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腾讯登录Lancet Oncol述评：EGFR基因突变非小细胞肺癌患者需要接受酪氨酸激酶抑制剂治疗
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在《柳叶刀肿瘤学》杂志上，Siow Ming Lee和他的同事发表了TOPICAL研究的最终结果，该研究是一个随机对照3期临床研究，旨在比较一线治疗厄洛替尼和安慰剂治疗对不适宜进行化疗的晚期非小细胞肺癌患者的疗效，这些患者或由于一般状态不佳（东部肿瘤协作组一般状态评分≥2），或由于合并症的存在而不适宜进行化疗。<!--more-->
研究开始纳入患者的时间为2005年，在那个时候，EGFR突变状态而没有作为入组标准。与安慰剂组相比，使用厄洛替尼进行治疗的患者的总体生存率并没有得到改善。在应用厄洛替尼进行治疗的患者中，研究者又进行了亚组分析，多变量分析结果指出在治疗的第一个疗程中出现皮疹是唯一与预后显著改善相关的独立影响因子。Lee和他的同事总结道厄洛替尼能延长不适宜进行化疗的晚期非小细胞肺癌患者的总体生存率和无进展生存率，但是这种效果仅局限在在治疗第一个疗程中出现皮疹的患者。
<div>研究者对在过去的10年中得益于EGFR酪氨酸激酶抑制剂（吉非替尼或厄洛替尼）的肺癌患者亚组的数据进行了归纳。最初批准厄洛替尼用于临床治疗是因为与安慰剂相比，该药物能显著改善既往接受过治疗的晚期非小细胞肺癌患者的总体生存率，但是最近的研究将注意力集中在了该药物对EGFR基因突变的肺癌患者的治疗效果。当这些患者接受EGFR酪氨酸激酶抑制剂治疗后，与接受常规化疗的患者相比，他们对治疗的反应率和无进展生存率都得到了改善。</div>
<div></div>
<div>在最初进行的临床研究的基础上，厄洛替尼经常用于既往接受过治疗的晚期非小细胞肺癌患者的治疗，但是研究结果提示，对于不存在EGFR基因突变的患者而言，似乎常规化疗的效果更佳。TORCH研究比较了两种治疗方案的疗效，方案一为在厄洛替尼治疗后继之以二线的化疗方案进行治疗，方案二为在常规化疗后继之以厄洛替尼治疗，研究并未对入组患者的EGFR基因型进行分类。由于在未经选择的患者中厄洛替尼的疗效不佳，这个研究在早期就被叫停了。在IPASS研究中，研究者纳入的受试者为存在对可能影响对治疗反应特征的人群，包括亚洲人、吸烟较少和腺癌，但是这些患者都不存在EGFR基因突变，研究结果提示与EGFR酪氨酸激酶抑制剂相比，卡铂和紫杉醇对这类患者的疗效更好。此外，TAILOR研究提示在已经证实的EGFR野生型患者中，与厄洛替尼相比，docetaxel更能增加患者的无进展生存率，HR为0.70，差异具有显著统计学意义。现有的数据提示EGFR酪氨酸激酶抑制剂对EGFR基因突变的肿瘤效果最佳。</div>
<div></div>
<div>TOPICAL所纳入的患者为一般状况较差和存在很多合并症的人群，这类患者是很多临床研究所排出的研究对象。就如研究者所指出的一样，该研究的一个不足在于其入组标准为东部肿瘤协作组一般状态评分为2。对于这些患者来说，既往的研究结果显示与厄洛替尼相比，他们对常规化疗的反应更好。在TOPICAL研究中，8.56%的受试者ECOG一般状态评分为2。虽然在这一受试者人群中存在异质性，但是很多肿瘤学专科医生建议对这些患者进行常规化疗。</div>
<div></div>
<div>TOPICAL和其他研究的结果提示厄洛替尼治疗所带来的皮疹和预后的改善相关，但是因为无法在治疗之前就预测皮疹是否会出现，所以限制了皮疹作为有效的预测标志物的作用。在TOPICAL研究中，在第一个疗程就出现皮疹的患者的总体生存率显著改善。但是目前还不能对这种联系做出生物学解释。皮疹的出现可能提示对实施治疗的反应。厄洛替尼诱导的皮疹可能是一种预后预测指标，但是可能并不能预测患者对药物的治疗反应。比如，皮疹的出现可能是患者存在间接炎症反应或免疫应答的标志，并不是对特异治疗的反应。将皮疹作为预测标志很难应用到常规临床工作中。厄洛替尼诱导的皮疹并不会在治疗前就出现，然而，在治疗开始之后其他的预测标志如影像学反应和临床表现的改善则能更精确的预测患者的临床结局。</div>
<div></div>
<div>总之，EGFR的体细胞突变预示着能从EGFR酪氨酸激酶抑制剂治疗中获益。应该多所有晚期的非小细胞肺癌患者进行EGFR基因突变测试，并对存在EGFR基因突变的患者进行EGFR酪氨酸激酶抑制剂治疗，无论这些患者的一般状态如何。EGFR野生型的患者，无论其一般状态如何，包括ECOG一般状态2分的患者在内，应该接受细胞毒药物的化疗。更深入的研究可能解释患者预后与厄洛替尼及皮疹之间的联系，但是现有的数据不足以将皮疹作为对厄洛替尼治疗反应的评价指标。在TOPICAL研究之后，靶向治疗临床研究所纳入的患者转变为对靶向治疗有效的患者人群。这种研究设计的转变更能帮助确定对患者治疗有效的药物成分。</div>
<div></div>
<div>原文摘要：</div>
