无进展生存期是16.8个月。在二线方案中,与厄洛替尼或培美曲塞单药相比,培美曲塞(第1天)加穿插的厄洛替尼(21天为1周期的第2-14天)可能延长不吸烟非鳞细胞癌患者的无进展生存期。在厄洛替尼单药或与卡铂和紫杉醇联合(最多6周期)治疗从不吸烟或曾经轻微吸烟的晚期肺腺癌患者的随机Ⅱ期试验(CALGB 30406试验)中,化疗的加入不能延长无进展生存期(5.0个月对6.6个月,P=0.1988)。

In the study led by Cheng et al. they added concomitant pemetrexed to gefitinib in the patients with EGFR mutated tumor and showed PFS of 15.8 months (95% CI, 12.6–18.3) compared with 10.9 months [95% CI, 9.7–13.8, adjusted hazard ratio 0.68 (95% CI, 0.48–0.96)] with gefitinib alone (P=0.14) (14). The result was regardless of the mutational type (exon 19 deletion or L858R point mutation). This is the first report of successful concurrent pemetrexed plus EGFR TKI therapy against EGFR TKI alone in the patients with EGFR mutated tumor. Interestingly, two PFS curves run along initially then began to divert after more than 6 months later of treatment, which suggests that the PFS prolonging effect would be attributed to the suppression of resistant clones by the addition of concurrent pemetrexed. Continuous treatment with pemetrexed might have produced different results rather than combining up to six cycles of chemotherapy in CALGB 30406 trial.在由程等主持的这项研究中,同时将培美曲塞加入到吉非替尼中治疗表皮生长因子受体突变的肿瘤患者,显示无进展生存期15.8个月(95%CI,12.6-18.3)而吉非替尼单药为10.9个月[95%CI,9.7-13.8,校正后的风险比为0.68(95%CI,0.48-0.96)](P=0.14)。结果与突变类型无关(外显子19缺失或L858R点突变)。在表皮生长因子受体突变的肿瘤患者中,这是培美曲塞+表皮生长因子受体酪氨酸激酶抑制剂同时治疗对比表皮生长因子受体酪氨酸激酶抑制剂单药成功的第一个报告。有趣的是,两个无进展生存曲线最初是叠合的,在治疗超过6个月后则开始分开,这表明无进展生存期延长的效果应归因于同时增加的培美曲塞消除了耐药克隆。培美曲塞持续治疗而不是CALGB30406试验中最多化疗6周期可能具有不同的结果。

In preclinical study, when PC9 and HCC827 cells were simultaneously exposed to gefitinib and pemetrexed, selection of resistant clones were not observed, suggesting that combined treatment prevented the appearance of EGFR TKI resistance. It was also known that the expression of thymidylate synthase was reduced with gefitinib treatment. So the enhancement of cytotoxicity when pemetrexed is added to gefitinib might suppress the small subpopulation of cells harboring T790M mutation or with the mesenchymal phenotype. Preclinical studies indicated there is cell cycle dependent synergism or antagonism when combining chemotherapy and EGFR TKI, however clinical data do not support it well.在临床前研究中,当PC9(人肺腺癌细胞株)和HCC827(人非小细胞肺癌细胞系)细胞同时暴露于吉非替尼和培美曲塞,未观察到选择性耐药克隆,表明联合治疗阻止了表皮生长因子受体酪氨酸激酶抑制剂耐药性的出现。我们还知道胸苷酸合成酶的表达降低吉非替尼治疗的疗效。当培美曲塞添加至吉非替尼可能会抑制少许荷T790M突变或具有间充质表型的细胞亚群,因此细胞毒性增强。临床前研究表明,当化疗与表皮生长因子受体酪氨酸激酶抑制剂联合时,有细胞周期依赖性协同或拮抗作用,不过,临床数据并不充分支持。

Treatment with front-line combination of erlotinib and bevacizumab was highly effective in patients with EGFR mutated tumors. Although the response rate was similar (69% vs. 64%), median PFS was 16.0 months (95% CI, 13.9–18.1) in combination group compared with 9.7 months (95% CI, 5.7–11.1) with erlotinib alone. This finding suggests that the addition of bevacizumab to erlotinib might help maintain the tumor suppressing effect after reduction in tumor size. Improved drug delivery with bevacizumab could achieve higher intra-tumor concentration of erlotinib, which could delay the appearance of resistant cells. Or VEGF receptor blocking might contribute to delay the appearance of T790M mutation. In the phase II BELIEF trial, the combination of bevacizumab and erlotinib resulted in a 1-year PFS of 72.4% (95% CI, 53.4–84.7) in patients with T790M. BEVERLY trial (erlotinib plus bevacizumab vs. erlotinib alone) and RELAY trial (erlotinib/ramucirumab vs. erlotinib/placebo) are ongoing. Other combination such as gefitinib plus durvalumab (PD-L1 inhibitor) trial was reported but PFS data are immature.在具有表皮生长因子受体突变的肿瘤患者中,厄洛替尼联合贝伐单抗一线治疗非常有效。虽然缓解率相似(69%对64%),但是中位无进展生存期联合组是16.0个月(95%CI,13.9-18.1),而厄洛替尼单药组是9.7个月(95%CI,5.7-11.1)。这一发现表明,贝伐单抗加入到厄洛替尼中可能有助于在肿瘤缩小后维持肿瘤的抑制效果。改进贝伐单抗给药可以获得更高的厄洛替尼瘤内浓度,从而延缓耐药细胞的出现。或者血管内皮生长因子受体阻断可能延迟T790M突变的出现。在Ⅱ期BELIEF试验中,贝伐单抗和厄洛替尼联合治疗T790M患者获得1年无进展生存率72.4%(95%CI,53.4-84.7)。BEVERLY试验(厄洛替尼加贝伐单抗对比厄洛替尼单药)和RELAY试验(厄洛替尼/雷莫芦单抗对比厄洛替尼/安慰剂)正在进行中。其他联合如吉非替尼加durvalumab(PD-L1抑制剂)试验已经报告但无进展生存期数据还不够成熟。

While there are many therapeutic options for patients with EGFR mutated tumor: first generation EGFR TKI, second generation EGFR TKI, third generation EGR TKI, immunotherapy and conventional chemotherapy, PFS for each therapy might not be a relevant surrogate to see the overall survival. Some patients progress rapidly during initial treatment and might not have the next opportunity to overcome resistance. So, initial decision of front-line therapy would be important for the patients. As the most prominent resistant mechanism after EGFR TKI is the appearance T790M or mesenchymal phenotype, those combination strategies to overcome the appearance of resistant clones during EGFR TKI treatment are encouraging. More data will be needed to accept such strategy as front-line therapy of patients with EGFR mutation.对于具有表皮生长因子受体突变的肿瘤患者,同时有很多治疗选择:第一、二、三代表皮生长因子受体酪氨酸激酶抑制剂、免疫疗法以及传统化疗,每种治疗的无进展生存期可能不是总生存期相关的替代指标。一些患者在最初治疗期间进展迅速,因此可能没有下一个机会来克服耐药。所以,患者一线治疗的最初决策很重要。在表皮生长因子受体酪氨酸激酶抑制剂后,由于最突出的耐药机制是出现T790M或间质表型,因此,在表皮生长因子受体酪氨酸激酶抑制剂治疗期间,为克服耐药克隆的出现,这些联合策略令人鼓舞。接受上述策略作为具有表皮生长因子受体突变患者的一线治疗还需要更多的数据。

J Clin Oncol. 2016 Sep 20;34(27):3258-66.

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发表于:2017-03-27 09:48

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