Abstract

Worldwide the second most common cancer is lung cancer with tobacco as the main reason for the disease. Lung cancer is chiefly classified into Small cell lung cancer and non-small cell lung cancer. Various genes that cause tumorigenesis in non-small cell lung cancer are linked to multiple pathways like ALK, MET, EGFR, and RET. Genomic profiling and mutational analysis in recent years have progressed the field of genetics of lung cancer substantially. In this present review, we converse about the various targeted therapeutic drugs and their advancement in treatment of non-small cell lung cancer (NSCLC). The present review scrutinize the existing documentation in the literature related to the targeted therapies of non-small cell lung cancer (NSCLC). English language articles were searched in various databases such as Pubmed, Scopus, Science direct and Google scholar. The keyword used for searching are “non-small cell lung cancer”, “Targeted therapy”, “Therapeutic drugs”.

Keywords

Introduction

One of the principal reasons for cancer-related mortality is lung cancer. Worldwide more than one million deaths occur because of lung cancer. Death from lung cancer and other respiratory system cancer would surpass the number of deaths from cancers of the colon, breast, pancreas, and prostate combined. About 80% of all cases of lung cancer are NSCLC (Non-small cell lung cancer) and are actively associated with smoking habits. Small cell lung cancer is solely diagnosed in smokers.^1,2,3

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes of non-small cell lung cancer.⁴ Smoking tobacco is precisely linked with non-small cell lung cancer and more than 50 carcinogens are found in the smoke of tobacco.⁵

Tobacco regulation is expected to be an advantageous and useful method to decrease the mortality and incidence of cancer of the lung. Various carcinogenic factors like genetic mutations, bad lifestyle, and a history of cancer in the family also contribute to cancer of the lung. Other than the prevention of cancer, screening of lung cancer is also important in detection in early-stage patients, in which low-dose computed tomographic screening decreases lung cancer mortality.⁶

During the last few decades, much development has been done in various therapeutic strategies for advanced non-small cell lung cancer specifically in the development of immunotherapy and targeted therapy. Various considerable small molecular tyrosine kinase inhibitors (TKIs), which target fusions in ROS1(ROS proto-oncogene 1), EGFR (epidermal growth factor receptor) mutation, MET (mesenchymal-epithelial transition) exon 14 skipping, rearrangements in ALK (anaplastic lymphoma kinase), NTRK (neurotrophic tyrosine receptor kinase)1/2/3 gene fusion, and RET (rearranged during transfection) rearrangement and BRAF (v-Raf murine sarcoma viral oncogene homolog B) V600E have been recognized by the U.S food and drug administration for the treatment and therapy of driven gene mutation-positive non-small cell lung cancer.

As a result of comprehensive genomic profiling, different genetic aberrances in non-small cell lung cancer, like an amplification of HERS-2 (human epidermal growth factor-2), mutations in KRAS (Kirsten rat sarcoma), and different genotypes of driver genes thought to be highly targetable and researched in various preclinical and clinical trials. Monoclonal antibodies (mAbs) that target programmed cell death ligand-1(PD-L1), programmed cell death-1(PD-1), and cytotoxic T-lymphocytes associated antigen-4 (CTLA-4) immune checkpoints have been accepted for the treatment of various type cancers including non-small cell lung cancer. There are five immune checkpoint inhibitors that are approved by the food and drug administration including ipilimumab (anti-CTLA-4 antibody), atezolizumab and durvalumab (anti-PD-L1 antibodies), and nivolumab and pembrolizumab (anti-PD1 antibodies).⁷

Various molecular testing for NSCLC

Non-small cell lung cancer is a molecularly heterogeneous disease, that makes initial recognition of tumor genotype analytical. ALK, EGFR, and ROS1 at first approved as three targetable oncogenic drivers, which are essentially tested if the tissue is restricted for NGS (next-generation sequencing) panel. NCCN advised that all patients must be screened for ALK, BRAF, EGFR, MET, KRAS, PD-L1, and RET expression.⁸ The most traditional way to determine genomic mutations is DNA sequencing which needs comparably enriched tumor cells. Oncogenic fusion mutation can be examined by PCR or FISH (fluorescence in situ hybridization). NGS is now considered a typical molecular testing method and has adequate potential to evaluate the data from DNA and RNA.^9,10 RNA NGS is also efficient to determine the fusion partners of ROS1, NTRK, ALK, and RET.^11-14To identify circulating tumor DNA, liquid biopsies are used.¹⁵ Immunohistochemistry (IHC) is an alternate method for testing, mainly ROS1, ALK and NTRK.^16,17

Various Targeted Therapy For Nsclc

Patients with progressive non-small cell lung cancer benefit a lot from the advancement of targeted therapy. Approximately more than 65% of patients with progressive non-small cell lung cancer have a probable targetable genomic alteration. Targeted therapy is now recognized as first-line treatment for selected non-small cell lung cancer patients which includes inhibitors for BRAF, MET, EGFR, ROS1, RET, ALK and NTRK1/2/3.¹⁸

EGFR (Epidermal Growth Factor Receptor)

The EGFR (epidermal growth factor receptor or ErbB1 or HER1) is part of a family of receptor tyrosine kinases that can provoke a broad array of signaling pathways that result in cell growth, survival, and proliferation. These signaling pathways include the PI3K-AKT-mTOR pathways and RAS-RAF-MEK-ERK or MAPK pathway.^19,20

EGFR activation occurs by three mechanisms. These are enhanced ligand production by malignant cells; increased expression of EGFR on malignant cells and activating mutations of EGFR within malignant cells.^21,22 In humans, there are 58 RTKs (receptor tyrosine kinases).EGFR (epidermal growth factor receptor) is one of the first receptor tyrosine kinases marked as an anticancer target and causes meaningful development in survival in patients of non-small cell lung cancer.²³