<div>In <em>The Lancet Oncology, </em>Siow Ming Lee and colleagues present fi nal results of TOPICAL,1 a randomized phase 3 trial of fi rst-line erlotinib compared with placebo in patients with advanced non-small-cell lung cancer (NSCLC) who were deemed unsuitable for chemotherapy because of poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status ≥2) or comorbidities. This trial began enrolling patients in 2005 and, as such, <em>EGFR</em> mutation status was not used as an enrolment criterion. Overall survival did not improve with use of erlotinib compared with placebo (unadjusted hazard ratio [HR] 0·94, 95% CI 0·81–1·10, p=0·46). Among patients who received erlotinib, a subset analysis showed that development of a rash during the fi rst cycle of treatment was the only signifi cant independent factor associated with improved overall survival from a multivariate analysis (HR 0·24, 0·16–0·35, p<0·0001). Lee and colleagues conclude that erlotinib prolongs overall survival and progression-free survival in patients with NSCLC deemed unsuitable for chemotherapy, but only in those who develop fi rst-cycle rash.
The subset of patients with lung cancer who derive benefit from EGFR tyrosine-kinase inhibitors (gefi tinib and erlotinib) has been refi ned during the past decade. Whereas initial approval of erlotinib was based on improved overall survival compared with placebo in patients with advanced, previously-treated NSCLC,2 more recent studies have focused on patients with <em>EGFR</em> mutant lung cancers. When such patients were given EGFR tyrosine-kinase inhibitors, they had improved response rate and progression-free survival compared with those who received conventional chemotherapy.
On the basis of initial trials, erlotinib is often used as a treatment for patients with advanced NSCLC who have received previous therapy, but patients without <em>EGFR </em>mutations seem to do better with conventional chemotherapy. The TORCH study5 compared first-line erlotinib followed by second-line chemotherapy to initial chemotherapy followed by erlotinib, irrespective of <em>EGFR </em>genotype. The study was stopped early because of inferiority of first-line erlotinib in unselected patients. In IPASS,6 patients with clinical characteristics suggestive of response (Asian, minimal smokers, adenocarcinoma) but who did not have an <em>EGFR </em>mutation had longer progression-free survival with carboplatin and paclitaxel than with an EGFR tyrosine-kinase inhibitor. The TAILOR study7 showed superiority of docetaxel compared with erlotinib in a confi rmed <em>EGFR </em>wild-type population with a progression-free survival HR of 0·70 (95% CI 0·53–0·94, p=0·016). Available data suggest that EGFR tyrosine-kinase inhibitors are best used in patients with <em>EGFR </em>mutant tumours for whom the strongest evidence of benefit exists.
