Non small cell lung cancer NCCN guide 2017 edition of the discussion (biomarkers) (fourth)

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Predictive and Prognostic Biomarkers predictive and prognostic biomarkersSeveral biomarkers have emerged as predictive and prognostic marker

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Predictive and Prognostic Biomarkers 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). A number of biomarkers has become NSCLC's prediction and prognostic markers. Predictive biomarkers are an indicator of therapeutic efficacy because there is an interaction between biomarkers and treatment for patient outcomes. Prognostic markers are independent prognostic factors for patients receiving treatment, since the biomarker is an inherent tumor invasion index (see the KRAS mutation 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 include (HER2). Biomarkers 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); th Erefore, these mutations are referred to as sensitizing EGFR mutations (see EGFR Mutations in this Discussion the presence). However, 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). The prediction of biomarkers including ALK fusion (ALK gene and other genes such as animal echinoderm microtubule associated protein 4] fusion), ROS1 gene rearrangement and EGFR sensitive mutant (see NSCLC NCCN in the pathological examination guide principle). New biomarkers including HER2 (also called ERBB2) and BRAF V600E mutation, RET gene rearrangement, high levels of MET or MET amplification of exon 14 skipping mutation (see NSCLC in the NCCN guidelines with genetic changes to drug target emerging patients). The presence of EGFR exon 19 deletion or exon 21 L858R mutation prediction of growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the skin treatment (i.e., erlotinib, gefitinib, afatinib) treatment benefit; therefore, these mutations called sensitive EGFR mutation (see the discussion in the EGFR mutation). However, the presence of EGFR exon 19 deletion (LREA) or exon 21 L858R mutation does not seem to be independent of the treatment that predicts survival in NSCLC patients. Anaplastic lymphoma kinase fusion gene (recombinant ALK gene) and ROS1 rearrangement is the prediction of biomarkers have been identified in patients with NSCLC in a small subgroup; both predict benefit from Kezuo tinib (see the discussion of the principle of pathological examination of ALK gene rearrangement and ROS1 gene rearrangement and NSCLC NCCN guidelines the). 2017 updated first edition, the NCCN team has added a new chapter, ROS1 gene rearrangement pathology recommended (see pathological examination principle of NSCLC in the NCCN guidelines) has recently been identified for targeting gene rearrangement for sensitive (i.e., gene fusion) (RET) (see NSCLC in the NCCN guidelines with emerging genetic changes patients with target to drug).

Testing for ALK gene rearrangements and EGFR mutations is recommended (Category 1 for both in NSCLC algorithm for) the 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 SQUAMOU S 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. in NSCLC steps, for non NSCLC and NSCLC scales unspecified (NOS) were recommended to detect ALK gene rearrangement and EGFR mutation (are 1), so that these genetic abnormalities of the patients can receive effective targeted drug therapy, such as erlotinib, gefitinib, afatinib and J Tini (see the discussion in the NCCN guidelines and NSCLC targeted therapy). ROS1 rearrangements (class 2A) are also recommended in the NCCN guidelines. Although rare, patients with ALK rearrangements or EGFR mutations may have mixed squamous cell histological components. Therefore, it has been reported that ALK rearrangement, ROS1 rearrangement and EGFR mutation may be considered in patients with squamous cell carcinoma if they do not smoke, have small biopsy specimens that can be used for detection, or mixed histology. Genetic alterations in EGFR, KRAS, ROS1, and ALK generally do not 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& #39; 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-g Eneration 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. NSCLC patients may have other genetics Change (see NSCLC NCCN guidelines for emerging target drugs with genetically altered patients). Mutation screening analysis (Sequenom', s; MassARRAY®, SNaPshot®, and the composite system) has been developed for simultaneous detection of multiple biomarkers. More than and 50 point mutations, including EGFR, can be detected. However, these composite polymerase chain reaction (PCR) detection of gene rearrangement system can not, because they are not the point mutation. ROS1 and ALK gene rearrangements can be detected by fluorescence in situ hybridization (FISH) (see ALK gene rearrangement and ROS1 gene rearrangement) in this study. Extensive molecular analysis system, such as next-generation sequencing (NGS) (also known as massively parallel sequencing), can detect a group of mutations and gene rearrangement, if the NGS platform for detection of these genes have been changed to design and verify. It is important to recognize that, like many other diagnostic techniques, NGS requires quality control; because it relies on primers, a set of genes and abnormalities detected by NGS will depend on the design of different NGS platforms. For example, some NGS platforms can detect mutations and gene rearrangements, as well as copy number changes, but they will not be unified in all commercial or institutional laboratories in the NGS analysis.

