Targeted therapeutic drug,having such advantages as targeting,safety,convenience,etc,is increasingly favored by non-small cell lung cancer (NSCLC) patients.At present,there are many kinds of molecular targeted drugs used in clinic,and remarkable efficacy was achieved,and the pain caused by conventional chemotherapy was avoided.At the same time,with the deepening of the understanding of the mechanism of tumor immune,new targeted drugs will also continue to be developed.The emergence of the third generation EGFR-TKI brings new hope for first generation EGFR-TKI resistant patients.Combined use of different immune therapeutic agents,combined application of immunotherapy drugs and cytotoxic chemotherapy drugs and radiotherapy,and the exploration of its predictive biomarkers will become a hot spot in the research of lung cancer.This will undoubtedly bring a new dawn for the treatment of NSCLC.Based on the domestic and foreign research literatures and related materials,this article reviews the latest research progress of various molecular targeted drugs for treatment of NSCLC.
Key words:
Cancer
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lung
;
non-small cell
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Targeted therapy
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Precision Medicine
棘皮动物微管结合蛋白4(echinoderm microtubule associated protein like 4,EML4)与间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因EML4-ALK在动物体内外均有致瘤活性,并在NSCLC发生发展过程中发挥重要的作用。目前研究认为ALK基因重排后与EML4形成融合基因,会引起酪氨酸激酶异常表达,从而导致TKI治疗无效。克唑替尼是ALK受体和肝细胞生长因子受体(C-MET)的抑制药,它通过选择性竞争三磷酸腺苷(adenosine triphosphate,ATP),阻断激酶蛋白来发挥作用,从而抑制肿瘤细胞增殖和诱导凋亡[26]。2011年,美国FDA批准克唑替尼治疗ALK基因表达异常的晚期NSCLC,而且取得了较好的临床效果。但令人遗憾的是,克唑替尼治疗一段时间后,ALK阳性的患者也会不可避免的出现耐药,色瑞替尼作为第2代ALK抑制药不仅对ALK融合基因阳性患者具显著疗效,对克唑替尼获得性耐药患者亦有效,近期已被FDA批准用于治疗已接受过克唑替尼的ALK融合基因阳性患者[27]。色瑞替尼上市后,虽然克唑替尼耐药的患者能从色瑞替尼的治疗中获益,但由于色瑞替尼不良反应发生率相对较高,在一定程度上也限制其在临床上的应用。同样作为第2代ALK抑制药,艾乐替尼治疗克唑替尼耐药患者取得了较好的缓解率,而且对中枢神经系统转移的患者有非常好的疗效。目前,艾乐替尼的Ⅱ期临床试验正在进行。
免疫治疗是近2年来继ALK-EML4、EGFR等驱动基因主导的NSCLC 靶向治疗之后一个新NSCLC治疗的研究热点。迄今为止,FDA已经批准4个免疫检验点抑制药:细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)的伊匹单抗(ipilimumab)和替西木单抗(tremelimumab),抗程序性死亡受体1(programmed death 1,PD-1)的纳武单抗(nivolumab)和派姆单抗(pembrolizumab)。CTLA-4与CD28具有高度的同源性,具有相同的配体即CD86(B7-2)或CD80(B7-1),但与CD28的功能相反,CTLA-4与B7分子结合后抑制T细胞活化。阻断B7/CTLA-4通路,将导致肿瘤特异性T细胞的选择性激活增强[32]。替西木单抗与伊匹单抗类似的单克隆抗体正处于治疗晚期NSCLC患者的Ⅱ期临床试验阶段。2015年纳武单抗已被批准用于进展的转移性的鳞状细胞肺癌,在欧盟则用于初始化疗后的局部晚期或者转移性的鳞状细胞肺癌。派姆单抗是有效的抗PD-1的人源化单克隆抗体,可以通过与其配体PD-L1和PD-L2结合从而特异性阻断PD-L1。它在多种肿瘤类型中具有强有力的抗肿瘤活性和可控的毒性反应。2015年11月FDA批准派姆单抗单药治疗铂类治疗失败后的转移性NSCLC。
Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67-1·05; median progression-free survival 4·6 months [95% CI 3·5-6·3] vs 3·4 months [2·3-3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.
