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NCCN Guidelines Version 3.2017 NCCN指南2017第3版 Non-Small Cell Lung Cancer 非小細(xì)胞肺癌山東省腫瘤醫(yī)院腫瘤內(nèi)科張品良 Discussion 討論 Predictive and Prognostic Biomarkers 預(yù)報(bào)和預(yù)后性生物標(biāo)志物 EGFR Mutations EGFR突變 ALK Gene Rearrangements ALK基因重排 ROS1 Rearrangements ROS1重排 KRAS Mutations KRAS突變 Predictive and Prognostic Biomarkers Several biomarkers have emerged as predictive and prognostic markers for NSCLC. A predictive biomarker is indicative of therapeutic efficacy, because there is an interaction between the biomarker and therapy on patient outcome. A prognostic biomarker is indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumor aggressiveness (see KRAS Mutations at the end of this section). Predictive biomarkers include the ALK fusion oncogene (fusion between ALK and other genes [eg, echinoderm microtubule-associated protein-like 4]), ROS1 gene rearrangements, and sensitizing EGFR mutations (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). Emerging biomarkers include HER2 (also known as ERBB2) and BRAF V600E mutations, RET gene rearrangements, and high-level MET amplifications or MET exon 14 skipping mutations (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). The presence of EGFR exon 19 deletions or exon 21 L858R mutations is predictive of treatment benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy (ie, erlotinib, gefitinib, afatinib); therefore, these mutations are referred to as sensitizing EGFR mutations (see EGFR Mutations in this Discussion). However, the presence of EGFR exon 19 deletions (LREA) or exon 21 L858R mutations does not appear to be prognostic of survival for patients with NSCLC, independent of therapy. ALK fusion oncogenes (ie, ALK gene rearrangements) and ROS1 rearrangements are predictive biomarkers that have been identified in a small subset of patients with NSCLC; both predict for benefit from crizotinib (see ALK Gene Rearrangements and ROS1 Gene Rearrangements in this Discussion and Principles of Pathologic Review in the NCCN Guidelines for NSCLC). For the 2017 update (Version 1), the NCCN Panel added a new section on ROS1 Gene Rearrangements to the pathology recommendations (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC) Other gene rearrangements (ie, gene fusions) have recently been identified (such RET) that are susceptible to targeted therapies (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). Testing for ALK gene rearrangements and EGFR mutations is recommended (category 1 for both) in the NSCLC algorithm for patients with non-squamous NSCLC or NSCLC not otherwise specified (NOS) so that patients with these genetic abnormalities can receive effective treatment with targeted agents such as erlotinib, gefitinib, afatinib, and crizotinib (see Targeted Therapies in this Discussion and the NCCN Guidelines for NSCLC). Testing for ROS1 rearrangements (category 2A) is also recommended in the NCCN Guidelines. Although rare, patients with ALK rearrangements or EGFR mutations can have mixed squamous cell histology. Therefore, testing for ALK rearrangements, ROS1 rearrangements, and EGFR mutations can be considered in patients with squamous cell histology if they are never smokers, small biopsy specimens were used for testing, or mixed histology was reported. EGFR, KRAS, ROS1, and ALK genetic alterations do not usually overlap. Patients with NSCLC may have other genetic alterations (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). Mutation screening assays for detecting multiple biomarkers simultaneously (eg, Sequenom's MassARRAY(R) system, SNaPshot(R) Multiplex System) have been developed that can detect more than 50 point mutations, including EGFR. However, these multiplex polymerase chain reaction (PCR) systems do not detect gene rearrangements, because they are not point mutations. ROS1 and ALK gene rearrangements can be detected using fluorescence in situ hybridization (FISH) (see ALK Gene Rearrangements and ROS1 Gene Rearrangements in this Discussion). Broad molecular profiling systems, such as next-generation sequencing (NGS) (also known as massively parallel sequencing), can detect panels of mutations and gene rearrangements if the NGS platforms have been designed and validated to detect these genetic alterations. It is important to recognize that NGS requires quality control as much as any other diagnostic technique; because it is primer dependent, the panel of genes and abnormalities detected with NGS will vary depending on the design of