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 the NCCN). Thus, Panel strongly advises broader molecular profiling (also known as precision medicine to rare driver mutations) identify to ensure that patients receive the most appropriate treatment patients may be eligible for; clinical trials for some of the Se 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 Cancer Genome. The) My 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. Other driver mutations and gene rearrangements (i.e., driving events), such as BRAF V600E mutation, RET gene rearrangement, high level MET amplification or MET exon 14 mutation and HER2 (i.e., ERBB2) are being identified. For patients with NSCLC who have other genetic alterations, there are available targeted drugs, although the FDA is approved for other indications (see NSCLC's NCCN guidelines for the development of genetically modified patients with targeted drugs). Therefore, the expression of NCCN group strongly recommended that more extensive molecular spectrum detection (also known as medicine) to identify rare driver mutations, ensure that patients receive the most reasonable treatment; patients may be suitable for these targeted drugs in some clinical trials. Some of the available online resources available at the DNA genome (My Cancer Genome) are now available for NSCLC driven event descriptions, such as DIRECT (improved and improved cancer treatment). KRAS oncogene is a prognostic biomarker. Compared with the absence of KRAS mutations, the presence of KRAS mutations predicted poor survival in patients with NSCLC, which was unrelated to treatment (see the KRAS mutation in this study). The KRAS mutation also indicates a benefit from platinum / Changchun chemotherapy or EGFR TKI treatment. Genetic alterations in EGFR, KRAS, ROS1, and ALK generally do not overlap. In patients with KRAS mutations, ALK gene rearrangements, or ROS1 rearrangements, sensitive EGFR TKI therapy is ineffective.

EGFR Mutations EGFR mutation

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 mutations patients with EGFR a mutation in) and 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 these mutations). Thus, 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 with metastatic non-squamous NSCLC the most common patients who have sensitizing EGFR mutations. NSCLC in patients with EGFR mutation is a deletion of exon 19 (Exon19del[and LREA conserved sequences the lack of EGFR mutation patients accounted for 45%) and exon 21 (L858R 40%). Two kinds of mutations that cause activation of the tyrosine kinase domain, and both are small TKIs molecules such as erlotinib, gefitinib and afatinib sensitivity (see the discussion in the targeted therapy). Thus, these mutations are known as EGFR mutations. Once in the United States due to the limitation of gefitinib, erlotinib in patients with common EGFR mutations in imatinib sensitive. However, based on a phase 4 study, FDA has recently been re approved by gefitinib, so it is currently available in the United states. Imatinib is an oral tyrosine kinase inhibitor that inhibits all ERBB/HER receptor families including EGFR and HER2. FDA has been approved for first-line treatment of patients with metastatic non - squamous NSCLC with a sensitive EGFR mutation.

These sensitizing EGFR mutations are found in approximately of Caucasian patients with NSCLC and 10% 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 patients with disease progression 60% of after initial response to erlotinib, gefitinib or, afatinib. Most patients with sensitizing EGFR mutations become resistant to erlotinib, gefitinib or, afatinib after about 9 to 13 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 (Category 1) 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). The gene mutation of EGFR sensitive found in about 10% of Caucasian NSCLC patients and up to 50% of the patients in asia. Other drug sensitive mutations included exon 21 (L861Q) and exon 18 (G719X) mutation. Primary resistance to TKI was associated with KRAS mutations and ALK or ROS1 gene rearrangements. Mutations in exon 20 were also resistant to tyrosine kinase inhibitors. EGFR T790M is a kind of EGFR and TKI in the treatment of acquired resistance related mutations have been reported in approximately 60% of patients in the initial erlotinib, gefitinib or afatinib effective treatment after disease progression. Most sensitive patients with EGFR mutations for 9 to 13 months at about tyrosine kinase inhibitors into the erlotinib, gefitinib or afatinib resistance. However, studies have shown that T790M may also occur in patients who have not previously received tyrosine kinase inhibitors, although this is a rare event. For sensitive EGFR TKI such as erlotinib, gefitinib, afatinib treated patients with T790M, EGFR has progressed, recommended OHI imatinib (1) and above (follow-up) as second-line treatment (see the discussion in Ohiti Ni). Acquired resistance may also be associated with the conversion of histology from NSCLC to small cell lung cancer and epithelial mesenchymal transition (see the NCCn pathology guidelines in the NSCLC guidelines).