Patients with poor performance status or many comorbidities, the group targeted by TOPICAL, have historically been excluded from many trials. A limitation of this study, which the investigators acknowledge, is the inclusion of patients with ECOG performance status 2. For such patients, results of a previous study showed better progression-free survival with chemotherapy than with erlotinib (HR 1·45, 95% CI 0·98–2·15, p=0·063).8 56% (372 of 670) of the TOPICAL study population had an ECOG performance status of 2. Although this is certainly a heterogeneous population, many oncologists would recommend conventional chemotherapy to these patients.
Results from TOPICAL and others suggest that the rash from erlotinib is associated with improved outcomes,9 although the rash cannot be predicted before treatment initiation, limiting its usefulness as a predictive marker. In TOPICAL, erlotinib improved overall survival in patients who developed a fi rst-cycle rash (HR 0·76, 95% CI 0·63–0·92, p=0·0058). No clear biological explanation for this association exists. The presence of rash might be an indicator of adherence to the prescribed treatment. Erlotinib-induced rash could be a prognostic marker, but might not necessarily predict response to erlotinib. For example, development of a rash might be a marker of patients with an intact infl ammatory or immune response that portends improved prognosis irrespective of specifi c treatment. Rash as a predictive marker would be diffi cult to incorporate into routine practice. Erlotinib-induced rash is not present before treatment, and after initiation of treatment other markers, such as radiographic response and clinical benefi t, are more likely to accurately predict outcomes.
In summary, presence of somatic activating mutations in <em>EGFR </em>predicts the benefit of EGFR tyrosine-kinase inhibitors. Testing for <em>EGFR </em>mutations should be standard in all patients with advanced NSCLC and those with <em>EGFR</em> mutant tumours should receive an EGFR tyrosine-kinase inhibitor as treatment independent of performance status, preferably in the fi rst-line. <em>EGFR </em>wild-type patients with an adequate performance status, including ECOG performance status 2, should be off ered cytotoxic chemotherapy. Further research might elucidate the association between outcomes with erlotinib and rash, but insufficient data exists to use rash as a marker for
erlotinib response in clinical practice. Since TOPICAL was designed, clinical trials of targeted therapies have moved toward enrollment of only patients whose tumours have the molecular target of interest. These designs are more likely to identify truly active agents for our patients.</div>
<div></div>
<div>文献链接：<a href="http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70434-5/fulltext">http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70434-5/fulltext</a></div>
<div></div>
<div><br/>来源：丁香园</div>
在《柳叶刀肿瘤学》杂志上，Siow Ming Lee和他的同事发表了TOPICAL研究的最终结果，该研究是一个随机对照3期临床研究，旨在比较一线治疗厄洛替尼和安慰剂治疗对不适宜进行化疗的晚期非小细胞肺癌患者的疗效，这些患者或由于一般状态不佳（东部肿瘤协作组一般状态评分≥2），或由于合并症的存在而不适宜进行化疗。<!--more-->