the NGS platform. For example, some NGS platforms can detect both mutations and gene rearrangements, as well as copy number variation, but they are not uniformly present in all NGS assays being conducted either commercially or in institutional laboratories. Other driver mutations and gene rearrangements (ie, driver events) are being identified such as BRAF V600E mutations, RET gene rearrangements, high-level MET amplification or MET exon 14 skipping mutation, and HER2 (also known as ERBB2). Targeted agents are available for patients with NSCLC who have these other genetic alterations, although they are FDA approved for other indications (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). Thus, the NCCN Panel strongly advises broader molecular profiling (also known as precision medicine) to identify rare driver mutations to ensure that patients receive the most appropriate treatment; patients may be eligible for clinical trials for some of these targeted agents. Several online resources are available that describe NSCLC driver events such as DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment) and My Cancer Genome. The KRAS oncogene is a prognostic biomarker. The presence of KRAS mutations is prognostic of poor survival for patients with NSCLC when compared to the absence of KRAS mutations, independent of therapy (see KRAS Mutations in this Discussion). KRAS mutations are also predictive of lack of benefit from platinum/vinorelbine chemotherapy or EGFR TKI therapy. EGFR, KRAS, ROS1, and ALK genetic alterations do not usually overlap. Sensitizing EGFR TKI therapy is not effective in patients with KRAS mutations, ALK gene rearrangements, or ROS1 rearrangements. EGFR Mutations In patients with NSCLC, the most commonly found EGFR mutations are deletions in exon 19 (Exon19del [with conserved deletion of the LREA sequence] in 45% of patients with EGFR mutations) and a mutation in exon 21 (L858R in 40%). Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small molecule TKIs, such as erlotinib, gefitinib, and afatinib (see Targeted Therapies in this Discussion). Thus, these mutations are referred to as sensitizing EGFR mutations. Previously, erlotinib was commonly used in the United States in patients with sensitizing EGFR mutations because of restrictions on the use of gefitinib. However, gefitinib was recently re-approved by the FDA based on a phase 4 study and is now available in the United States. Afatinib is an oral TKI that inhibits the entire ErbB/HER family of receptors including EGFR and HER2. The FDA has approved afatinib for first-line treatment of patients with metastatic non-squamous NSCLC who have sensitizing EGFR mutations. These sensitizing EGFR mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients. Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X). Primary resistance to TKI therapy is associated with KRAS mutations and ALK or ROS1 gene rearrangements. Patients with exon 20 insertion mutations are also resistant to TKIs. EGFR T790M is a mutation associated with acquired resistance to EGFR TKI therapy and has been reported in about 60% of patients with disease progression after initial response to erlotinib, gefitinib, or afatinib. Most patients with sensitizing EGFR mutations become resistant to erlotinib, gefitinib, or afatinib after about 8 to 16 months of EGFR TKI therapy. However, studies suggest T790M may also occur in patients who have not previously received EGFR TKI therapy, although this is a rare event. Osimertinib is recommended as second-line and beyond (subsequent) therapy for patients with EGFR T790M who have progressed on sensitizing EGFR TKI therapy such as, erlotinib, gefitinib, afatinib (see Osimertinib in this Discussion). Acquired resistance may also be associated with histologic transformation from NSCLC to SCLC and with epithelial to mesenchymal transition (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). DNA mutational analysis is the preferred method to assess for EGFR status. Various DNA mutation detection assays can be used to determine the EGFR mutation status in tumor cells. Direct sequencing of DNA corresponding to exons 18 to 21 (or just testing for exons 19 and 21) is a reasonable approach; however, more sensitive methods are available. Mutation screening assays using multiplex PCR (eg, Sequenom's MassARRAY(R) system, SNaPshot(R) Multiplex System) can detect more than 50 point mutations, including EGFR. NGS can also be used to detect EGFR mutations. The predictive effects of the drug-sensitive EGFR