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. DNA mutation analysis is the preferred method for evaluation of EGFR status. Various DNA mutation detection analysis can be used to determine the EGFR mutation status of tumor cells. Direct sequencing of the corresponding DNA 18 to exon 19 (or only exon 2 and 21) is a reasonable method; however, there are more sensitive methods available. Mutation detection using multiplex PCR (e.g., Sequenom' s MassARRAY® system, SNaPshot® composite system) can detect more than and 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 with a median progression-free survival 80% (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 mutations North American patients with non-squamous NSCLC and sensitizing EGFR (Exon19del [LREA 53% deletion], 26% L858R, 21% and other mutations is with a median) 55% PFS of 9.2 months. EG FR 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. EGFR forecast effect of drug sensitive mutations of exon 19 deletion (LREA deletion) and L858R - meaning. With these mutations in response to erlotinib and gefitinib or afatinib significantly better. A retrospective study showed that in patients with adenocarcinoma of the alveolar variant and sensitive to EGFR mutation, the objective response rate was 80% for single drug EGFR TKI, and median progression free survival (PFS) was about 13 months. A prospective study showed that the objective response rate of patients with non squamous NSCLC and sensitive EGFR mutations (exon 19 deletion [LREA deletion of]53%, L858R, and other mutation of 21%) was about 55%, with a median PFS of 9.2 months. In patients with pure squamous cell carcinoma, if for just a small biopsy histological assessment (i.e., non surgery), or if the organization is mixed, is generally not recommended for EGFR mutation detection, unless never smoking. The data suggest that EGFR mutations may be present in patients with adenocarcinoma of the prostate, which is difficult to distinguish from squamous cell carcinoma in small samples.

Data show that erlotinib, gefitinib or, afatinib (instead of standard first-line chemotherapy should used as first-line) be 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 showed that gefitinib is 4 trial 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 fir St-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. data show that in the first-line treatment Before that is sensitive in patients with the EGFR mutation, erlotinib, gefitinib or afatinib (instead of the standard first-line chemotherapy) should be used as first-line systemic therapy. In patients with a EGFR mutation, the use of EGFR TKI improved progression free survival compared with standard chemotherapy, although overall survival was not statistically significant. Compared with chemotherapy, patients receiving erlotinib treatment-related serious adverse events and fewer deaths. A phase 4 trial showed that gefitinib was safe and effective in patients with a EGFR mutation. Based on these data and the approval of FDA, with sensitivity in patients with the EGFR mutation, recommended erlotinib and gefitinib (1) as first-line therapy. In a phase 3 randomized trial, patients treated with cisplatin / pemetrexed received a reduction in cough, dyspnea, and quality of life. Based on these data and the approval of FDA, 1 patients with EGFR mutations were also recommended as first-line systemic therapy. However, it may be associated with 4 treatment-related deaths, but not in the chemotherapy group. In a joint analysis of LUX 3 and LUX, patients who had a deletion of exon 6 had a survival advantage compared with chemotherapy, compared with chemotherapy in patients with a deletion of exon 19.

ALK Gene Rearrangements gene rearrangement in ALK

Estimates are that 2% to 7% of patients with NSCLC have ALK gene rearrangements, about whom live in the 10000 of 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 patients will have ALK 30% of 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, P Atients 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. estimated that 2% to 7% NSC LC patients with ALK gene rearrangement, of which about 10000 people living in the United states. Patients with ALK rearrangements were resistant to EGFR TKIs, but were similar to those with EGFR mutations (such as adenocarcinoma histology, never smoking, mild smoking), except that they were more likely to be male and younger. In these selected populations, it is estimated that about 30% of patients with ALK rearrangement. ALK rearrangement is uncommon in patients with squamous cell carcinoma. In rare cases, patients with ALK gene rearrangements may have mixed squamous cell histology. It is challenging to accurately determine histology in small biopsy specimens; therefore, patients may have mixed squamous cell histology (or squamous epithelium) rather than pure squamous cells. If histological evaluation was performed using small biopsy specimens, the report was mixed or the patient never smoked, the NCCN team recommended the detection of ALK rearrangement. FDA has been approved for molecular diagnostics (using FISH) for the detection of ALK rearrangements and is a prerequisite for the treatment of imatinib. ALK rearrangement can be assessed by rapid pre screening of immunohistochemistry; if positive, FISH analysis can confirm ALK positive. NGS (next generation sequencing technology) can also be used to assess the presence of ALK rearrangements, if the platform has been designed and validated for the detection of 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 a few). However, patients have had life-threatening pneumonitis crizotinib should be discontinued in; these patients. Patients whose disease responds to crizotinib may have rapid imp Rovement in symptoms (eg, cough, dyspnea, pain); median time to progression on crizotinib is about 7 months to 1 year. crizotinib - a ALK, ROS1 and MET tyrosine kinase inhibitors (high level MET or MET amplification of exon 14 skipping mutation) - approved by the FDA for the treatment of ALK gene rearrangement (ALK positive) or ROS1 rearrangements in patients with locally advanced or metastatic NSCLC. When ALK is used in patients with advanced NSCLC, including patients with brain metastases, a highly efficient (60%). Side effects (such as eye diseases, edema, transient renal function changes) are relatively small. However, a small number of patients with life-threatening pneumonia should be discontinued. The symptoms of the patients who responded to the treatment (such as cough, dyspnea, and pain) were rapidly improved, and the median time to progression was 7 months to 1 years.

