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Current Oncology Reports
Erschienen in: Current Oncology Reports 3/2019

01.03.2019 | Lung Cancer (H Borghaei, Section Editor)

Emerging Targeted Therapies for the Treatment of Non-small Cell Lung Cancer

verfasst von: Patrick R. Halliday, Collin M. Blakely, Trever G. Bivona

Erschienen in: Current Oncology Reports | Ausgabe 3/2019

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Abstract

Purpose of Review

Lung cancer remains the leading cause of cancer-related mortality worldwide. Genetic and molecular profiling of non-small cell lung cancer (NSCLC) has led to the discovery of actionable oncogenic driver alterations, which has revolutionized treatment for this disease. This review will move beyond traditional mutational drivers such as EGFR and ALK and will instead focus on emerging targets and the efficacy of new precision therapies.

Recent Findings

Here, we discuss both established and emerging targeted therapy approaches, as well as ongoing challenges for the treatment of NSCLC patients harboring oncogenic alterations of the following types—gene fusions (ROS1, RET, NTRK), receptor tyrosine kinases (MET amplification and exon 14 mutations and EGFR/HER2 exon 20 insertion mutations), and MAPK signaling (SHP2 and altered BRAF and NF1).

Summary

The treatment of lung cancer is increasingly biomarker-driven, as patients are selected for targeted agents based on the identification of genetic alterations amenable to inhibition. Our ability to further improve patient outcomes with this precision medicine approach will require continued efforts to identify, characterize, and target lesions driving lung cancer tumorigenesis and progression.
Literatur
1.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung Cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.PubMed
2.
Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.PubMed
3.
Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy 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. Lancet Oncol. 2011;12:735–42.PubMed
4.
Wu Y-L, Zhou C, Hu C-P, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–22.PubMed
5.
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40.PubMed
6.
•• Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25 This trial established Osimertinib as first-line therapy for patients with EGFR-mutant NSCLC. PubMed
7.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.PubMed
8.
Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.PubMed
9.
Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4:662–73.PubMedPubMedCentral
10.
Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15:1119–28.PubMed
11.
Kim D-W, Tiseo M, Ahn M-J, Reckamp KL, Hansen KH, Kim S-W, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35:2490–8.PubMed
12.
• Camidge DR, Kim HR, Ahn M-J, Yang JC-H, Han J-Y, Lee J-S, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379:2027–39 This trial demonstrated superior PFS for ALK-rearranged NSCLC patients who received brigatinib compared to crizotinib. PubMed
13.
Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18:1590–9.PubMedPubMedCentral
14.
•• Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim D-W, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829–38 This trial established alectinib as first-line therapy for ALK-positive NSCLC. PubMed
15.
Bergethon K, Shaw AT, Ignatius Ou S-H, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863–70.PubMedPubMedCentral
16.
17.
Park S, Ahn B-C, Lim SW, Sun J-M, Kim HR, Hong MH, et al. Characteristics and outcome of ROS1-positive non-small cell lung cancer patients in routine clinical practice. J Thorac Oncol. 2018;13:1373–82.PubMed
18.
Shaw AT, Ou S-HI, Bang Y-J, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–71.PubMedPubMedCentral
19.
Gainor JF, Tseng D, Yoda S, Dagogo-Jack I, Friboulet L, Lin JJ, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precision Oncol. 2017;1:1–13.
20.
Lim SM, Kim HR, Lee J-S, Lee KH, Lee Y-G, Min YJ, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. JCO. 2017;35:2613–8.
21.
Solomon BJ, Martini J-F, Ou S-HI, Chiari R, Soo RA, Bearz A, et al. 1380PD Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations. Ann Oncol. 2018;29:mdy292.003.
22.
Doebele R, Ahn M, Siena S, Drilon A, Krebs M, Lin C, et al. OA02.01 Efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). J Thorac Oncol. 2018;13:S321–2.
23.
24.
Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642–50.PubMedPubMedCentral
25.
•• Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–16 This trial led to the approval of combination dabrafenib and trametinib for metastatic BRAF V600E NSCLC. PubMed
26.
Heymach J, Negrao M, Robichaux J, Carter B, Patel A, Altan M, et al. OA02.06 a phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2018;13:S323–4.
27.
Stinchcombe T, Stahel RA, Bubendorf L, Bonomi P, Villegas AE, Kowalski D, et al. Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC). JCO. 2017;35:8509.
28.
Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004;15:19–27.PubMed
29.
Gandhi L, Besse B, Mazieres J, Waqar S, Cortot A, Barlesi F, et al. MA04.02 Neratinib ± temsirolimus in her2-mutant lung cancers: an international, randomized phase ii study. J Thorac Oncol. 2017;12:S358–9.
30.
Camidge DR, Otterson GA, Clark JW, Ou S-HI, Weiss J, Ades S, et al. Crizotinib in patients (pts) with MET-amplified non-small cell lung cancer (NSCLC): updated safety and efficacy findings from a phase 1 trial. JCO. 2018;36:9062.
31.
Drilon A, Clark J, Weiss J, Ou S, Camidge DR, Solomon B, et al. OA12.02 Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. J Thorac Oncol. 2018;13:S348.
32.
Felip E, Sakai H, Patel J, Horn L, Veillon R, Griesinger F, et al. OA12.01 Phase II data for the MET inhibitor tepotinib in patients with advanced NSCLC and MET exon 14-skipping mutations. J Thorac Oncol. 2018;13:S347.
33.
Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. LBA52 Results of the GEOMETRY mono-1 phase II study for evaluation of the MET inhibitor capmatinib (INC280) in patients (pts) with METΔex14 mutated advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2018;29:mdy424.090.
34.
•• Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731–9 The success of this trial led to FDA approval for adult and pediatric patients with solid tumors harboring NTRK gene fusions. This is the first pan-cancer approval of a TKI. PubMedPubMedCentral
35.
Lee S-H, Lee J-K, Ahn M-J, Kim D-W, Sun J-M, Keam B, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol. 2017;28:292–7.PubMed
36.
Velcheti V, Hida T, Reckamp KL, Yang JC, Nokihara H, Sachdev P, et al. Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung. Ann Oncol. 2016;27:1204PD.
37.
Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17:1653–60.PubMedPubMedCentral
38.
• Oxnard G, Subbiah V, Park K, Bauer T, Wirth L, Velcheti V, et al. OA12.07 Clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET fusion+ non-small cell lung cancer. J Thorac Oncol. 2018;13:S349–50 LOXO-292 is a promising targeted agent for RET-rearranged NSCLC patients, for whom there are no RET-selective inhibitors currently FDA approved.
39.
Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352–9.PubMed
40.
Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011;7:569–80.PubMed
41.
Ju YS, Lee W-C, Shin J-Y, Lee S, Bleazard T, Won J-K, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22:436–45.PubMedPubMedCentral
42.
Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13:27–45.PubMed
43.
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378–81.PubMed
44.
Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, Multicenter RET Registry. J Clin Oncol. 2017;35:1403–10.PubMedPubMedCentral
45.
Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29:1869–76.PubMedPubMedCentral
46.
Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169:107–14.PubMed
47.
Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19:1469–72.PubMedPubMedCentral
48.
Wang W, Xu C, Zhu Y, Liu Y, Chen Y, Zhang Q, et al. P2.03-09 the real world of NTRK fusion data in the Chinese lung cancer populations: a multicenter study. J Thorac Oncol. 2018;13:S719.
49.
Kheder ES, Hong DS. Emerging targeted therapy for tumors with NTRK fusion proteins. Clin Cancer Res. 2018;24:5807–14.
50.
Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 2015;5:1049–57.PubMedPubMedCentral
51.
Farago A, Kummar S, Ibabekci S, Corsi-Travali S, Cruickshank S, Cox M, et al. P1.13-40 rapid, robust and durable responses to Larotrectinib in patients with TRK fusion non-small cell lung Cancer. J Thorac Oncol. 2018;13:S597–8.
52.
53.
Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 2017;7:963–72.PubMedPubMedCentral
54.
Drilon A, Siena S, Ou S-HI, Patel M, Ahn MJ, Lee J, et al. Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7:400–9.PubMedPubMedCentral
55.
Demetri GD, Paz-Ares L, Farago AF, Liu SV, Chawla SP, Tosi D, et al. LBA17 Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2018;29:mdy424.017.
56.
57.
Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression. J Clin Oncol. 2016;34:721–30.PubMed