研究开始纳入患者的时间为2005年，在那个时候，EGFR突变状态而没有作为入组标准。与安慰剂组相比，使用厄洛替尼进行治疗的患者的总体生存率并没有得到改善。在应用厄洛替尼进行治疗的患者中，研究者又进行了亚组分析，多变量分析结果指出在治疗的第一个疗程中出现皮疹是唯一与预后显著改善相关的独立影响因子。Lee和他的同事总结道厄洛替尼能延长不适宜进行化疗的晚期非小细胞肺癌患者的总体生存率和无进展生存率，但是这种效果仅局限在在治疗第一个疗程中出现皮疹的患者。
<div>研究者对在过去的10年中得益于EGFR酪氨酸激酶抑制剂（吉非替尼或厄洛替尼）的肺癌患者亚组的数据进行了归纳。最初批准厄洛替尼用于临床治疗是因为与安慰剂相比，该药物能显著改善既往接受过治疗的晚期非小细胞肺癌患者的总体生存率，但是最近的研究将注意力集中在了该药物对EGFR基因突变的肺癌患者的治疗效果。当这些患者接受EGFR酪氨酸激酶抑制剂治疗后，与接受常规化疗的患者相比，他们对治疗的反应率和无进展生存率都得到了改善。</div>
<div></div>
<div>在最初进行的临床研究的基础上，厄洛替尼经常用于既往接受过治疗的晚期非小细胞肺癌患者的治疗，但是研究结果提示，对于不存在EGFR基因突变的患者而言，似乎常规化疗的效果更佳。TORCH研究比较了两种治疗方案的疗效，方案一为在厄洛替尼治疗后继之以二线的化疗方案进行治疗，方案二为在常规化疗后继之以厄洛替尼治疗，研究并未对入组患者的EGFR基因型进行分类。由于在未经选择的患者中厄洛替尼的疗效不佳，这个研究在早期就被叫停了。在IPASS研究中，研究者纳入的受试者为存在对可能影响对治疗反应特征的人群，包括亚洲人、吸烟较少和腺癌，但是这些患者都不存在EGFR基因突变，研究结果提示与EGFR酪氨酸激酶抑制剂相比，卡铂和紫杉醇对这类患者的疗效更好。此外，TAILOR研究提示在已经证实的EGFR野生型患者中，与厄洛替尼相比，docetaxel更能增加患者的无进展生存率，HR为0.70，差异具有显著统计学意义。现有的数据提示EGFR酪氨酸激酶抑制剂对EGFR基因突变的肿瘤效果最佳。</div>
<div></div>
<div>TOPICAL所纳入的患者为一般状况较差和存在很多合并症的人群，这类患者是很多临床研究所排出的研究对象。就如研究者所指出的一样，该研究的一个不足在于其入组标准为东部肿瘤协作组一般状态评分为2。对于这些患者来说，既往的研究结果显示与厄洛替尼相比，他们对常规化疗的反应更好。在TOPICAL研究中，8.56%的受试者ECOG一般状态评分为2。虽然在这一受试者人群中存在异质性，但是很多肿瘤学专科医生建议对这些患者进行常规化疗。</div>
<div></div>
<div>TOPICAL和其他研究的结果提示厄洛替尼治疗所带来的皮疹和预后的改善相关，但是因为无法在治疗之前就预测皮疹是否会出现，所以限制了皮疹作为有效的预测标志物的作用。在TOPICAL研究中，在第一个疗程就出现皮疹的患者的总体生存率显著改善。但是目前还不能对这种联系做出生物学解释。皮疹的出现可能提示对实施治疗的反应。厄洛替尼诱导的皮疹可能是一种预后预测指标，但是可能并不能预测患者对药物的治疗反应。比如，皮疹的出现可能是患者存在间接炎症反应或免疫应答的标志，并不是对特异治疗的反应。将皮疹作为预测标志很难应用到常规临床工作中。厄洛替尼诱导的皮疹并不会在治疗前就出现，然而，在治疗开始之后其他的预测标志如影像学反应和临床表现的改善则能更精确的预测患者的临床结局。</div>
<div></div>
<div>总之，EGFR的体细胞突变预示着能从EGFR酪氨酸激酶抑制剂治疗中获益。应该多所有晚期的非小细胞肺癌患者进行EGFR基因突变测试，并对存在EGFR基因突变的患者进行EGFR酪氨酸激酶抑制剂治疗，无论这些患者的一般状态如何。EGFR野生型的患者，无论其一般状态如何，包括ECOG一般状态2分的患者在内，应该接受细胞毒药物的化疗。更深入的研究可能解释患者预后与厄洛替尼及皮疹之间的联系，但是现有的数据不足以将皮疹作为对厄洛替尼治疗反应的评价指标。在TOPICAL研究之后，靶向治疗临床研究所纳入的患者转变为对靶向治疗有效的患者人群。这种研究设计的转变更能帮助确定对患者治疗有效的药物成分。</div>
<div></div>
<div>原文摘要：</div>
<div>In <em>The Lancet Oncology, </em>Siow Ming Lee and colleagues present fi nal results of TOPICAL,1 a randomized phase 3 trial of fi rst-line erlotinib compared with placebo in patients with advanced non-small-cell lung cancer (NSCLC) who were deemed unsuitable for chemotherapy because of poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status ≥2) or comorbidities. This trial began enrolling patients in 2005 and, as such, <em>EGFR</em> mutation status was not used as an enrolment criterion. Overall survival did not improve with use of erlotinib compared with placebo (unadjusted hazard ratio [HR] 0·94, 95% CI 0·81–1·10, p=0·46). Among patients who received erlotinib, a subset analysis showed that development of a rash during the fi rst cycle of treatment was the only signifi cant independent factor associated with improved overall survival from a multivariate analysis (HR 0·24, 0·16–0·35, p<0·0001). Lee and colleagues conclude that erlotinib prolongs overall survival and progression-free survival in patients with NSCLC deemed unsuitable for chemotherapy, but only in those who develop fi rst-cycle rash.