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 months; P <.001 and response rate (65%) vs. 20%; P <.001 when compared single-agent (therapy) with 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. randomized phase 3 trials for azole g Indonesia and the standard second-line (i.e. follow-up treatment) (PROFILE 1007) and the standard first-line treatment (PROFILE 1014) were compared. With chemotherapy (pemetrexed combined with cisplatin or carboplatin) compared to crizotinib, first-line therapy to improve PFS efficiency (74% versus 45%; P< 0.001), lung cancer symptoms and quality of life. Based on this trial, the recommended first-line treatment for patients with ALK positive NSCLC (1 NCCN) is recommended (NSCLC). In advance, after first-line chemotherapy in ALK positive NSCLC patients, with monotherapy (docetaxel or pemetrexed) compared to crizotinib follow-up treatment improve PFS (7.7 to 3 months; P< 0.001) and efficiency (65% to 20%; P< 0.001). Based on the trial, the recommended treatment for patients with ALK positive disease as a treatment for the disease. The phrase "follow-up therapy" has recently been replaced by the phrase "second or more systemic therapy" because the treatment of the "line" may be different from the previous target drug treatment.

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 trial showed that ceritinib was very 1 active in 122 patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements. The overall response rate to ceritinib was patients who had previously 56% in 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 wit H 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. for crizotinib in patients, the two generation ALK inhibitors including Shairui imatinib and imatinib arlei; the other in development. Shairui imatinib is an orally active ALK TKI, also inhibits insulin-like growth factor -1 receptor (IGF-1) but did not inhibit MET. The expansion of a phase 1 trial showed that in 122 cases of locally advanced or metastatic NSCLC patients with ALK gene rearrangement, Shairui imatinib is very effective. In the past received crizotinib in patients with imatinib, Shairui total efficiency is 56%; the median PFS was 7 months. Based on the study, FDA Shairui approved erlotinib for crizotinib progression or intolerance, metastatic ALK positive NSCLC patients. Shaw data and FDA approval based on NCCN group of experts recommended Shairui imatinib for ALK positive, crizotinib has advanced or metastatic NSCLC patients to crizotinib intolerant.

Alectinib is another oral TKI of ALK, which also inhibits RET but not MET or ROS1. Two phase in patients with ALK 2 trials 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 (CI 95% of 50% 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 with baseline CNS metastases 23 patients and no previous bra In 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 of patients had an objective response 48% to alectinib. Of 16 patients with baseline CNS metastases, 4 (25%) achieved a complete response in the CNS of these patients had 11; 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 o R 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 trials and FDA 2 approval. Aguirre imatinib is another oral ALK TKI also inhibited RET but does not inhibit MET or ROS1. ALK rearrangement of the two patients with phase 2 trial, Aguirre in crizotinib has progressed in patients with imatinib is very effective. In a larger trial by Ou et al. (138 patients), the effective rate of Arati Ni's patients was 50% (CI, 41%-59%), median duration of treatment was 11.2 months (range, 95% CI, and was not reached). For central nervous system (CNS) lesions, the control rate was 83% (CI, 74%-91%), median duration of treatment was 10.3 months (range, CI, 7.6-11.2). 84 patients with baseline CNS metastases, Aguirre imatinib treatment in 23 patients after complete remission (27%) CNS. 23 patients with baseline CNS metastasis and previous brain radiotherapy in patients who imatinib treatment in 10 cases after complete remission (43%) CNS. The majority of adverse events were only 1 to grade 2 (constipation, fatigue, and peripheral edema). In all, 4 patients (3%) had grade 3 dyspnea. 1 cases of intestinal perforation due to death, and Aguirre icotinib on. In addition, a positive ALK in 87 cases of crizotinib in patients with NSCLC in the phase 2 trial reported that 48% of the patients who had imatinib objective response. Of the 16 patients with baseline CNS metastases, complete remission was achieved in 4 (CNS) of patients (25%); of these, 11 patients had received radiotherapy. 1 cases of bleeding related to treatment. Based on these studies, the FDA approved Aguirre erlotinib for crizotinib progression or intolerance, metastatic ALK positive NSCLC patients. The two studies and the approval of FDA based on NCCN, the panel recommends Aguirre imatinib (2A) for ALK positive, crizotinib has advanced or metastatic NSCLC patients to crizotinib intolerant.