mutations— Exon19del (LREA deletion) and L858R—are well defined. Patients with these mutations have a significantly better response to erlotinib, gefitinib, or afatinib. Retrospective studies have shown an objective response rate of approximately 80% with a median progression-free survival (PFS) of 13 months to single-agent EGFR TKI therapy in patients with a bronchioloalveolar variant of adenocarcinoma and a sensitizing EGFR mutation. A prospective study has shown that the objective response rate in North American patients with non-squamous NSCLC and sensitizing EGFR mutations (53% Exon19del [LREA deletion], 26% L858R, and 21% other mutations) is 55% with a median PFS of 9.2 months. EGFR mutation testing is not usually recommended in patients with pure squamous cell carcinoma unless they never smoked, if only a small biopsy specimen (ie, not a surgical resection) was used to assess histology, or if the histology is mixed. Data suggest that EGFR mutations can occur in patients with adenosquamous carcinoma, which is harder to discriminate from squamous cell carcinoma in small specimens. Data show that erlotinib, gefitinib, or afatinib (instead of standard first-line chemotherapy) should be used as first-line systemic therapy in patients with sensitizing EGFR mutations documented before first-line therapy. PFS is improved with use of EGFR TKI in patients with sensitizing EGFR mutations when compared with standard chemotherapy, although overall survival is not statistically different. Patients receiving erlotinib have fewer treatment-related severe side effects and deaths when compared with those receiving chemotherapy. A phase 4 trial showed that gefitinib is safe and effective in patients with sensitizing EGFR mutations. Based on these data and the FDA approvals, erlotinib and gefitinib are recommended (category 1) as first-line systemic therapy in patients with sensitizing EGFR mutations. In a phase 3 randomized trial, patients receiving afatinib had decreased cough, decreased dyspnea, and improved health-related quality of life when compared with those receiving cisplatin/pemetrexed. Based on these data and the FDA approval, afatinib is also recommended (category 1) as first-line systemic therapy in patients with sensitizing EGFR mutations. However, afatinib was potentially associated with 4 treatment-related deaths, whereas there were none in the chemotherapy group. A combined analysis (LUX 3 and LUX 6) reported a survival advantage in patients with exon 19 deletions who received afatinib when compared with chemotherapy. ALK Gene Rearrangements Estimates are that 2% to 7% of patients with NSCLC have ALK gene rearrangements, about 10,000 of whom live in the United States. Patients with ALK rearrangements are resistant to EGFR TKIs but have similar clinical characteristics to those with EGFR mutations (ie, adenocarcinoma histology, never smokers, light smokers) except they are more likely to be men and may be younger. In these selected populations, estimates are that about 30% of patients will have ALK rearrangements. ALK rearrangements are not routinely found in patients with squamous cell carcinoma. Although rare, patients with ALK gene rearrangements can have mixed squamous cell histology. It can be challenging to accurately determine histology in small biopsy specimens; thus, patients may have mixed squamous cell histology (or squamous components) instead of pure squamous cell. The NCCN Panel recommends testing for ALK rearrangements if small biopsy specimens were used to assess histology, mixed histology was reported, or patients never smoked. A molecular diagnostic test (using FISH) has been approved by the FDA for detecting ALK rearrangements and is a prerequisite before treatment with crizotinib. Rapid prescreening with IHC to assess for ALK rearrangements can be done; if positive, FISH analysis can confirm ALK positivity. NGS can also be used to assess whether ALK rearrangements are present, if the platform has been appropriately designed and validated to detect ALK rearrangements. Crizotinib—an inhibitor of ALK, ROS1, and some MET tyrosine kinases (high-level MET amplification or MET exon 14 skipping mutation)—is approved by the FDA for patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements (ie, ALK-positive disease) or ROS1 rearrangements. Crizotinib yields very high response rates (>60%) when used in patients with advanced NSCLC who have ALK rearrangements, including those with brain metastases. Crizotinib has relatively few side effects (eg, eye