58.
Drilon A, Cappuzzo F, Ou S-HI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12:15–26.PubMed
59.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.PubMed
60.
Bean J, Brennan C, Shih J-Y, Riely G, Viale A, Wang L, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. PNAS. 2007;104:20932–7.PubMedPubMedCentral
61.
Kong-Beltran M, Seshagiri S, Zha J, Zhu W, Bhawe K, Mendoza N, et al. Somatic mutations Lead to an oncogenic deletion of met in lung Cancer. Cancer Res. 2006;66:283–9.PubMed
62.
Paik PK, Drilon A, Fan P-D, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5:842–9.PubMedPubMedCentral
63.
Dong H-J, Li P, Wu C-L, Zhou X-Y, Lu H-J, Zhou T. Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET exon 14 splicing alternations. Lung Cancer. 2016;102:118–21.PubMed
64.
Heist RS, Sequist LV, Borger D, Gainor JF, Arellano RS, Le LP, et al. Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2016;11:1242–5.PubMed
65.
Schrock AB, Lai A, Ali SM, Miller VA, Raez LE. Mutation of MET Y1230 as an acquired mechanism of crizotinib resistance in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2017;12:e89–90.PubMed
66.
Klempner SJ, Borghei A, Hakimian B, Ali SM, Ou S-HI. Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases. J Thorac Oncol. 2017;12:152–6.PubMed
67.
Pillai RN, Behera M, Berry LD, Rossi MR, Kris MG, Johnson BE, et al. HER2 mutations in lung adenocarcinomas: a report from the lung cancer mutation consortium. Cancer. 2017;123:4099–105.PubMed
68.
Song Z, Yu X, Shi Z, Zhao J, Zhang Y. HER2 mutations in Chinese patients with non-small cell lung cancer. Oncotarget. 2016;7:78152–8.PubMedPubMedCentral
69.
Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18:4910–8.PubMed
70.
Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. JCO. 2013;31:1997–2003.
71.
Mazières J, Barlesi F, Filleron T, Besse B, Monnet I, Beau-Faller M, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27:281–6.PubMed
72.
De Grève J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76:123–7.PubMed
73.
Chuang JC, Stehr H, Liang Y, Das M, Huang J, Diehn M, et al. ERBB2-mutated metastatic non-small cell lung cancer: response and resistance to targeted therapies. J Thorac Oncol. 2017;12:833–42.PubMedPubMedCentral
74.
Peters S, Curioni-Fontecedro A, Nechushtan H, Shih J-Y, Liao W-Y, Gautschi O, et al. Activity of Afatinib in heavily pretreated patients with ERBB2 mutation-positive advanced NSCLC: findings from a global named patient use program. J Thorac Oncol. 2018;13:1897–905.PubMed
75.
• Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24:638–46 Promising HER2/EGFR exon20ins-selective agent, however skin and GI toxicities are concerning. PubMedPubMedCentral
76.
Tsurutani J, Park H, Doi T, Modi S, Takahashi S, Nakagawa K, et al. OA02.07 Updated results of phase 1 study of DS-8201a in HER2-expressing or -mutated advanced non-small-cell lung cancer. J Thorac Oncol. 2018;13:S324.
77.
Li BT, Shen R, Buonocore D, Olah ZT, Ni A, Ginsberg MS, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. JCO. 2018;36:2532–7.
78.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46.PubMed
79.
Riess JW, Gandara DR, Frampton GM, Madison R, Peled N, Bufill JA, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018;13:1560–8.PubMedPubMedCentral
80.
Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci. 2016;107:1179–86.PubMedPubMedCentral
81.
Van Veggel B, Van Der Wekken A, Hashemi S, Cornelissen R, Monkhorst K, Heideman D, et al. P2.13-42 Osimertinib treatment for patients with EGFR exon 20 insertion positive non-small-cell lung cancer. J Thorac Oncol. 2018;13:S815.
82.
Hirano T, Yasuda H, Tani T, Hamamoto J, Oashi A, Ishioka K, et al. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget. 2015;6:38789–803.PubMedPubMedCentral
83.
Piotrowska Z, Fintelmann FJ, Sequist LV, Jahagirdar B. Response to osimertinib in an EGFR exon 20 insertion-positive lung adenocarcinoma. J Thorac Oncol. 2018;13:e204–6.PubMed
84.
Riess J, Floch N, Martin M, Orme J, Staniszewska A, Menard L, et al. Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions. JCO. 2017;35:9030.
85.
van Veggel B, de Langen AJ, Hashemi SMS, Monkhorst K, Heideman DAM, Thunnissen E, et al. Afatinib and cetuximab in four patients with EGFR exon 20 insertion-positive advanced NSCLC. J Thorac Oncol. 2018;13:1222–6.PubMed
86.
Estrada-Bernal A, Doak AE, Le AT, Zhu H, Chen N, Silva S, et al. Abstract A157: antitumor activity of tarloxotinib, a hypoxia-activated EGFR TKI, in patient-derived lung cancer cell lines harboring EGFR exon 20 insertions. Mol Cancer Ther. 2018;17:A157.