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 progr ESS on crizotinib. ALK or ROS1 rearrangements and sensitive EGFR mutations are usually mutually exclusive. Therefore, do not recommend erlotinib, gefitinib and afatinib as with ALK or ROS1 rearrangement, for follow-up treatment, the recurrence of G patients (see: NSCLC ALK positive follow-up treatment in the NCCN guide). Similarly, not recommended crizotinib, Shairui imatinib and Aguirre erlotinib for erlotinib and gefitinib or afatinib recurrence with sensitive EGFR mutation. For crizotinib in patients following treatment of ALK positive NSCLC including Shairui imatinib or Arati Ni (see the discussion of NSCLC and NCCN in the guide Shairui imatinib and Arati Ni). It may also be appropriate to continue the treatment of patients with imatinib.

ROS1 Rearrangements ROS1 rearrangement

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. the ROS1 is a distinct receptor tyrosine kinase, but with ALK and insulin receptor family are very similar (see NSCLC in the NCCN guidelines pathological assessment principle). It has been estimated that approximately 1% to 2% of NSCLC patients have ROS1 gene rearrangements, and are more common in young women who have never smoked adenocarcinoma, as well as those with EGFR mutations, KRAS mutations, and negative ALK gene rearrangements. The efficacy of in patients with ROS1 rearrangement was very effective, with a total effective rate of approximately. In 50 patients, the effective rate was (95%CI, 51%-79%) and median progression free survival was 18 months. FDA has been approved for the treatment of ROS1 rearrangement in patients with imatinib.

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 te ST 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. 2017 version first update, the NCCN team will recommend ROS1 detection move to the main work step (also delete the recommended ROS1 detection of footnotes), according to crizotinib for approval of ROS1 rearrangement patients with effective data and recent FDA, a new ROS1 work step increases, and added a new chapter on the molecular diagnosis of ROS1 (see NSCLC NCCN for pathological examination principle the). Similar to ALK rearrangement detection, ROS1 was also detected by FISH. NGS (next generation sequencing technology) can also be used to assess the presence of ROS1 rearrangements, if the platform has been designed and validated for the detection of ROS1 rearrangements. Because the ROS1 has not yet been approved for diagnostic tests, clinicians should use appropriate validation tests to test ROS1. Arlei imatinib and imatinib on Shairui g of ROS1 patients with imatinib resistant invalid rearrangement. New drug research is underway in the treatment of ROS1 resistant patients with imatinib resistance.

KRAS Mutations KRAS mutation

Data suggest that approximately patients with adenocarcinomas in 25% of 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 no T currently available for patients with KRAS mutations, although immune checkpoint inhibitors appear to be effective MEK inhibitors are in clinical; trials. data show that in the North American population of about 25% of patients with adenocarcinoma of the KRAS mutation is the most common mutation; KRAS. KRAS mutation rate was related to smoking. Patients with KRAS mutations seem to have shorter survival times than wild-type KRAS; therefore, KRAS mutations are prognostic markers. KRAS mutation status also indicates that EGFR-TKIs therapy is not effective; however, it does not seem to affect the efficacy of chemotherapy. KRAS mutation and epidermal growth factor receptor mutations generally do not overlap, screening recombinant or ROS1 recombinant. Thus, KRAS detection may identify patients who may not benefit from further molecular testing. Currently, there is no available targeted therapy for patients with KRAS mutations, although immune checkpoint inhibitors appear to be effective; MEK inhibitors are undergoing clinical trials.

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