disorders, edema, transient changes in renal function). However, a few patients have had life-threatening pneumonitis; crizotinib should be discontinued in these patients. Patients whose disease responds to crizotinib may have rapid improvement in symptoms (eg, cough, dyspnea, pain); median time to progression on crizotinib is about 7 months to 1 year. Randomized phase 3 trials have compared crizotinib with standard second-line (ie, subsequent) chemotherapy (PROFILE 1007) and with standard first-line therapy (PROFILE 1014). First-line therapy with crizotinib improved PFS, response rate (74% vs. 45%; P < .001), lung cancer symptoms, and quality of life when compared with chemotherapy (pemetrexed with either cisplatin or carboplatin). Based on this trial, crizotinib is recommended (category 1) for first-line therapy in patients with ALK-positive NSCLC (see the NCCN Guidelines for NSCLC). Subsequent therapy with crizotinib improved PFS (7.7 vs. 3.0 months; P < .001) and response rate (65% vs. 20%; P < .001) when compared with single-agent therapy (either docetaxel or pemetrexed) in patients with ALK-positive NSCLC who had progressed after first-line chemotherapy. Based on this trial, crizotinib is recommended as subsequent therapy in patients with ALK-positive disease. The phrase subsequent therapy was recently substituted for the terms second-line or beyond systemic therapy, because the line of therapy may vary depending on previous treatment with targeted agents. For patients who progress on crizotinib, second-generation ALK inhibitors include ceritinib and alectinib; others are in development. Ceritinib is an orally active TKI of ALK, which also inhibits the insulin-like growth factor–1 (IGF-1) receptor but not MET. An expanded phase 1 trial showed that ceritinib was very active in 122 patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements. The overall response rate to ceritinib was 56% in patients who had previously received crizotinib; the median PFS was 7 months. Based on this study, ceritinib was approved by the FDA for patients with ALK-positive metastatic NSCLC who progress on or are intolerant to crizotinib. The NCCN Panel recommends ceritinib for patients with ALK-positive metastatic NSCLC who have progressed on crizotinib or are intolerant to crizotinib based on the data from Shaw et al and FDA approval. Alectinib is another oral TKI of ALK, which also inhibits RET but not MET or ROS1. Two phase 2 trials in patients with ALK rearrangements showed that alectinib was very active in those who had progressed on crizotinib. In the larger trial (138 patients) by Ou et al, patients on alectinib had a response rate of 50% (95% CI, 41%–59%), and median duration of response of 11.2 months (95% CI, 9.6 months to not reached). For central nervous system (CNS) disease, the control rate was 83% (95% CI, 74%–91%), and the median duration of response was 10.3 months (95% CI, 7.6–11.2 months). Of 84 patients with baseline CNS metastases, 23 (27%) had a complete CNS response to alectinib. Of 23 patients with baseline CNS metastases and no previous brain RT, 10 (43%) had a complete CNS response to alectinib. Most adverse events were only grade 1 to 2 (constipation, fatigue, and peripheral edema); 4 patients (3%) had grade 3 dyspnea. One death due to intestinal perforation may have been related to alectinib. The other phase 2 trial in 87 patients with ALK-positive NSCLC who had progressed on crizotinib reported that 48% of patients had an objective response to alectinib. Of 16 patients with baseline CNS metastases, 4 (25%) achieved a complete response in the CNS; 11 of these patients had previously received RT. One treatment-related death occurred due to hemorrhage. Based on these studies, alectinib was approved by the FDA for patients with ALK-positive metastatic NSCLC who progress on or are intolerant to crizotinib. The NCCN Panel recommends alectinib (category 2A) for patients with ALK-positive metastatic NSCLC who have progressed on crizotinib or are intolerant to crizotinib based on these 2 trials and FDA approval. ALK or ROS1 rearrangements and sensitizing EGFR mutations are generally mutually exclusive. Thus, erlotinib, gefitinib, and afatinib are not recommended as subsequent therapy in patients with ALK or ROS1 rearrangements who relapse on crizotinib (see ALK Positive: Subsequent Therapy in the NCCN Guidelines for NSCLC). Likewise, crizotinib, ceritinib, and alectinib are not recommended for patients with sensitizing EGFR mutations who relapse on erlotinib, gefitinib, or