YANG JJ,QINGZ,YAN HH,et al.A randomized controlled trial of erlotinib versus gefitinib in advanced non-small-cell lung cancer harboring EGFR exon 19 or 21 mutations[J].Lancet Oncol,2015,15(1):854-856.
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YANG J CH,SEQUIST LV,SCHULER MH,et al.Overall survival(OS)in patients(pts)with advanced non-small cell lung cancer(NSCLC)harboring common(Del19/L858R)epidermal growth factor receptor mutations(EGFR mut):pooled analysis of two large open-label phase Ⅲ studies(LUX-Lung 3 [LL3]and LUX-Lung 6 [LL6])comparing afatinib with chemotherapy(CT)[J].J Clin Oncol,2014,32(5s):abstr 8004.
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SORIA JC,FELIPE,COBOM,et al.LUX-lung 8 investi-gators :a fatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung(LUX-Lung 8):an open-label randomised controlled phase Ⅲ trial[J].Lancet Oncol,2015,16(8):897-907.
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JANNE PA,RAMALINGAM SS,YANG J CH,et al.Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients(pts)with EGFR inhibitor-resistant non-small cell lung cancer(NSCLC)[J].J Clin Oncol,2014,32(5s):abstr 8009.
The first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Unfortunately, disease progression generally occurs after 9 to 14 months of targeted therapy. The substitution of threonine with methionine at amino acid position 790 (T790M), as the second mutation in EGFR, is the most common resistance mechanism and is detected in tumor cells from more than 50-60% of patients after disease progression. However, current targeted therapeutic strategies for patients with acquired resistance are limited. This has led to the development of "third generation" EGFR-TKIs that are designed to target T790M and EGFR-TKI sensitizing mutations more selectively than wild-type. AZD9291, as a mono-anilino-pyrimidine compound, is a novel, irreversible EGFR-TKI, has proved to be more effective against both EGFR-TKI sensitizing and resistance T790M mutations in preclinical models. This phase I clinical study showed that AZD9291 has robust efficacy and is well tolerated in EGFR mutant NSCLC patients with acquired resistance to EGFR-TKIs.
WALTER AO,SJIN RT,HARINGSMA HJ,et al.Discov-ery of a mutant - selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC[J].Cancer Discov,2013,3(12):1404-1415.
Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. (C) 2013 AACR.
WU YL,LEE JS,THONGPRASERTS,et al.Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer(FASTACT-2):a randomised,double-blind trial[J].Lancet Oncol,2013,14(8):777-786.
The article discusses research on the treatment of advanced stage non-small-cell lung cancer (NSCLC). It references the study "Intercalated Combination of Chemotherapy and Erlotinib for Patients With Advanced Stage Non-Small-Cell Lung Cancer (FASTACT-2): A Randomised, Double-Blind Trial," by S. Thongprasert and colleagues, which appeared in "The Lancet Oncology" on June 17, 2013. Intercalated combination of chemotherapy and erlotinib was found to be an effective therapy.
SUGAWARAS,OIZUMIS,MINATOK,et al.Randomized phase Ⅱ study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations:NEJ005/TCOG0902[J].Ann Oncol,2015,26(5):888-894.
Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. Patients and methods: Chemotherapy-naive patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. Results: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). Conclusion: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
CHENGY,MURAKAMIH,YANG PC,et al.Randomized open-label phase-2 of gifitinib with and without pemetrexed as first-line therapy in East Asian patients with advanced NS NSCLC with EGFR mutation[J].J Clin Oncol,2016,34(27):3258-3266.
THOMASY,HILDAW,PIERREC.Phase Ⅱ study of be-vacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease[J].Invest New Drugs,2012,30(6):2384-2390.
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SORIA JC,WU YL,NAKAGAWAK,et al.Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib(IMPRESS):a phase 3 randomised trial[J].Lancet Oncol,2015,16(8):990-998.
Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB–IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65–1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5–5·7 in the gefitinib group and 4·6–5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. AstraZeneca.
YU HA,ARCILA ME,REKHTMANN,et al.Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[J].Clin Cancer Res,2013,19(8):2240-2247.
All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted.Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2.Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%.This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.
SONGX,FAN PD,BANTIKASSEGNA,et al.ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas[J].Cancer Res,2015,75(6):1035-1045.
ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3K-AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFR(L858R)-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.
BEANJ,BRENNANC,SHJH JY,et al.MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib[J].Proc Natl Acad Sci USA,2007,104(52):20932-20937.
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SUDAK,MURAKAMII,KATAYAMAT,et al.Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer[J].Clin Cancer Res,2010,16(22):5489-5498.
In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.HCC827ER developed MET amplification, and clinically relevant resistance occurred at 4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification ( 4-fold).These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.
SEQUIST LV,WALTMAN BA,DIASANTAGATAD,et al.Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors [J].Sci Transl Med,2011,3(75):75ra26.
Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
YANG JJ,CHEN HJ,YAN HH,et al.Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer[J].Lung Cancer,2013,79(1):33-39.
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BANG YJ.The potential for crizotinib in non-small cell lu-ng cancer:a perspective review[J].Therap Advances Med Oncol,2011,3(6):279-291.
Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.
WILSON FH,JOHANNESSEN CM,PICCIONIF,et al.A functional landscape of resistance to ALK inhibition in lung cancer[J].Cancer Cell,2015,27(3):397-408.
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
BERGETHONK,SHAW AT,OU SH,et al.ROS1 rearr-angements define a unique molecular class of lung cancers[J].J Clin Oncol,2012,30(8):863-870.
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SHAW AT,CAMIDGE DR,ENGELMAN JA,et al.Clini-cal activity of crizotinib in advanced non-small cell lung cancer(NSCLC)harboring ROS1 gene rearrangement[J].J Clin Oncol,2012,30(supp1):abstr 7508.
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ZHOUC,WU YL,CHENG,et al.Beyond:a tandomized,double- blind,placebo- controlled,multicenter,phase Ⅲ study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer[J].J Clin Oncol,2015,33(19):2197-2204.
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PEROLM,CIULEANU TE,ARRIETAO,et al.Quality of life results from the phase 3 revel randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-doce-taxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy[J].Lung Cancer,2016,93(17):95-103.
Erlotinib versus chemo-therapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer(optimal,ctong-0802):a multicentre,open-label,randomised,phase 3 study
LUX-lung 8 investi-gators :a fatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung(LUX-Lung 8):an open-label randomised controlled phase Ⅲ trial
Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer(FASTACT-2):a randomised,double-blind trial
Randomized phase Ⅱ study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations:NEJ005/TCOG0902
Randomized open-label phase-2 of gifitinib with and without pemetrexed as first-line therapy in East Asian patients with advanced NS NSCLC with EGFR mutation
Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib(IMPRESS):a phase 3 randomised trial
Beyond:a tandomized,double- blind,placebo- controlled,multicenter,phase Ⅲ study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer
Quality of life results from the phase 3 revel randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-doce-taxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy
... 免疫治疗是近2年来继ALK-EML4、EGFR等驱动基因主导的NSCLC 靶向治疗之后一个新NSCLC治疗的研究热点.迄今为止,FDA已经批准4个免疫检验点抑制药:细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)的伊匹单抗(ipilimumab)和替西木单抗(tremelimumab),抗程序性死亡受体1(programmed death 1,PD-1)的纳武单抗(nivolumab)和派姆单抗(pembrolizumab).CTLA-4与CD28具有高度的同源性,具有相同的配体即CD86(B7-2)或CD80(B7-1),但与CD28的功能相反,CTLA-4与B7分子结合后抑制T细胞活化.阻断B7/CTLA-4通路,将导致肿瘤特异性T细胞的选择性激活增强[32].替西木单抗与伊匹单抗类似的单克隆抗体正处于治疗晚期NSCLC患者的Ⅱ期临床试验阶段.2015年纳武单抗已被批准用于进展的转移性的鳞状细胞肺癌,在欧盟则用于初始化疗后的局部晚期或者转移性的鳞状细胞肺癌.派姆单抗是有效的抗PD-1的人源化单克隆抗体,可以通过与其配体PD-L1和PD-L2结合从而特异性阻断PD-L1.它在多种肿瘤类型中具有强有力的抗肿瘤活性和可控的毒性反应.2015年11月FDA批准派姆单抗单药治疗铂类治疗失败后的转移性NSCLC. ...
, 张四喜, 王红玉, 王红