The subset of patients with lung cancer who derive benefit from EGFR tyrosine-kinase inhibitors (gefi tinib and erlotinib) has been refi ned during the past decade. Whereas initial approval of erlotinib was based on improved overall survival compared with placebo in patients with advanced, previously-treated NSCLC,2 more recent studies have focused on patients with <em>EGFR</em> mutant lung cancers. When such patients were given EGFR tyrosine-kinase inhibitors, they had improved response rate and progression-free survival compared with those who received conventional chemotherapy.
On the basis of initial trials, erlotinib is often used as a treatment for patients with advanced NSCLC who have received previous therapy, but patients without <em>EGFR </em>mutations seem to do better with conventional chemotherapy. The TORCH study5 compared first-line erlotinib followed by second-line chemotherapy to initial chemotherapy followed by erlotinib, irrespective of <em>EGFR </em>genotype. The study was stopped early because of inferiority of first-line erlotinib in unselected patients. In IPASS,6 patients with clinical characteristics suggestive of response (Asian, minimal smokers, adenocarcinoma) but who did not have an <em>EGFR </em>mutation had longer progression-free survival with carboplatin and paclitaxel than with an EGFR tyrosine-kinase inhibitor. The TAILOR study7 showed superiority of docetaxel compared with erlotinib in a confi rmed <em>EGFR </em>wild-type population with a progression-free survival HR of 0·70 (95% CI 0·53–0·94, p=0·016). Available data suggest that EGFR tyrosine-kinase inhibitors are best used in patients with <em>EGFR </em>mutant tumours for whom the strongest evidence of benefit exists.
Patients with poor performance status or many comorbidities, the group targeted by TOPICAL, have historically been excluded from many trials. A limitation of this study, which the investigators acknowledge, is the inclusion of patients with ECOG performance status 2. For such patients, results of a previous study showed better progression-free survival with chemotherapy than with erlotinib (HR 1·45, 95% CI 0·98–2·15, p=0·063).8 56% (372 of 670) of the TOPICAL study population had an ECOG performance status of 2. Although this is certainly a heterogeneous population, many oncologists would recommend conventional chemotherapy to these patients.
Results from TOPICAL and others suggest that the rash from erlotinib is associated with improved outcomes,9 although the rash cannot be predicted before treatment initiation, limiting its usefulness as a predictive marker. In TOPICAL, erlotinib improved overall survival in patients who developed a fi rst-cycle rash (HR 0·76, 95% CI 0·63–0·92, p=0·0058). No clear biological explanation for this association exists. The presence of rash might be an indicator of adherence to the prescribed treatment. Erlotinib-induced rash could be a prognostic marker, but might not necessarily predict response to erlotinib. For example, development of a rash might be a marker of patients with an intact infl ammatory or immune response that portends improved prognosis irrespective of specifi c treatment. Rash as a predictive marker would be diffi cult to incorporate into routine practice. Erlotinib-induced rash is not present before treatment, and after initiation of treatment other markers, such as radiographic response and clinical benefi t, are more likely to accurately predict outcomes.
In summary, presence of somatic activating mutations in <em>EGFR </em>predicts the benefit of EGFR tyrosine-kinase inhibitors. Testing for <em>EGFR </em>mutations should be standard in all patients with advanced NSCLC and those with <em>EGFR</em> mutant tumours should receive an EGFR tyrosine-kinase inhibitor as treatment independent of performance status, preferably in the fi rst-line. <em>EGFR </em>wild-type patients with an adequate performance status, including ECOG performance status 2, should be off ered cytotoxic chemotherapy. Further research might elucidate the association between outcomes with erlotinib and rash, but insufficient data exists to use rash as a marker for
erlotinib response in clinical practice. Since TOPICAL was designed, clinical trials of targeted therapies have moved toward enrollment of only patients whose tumours have the molecular target of interest. These designs are more likely to identify truly active agents for our patients.</div>
<div></div>
<div>文献链接：<a href="http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70434-5/fulltext">http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70434-5/fulltext</a></div>
<div></div>
<div><br/>来源：丁香园</div>
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