afatinib. For patients who progress on crizotinib, subsequent treatment for ALK-positive NSCLC includes ceritinib or alectinib (see Ceritinib and Alectinib in this Discussion and the NCCN Guidelines for NSCLC). Continuing crizotinib may also be appropriate for patients who progress on crizotinib. ROS1 Rearrangements Although ROS1 is a distinct receptor tyrosine kinase, it is very similar to ALK and members of the insulin receptor family (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). It is estimated that ROS1 gene rearrangements occur in about 1% to 2% of patients with NSCLC; they occur more frequently in younger women with adenocarcinoma who are never smokers and in those who are negative for EGFR mutations, KRAS mutations, and ALK gene rearrangements (also known as triple negative). Crizotinib is very effective for patients with ROS1 rearrangements with response rates of about 70% including complete responses. In 50 patients, crizotinib yielded a response rate of 66% (95% CI, 51%–79%); the median duration of response was 18 months. The FDA has approved crizotinib for patients with ROS1 rearrangements.
For the 2017 update (Version 1), the NCCN Panel moved the recommendation for ROS1 testing into the main algorithm (and deleted the footnote recommending ROS1 testing), added a new algorithm for ROS1, and added a new section on ROS1 to the molecular diagnostic studies section based on data showing the efficacy of crizotinib for patients with ROS1 rearrangements and on the recent FDA approval (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). Similar to testing for ALK rearrangements, testing for ROS1 is also done using FISH. NGS can also be used to assess whether ROS1 rearrangements are present, if the platform has been appropriately designed and validated to detect ROS1 rearrangements. Because a companion diagnostic test has not been approved for ROS1, clinicians should use an appropriately validated test to detect ROS1. Alectinib and ceritinib are not effective in patients with ROS1 rearrangements whose disease becomes resistant to crizotinib. Studies are ongoing regarding new agents for patients with ROS1 rearrangements whose disease becomes resistant to crizotinib. KRAS Mutations Data suggest that approximately 25% of patients with adenocarcinomas in a North American population have KRAS mutations; KRAS is the most common mutation. KRAS mutation prevalence is associated with cigarette smoking. Patients with KRAS mutations appear to have a shorter survival than patients with wild-type KRAS; therefore, KRAS mutations are prognostic biomarkers. KRAS mutational status is also predictive of lack of therapeutic efficacy with EGFR-TKIs; however, it does not appear to affect chemotherapeutic efficacy. KRAS mutations do not generally overlap with EGFR mutations, ALK rearrangements, or ROS1 rearrangements. Therefore, KRAS testing may identify patients who may not benefit from further molecular testing. Targeted therapy is not currently available for patients with KRAS mutations, although immune checkpoint inhibitors appear to be effective; MEK inhibitors are in clinical trials. 【要點(diǎn)】 預(yù)報(bào)性生物標(biāo)志物是治療療效的指標(biāo),。 預(yù)后性標(biāo)志物是與患者所接受治療無(wú)關(guān)的生存指標(biāo),。 預(yù)報(bào)性生物標(biāo)志物包括：ALK融合基因（ALK與其他基因融合）、ROS1基因重排,、敏感EGFR突變（外顯子19缺失或21外顯子L858R突變）,、HER2（為ERBB2）、BRAF V600E突變,、RET基因重排,、高水平MET擴(kuò)增或MET 14外顯子跳躍突變。 EGFR,、KRAS,、ROS1和ALK基因改變通常不重疊。 POS1和ALK基因重排可采用熒光原位雜交（FISH）檢測(cè),。 新一代測(cè)序（NGS）可以檢出一組突變和基因重排,，要認(rèn)識(shí)到像眾多其他任何診斷技術(shù)一樣NGS需要質(zhì)量控制；因?yàn)樗蕾?lài)于引物,。 KRAS基因是一個(gè)預(yù)后生物標(biāo)志物,。與沒(méi)有KRAS突變相比，存在KRAS突變預(yù)示非小細(xì)胞肺癌患者的生存差,，與治療無(wú)關(guān),。 KRAS突變也預(yù)示不能受益于鉑/長(zhǎng)春瑞濱化療或EGFR TKI治療。 在具有KRAS突變,、ALK基因重排或ROS1重排的患者中,，敏感EGFR TKI治療效果并不明顯。 對(duì)TKI治療原發(fā)耐藥與KRAS突變和ALK基因重排或ROS1基因重排有關(guān),。外顯子20插入突變的患者也對(duì)TKIs耐藥,。EGFR T790M是一種與對(duì)EGFR TKI治療獲得性耐藥有關(guān)的突變。 T790M也可能發(fā)生在既往未接受EGFR TKI治療的患者中,。 獲得性耐藥可能也與組織學(xué)從非小細(xì)胞肺癌轉(zhuǎn)變?yōu)樾〖?xì)胞肺癌以及上皮間質(zhì)轉(zhuǎn)化有關(guān),。 在腺鱗癌患者中可以存在EGFR突變。 為評(píng)估ALK重排可以進(jìn)行IHC快速預(yù)篩,；如果陽(yáng)性,，F(xiàn)ISH分析可確認(rèn)ALK陽(yáng)性。 對(duì)克唑替尼應(yīng)答的患者中位疾病進(jìn)展時(shí)間大約是7個(gè)月到1年。 對(duì)于克唑替尼進(jìn)展的患者,，二代ALK抑制劑包括色瑞替尼和阿雷替尼,。 約1%-2%的非小細(xì)胞肺癌患者存在ROS1基因重排。 克唑替尼可用于ROS1重排的患者,。 肺腺癌的三陰性是指EGFR突變,、KRAS突變和ALK基因重排陰性。 對(duì)于具有ROS1重排,、對(duì)克唑替尼耐藥的患者,，阿雷替尼和色瑞替尼是無(wú)效的。 KRAS突變率與吸煙有關(guān),。 KRAS突變的患者比野生型KRAS患者生存期短,；因此，KRAS突變是預(yù)后標(biāo)志物,。 KRAS突變狀態(tài)似乎不影響化療療效,。 KRAS突變的患者目前沒(méi)有可用的靶向治療，免疫檢查點(diǎn)抑制劑似乎有效,。 |
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