87.
88.
Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29:2046–51.PubMedPubMedCentral
89.
Villaruz LC, Socinski MA, Abberbock S, Berry LD, Johnson BE, Kwiatkowski DJ, et al. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the lung cancer mutation consortium. Cancer. 2015;121:448–56.PubMed
90.
Tissot C, Couraud S, Tanguy R, Bringuier P-P, Girard N, Souquet P-J. Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. Lung Cancer. 2016;91:23–8.PubMed
91.
Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532–40.PubMedPubMedCentral
92.
Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248–60.PubMed
93.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.PubMed
94.
Gautschi O, Milia J, Cabarrou B, Bluthgen M-V, Besse B, Smit EF, et al. Targeted therapy for patients with BRAF-mutant lung cancer results from the European EURAF cohort. J Thorac Oncol. 2015;10:1451–7.PubMed
95.
Long GV, Stroyakovsky DL, Gogas H, Levchenko E, de Braud F, Larkin JMG, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. JCO. 2014;32:9011.
96.
97.
Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28:370–83.PubMedPubMedCentral
98.
Joshi M, Rice SJ, Liu X, Miller B, Belani CP. Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. PLoS One. 2015;10:e0118210.PubMedPubMedCentral
99.
Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012;2:791–7.PubMedPubMedCentral
100.
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31:482–9.PubMed
101.
Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526:583–6.PubMed
102.
Okimoto RA, Lin L, Olivas V, Chan E, Markegard E, Rymar A, et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. PNAS. 2016;113:13456–61.PubMedPubMedCentral
103.
Yao Z, Gao Y, Su W, Yaeger R, Tao J, Na N, et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med. 2018;1 (accepted).
104.
Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20:1064–73.PubMedPubMedCentral
105.
Xu G, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990;62:599–608.PubMed
106.
Martin GA, Viskoohil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990;63:843–9.PubMed
107.
Redig AJ, Capelletti M, Dahlberg SE, Sholl LM, Mach S, Fontes C, et al. Clinical and molecular characteristics of NF1-mutant lung cancer. Clin Cancer Res. 2016;22:3148–56.PubMedPubMedCentral
108.
Rasmussen SA, Friedman JM. NF1 gene and neurofibromatosis 1. Am J Epidemiol. 2000;151:33–40.PubMed
109.
Søsrensen SA, Mulvihill JJ, Nielsen A. On the natural history of von Recklinghausen neurofibromatosis. Ann N Y Acad Sci. 1986;486:30–7.
110.
•• Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550–60 Important trial highlighting the effectiveness of MEK inhibition in NF1, and provided rationale that this approach could be adopted in NF1 -positive NSCLC. PubMedPubMedCentral
111.
Gross AM, Wolters P, Baldwin A, Dombi E, Fisher MJ, Weiss BD, et al. SPRINT: phase II study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). JCO. 2018;36:10503.
112.
Hayashi T, Desmeules P, Smith RS, Drilon A, Somwar R, Ladanyi M. RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smoking-associated non-small cell lung carcinomas sensitive to MEK inhibition. Clin Cancer Res. 2018;24:1436–47.PubMed
113.
Neel BG, Gu H, Pao L. The ‘Shping news’: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–93.PubMed
114.
Feng GS, Hui CC, Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993;259:1607–11.PubMed
115.
Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, et al. Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004;64:8816–20.PubMed
116.
Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci. 2009;100:1786–93.PubMed
117.
Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, Kabacaoglu D, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24:954–60.PubMed
118.
• Chen Y-NP, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535:148–52 Demonstrated that SHP2 inhibition is a valid treatment approach for cancers. PubMed
119.
Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, Yoda S, et al. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med. 2018;24:512–7.PubMedPubMedCentral
120.
Metadaten
Titel
Emerging Targeted Therapies for the Treatment of Non-small Cell Lung Cancer
verfasst von
Patrick R. Halliday
Collin M. Blakely
Trever G. Bivona
Publikationsdatum
01.03.2019
Verlag
Springer US
Erschienen in
Current Oncology Reports / Ausgabe 3/2019
Print ISSN: 1523-3790
Elektronische ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-019-0770-x

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