Expression of EGFR is normally seen on the surface of epithelial cells and manages cell growth, invasion, survival, and angiogenesis.²⁴ EGFR mutation in patients of non-small cell lung cancer takes place in nearly 40% of Asian patients and 10% of non-Asian patients.^25,26

The most frequent activating mutations of EGFR in non-small cell lung cancer consists of exon 19 deletions and point mutation on exon 21, which is accountable for oral tyrosine kinase inhibitor (TKIs) targeting EGFR.²⁷ There are three generations of EGFR TKIs used in clinical function. The first-generation EGFR TKIs reversibly attach to EGFR and aggressively restrict the binding of ATP to the tyrosine kinase domain. The first-generation EGFR TKIs include erlotinib, gefitinib, and icotinib.²⁸ The second-generation EGFR TKIs attach to the ATP binding domain of EGFR irreversibly. The second-generation EGFR TKIs include afatinib and dacomitinib and they are irreversible ERBB-family inhibitors. Depending on the results of three clinical trials, LUX-Lung 6, LUX-Lung 3, LUX-Lung 2, afatinib demonstrate extended PFS of almost 1 year in patients having progressive non-small cell lung cancer with EGFR mutations.^29,30,31

Almost all the patients who have taken first or second-generation EGFR TKIs treatment ultimately attained drug resistance which results in disease progression.³² Osimertinib is a third-generation EGFR TKI. They irreversibly and selectively target the T790 mutation and original EGFR-sensitizing mutations. The most common second mutation is T790M which causes drug resistance, which is attributed to threonine-to methionine substitution in exon 20.^33,34 The third-generation EGFR TKIs include olmutinib (HM61713),avitinib, rociletinib, nazartinib (EGF816), PF-06747775.^35-39 Osimertinib crosses the blood-brain barrier and enters the central nervous system and destroy the tumor cells. Currently, furmonertinib was approved by NMPA and is third generation EGFR TKI.⁴⁰

ALK (Anaplastic lymphoma kinase)

Anaplastic lymphoma kinase or ALK is an RTK commonly expressed in various human tissues like the small intestine, brain, and testis.⁴¹ ALK fusion proteins are mostly found as an oncogenic driver in different malignancies. ALK rearrangements in non-small cell lung carcinoma have been observed in 2007 by the early discovery of a fusion gene that consists of parts of the EML4 gene (echinoderm microtubule-associated protein-like 4) and ALK gene. More than 20 variants of ELM4-ALK fusion were recognized.^42-44

There are five ALK TKIs that have been recognized as targeted therapy for progressive non-small cell lung cancer patients who are proven to have ALK arrangements. These are alectinib, crizotinib, brigatinib, ceritinib, and loralatinib. Crizotinib is first generation ALK TKI that targets ROS1, ALK, and MET.⁴⁵ Ceritinib and alectinib are second-generation ALK TKIs that are approved to use in those cases of non-small cell lung cancer which fail in or tolerate crizotinib therapy. Ceritinib could adequately restrict certain ALK alteration patterns like G1269A, S1206Y, and L1196M mutations. On the other hand, they are not able to conquer two crizotinib resistant ALK mutations i.e. F1174C and G1202R.^44,46,47

Earlier, Brigatinib was accepted for second-line treatment in patients of progressive ALK-positive non-small cell lung cancer. Brigatinib targets both ALK and EGFR.^48,49 Currently in march 2021,lorlatinib, earlier second-line ALK TKI, has been recognized as a first-line treatment for progressive ALK-positive non-small cell lung cancer patients. Lorlatinib target numerous RTKs consisting of ROS1 and ALK.⁵⁰ Lorlatinib is a third-generation ALK TKI that has adequate potential to overcome ROS1 and ALK resistance mutations like G1202R and I1171T. Lorlatinib showed various advantages which include less drug resistance and penetration into the central nervous system on comparing with former-generation ALK TKIs.^51,52

ROS1

ROS1 is an oncogenic RTK of the insulin receptor family. They are encoded on chromosome 6q22 by the ROS1 gene. The oncogenic consequences of ROS1 depend on basic phosphorylation and are stimulated by fusions with partner genes like FIG (fused in glioblastoma), CD74, and SLC34A2 (so lute carrier family 34 member 2).^53-56 Crizotnib was accepted for the treatment of ALK-positive non-small cell lung cancer. Crizotinib has targeted agents used in ROS1-positive progressive non-small cell lung cancer. At the same time, Entrectinib has been accepted for the treatment of progressive ROS1-positive non-small cell lung cancer.^57,58

BRAF

In 3-8 % of non-small cell lung cancer, BRAF mutations have been seen.^59,60 Single point mutation at exon 15 is the most common alteration of BRAF mutations in which glutamate replaces the valine (V600E, Val600Glu). The threonine/serine protein kinase, which is linked in MAPK/ERK signaling pathway, is encoded by the BRAF gene. Mutation in V600E results in uncontrolled activation of BRAF, which further causes abnormal cell proliferation.⁶¹

KRAS (Kirsten rat sarcoma 2 viral oncogene homolog)

KRAS is an oncogene that is part of the RAS GTPase family. They assist in the regulation of various important cellular pathways encompassing PI3K/AKT and RAF/MEK/ERK.⁶²KRAS mutations are frequently seen in non-small cell lung cancer which accounts for 25% of adenocarcinomas. The genomic aberrations of KRAS result in constant stimulation of KRAS.^63,64

RET

On the cell surface, RET encodes a tyrosine kinase receptor. It participates in various important signaling pathways which comprise JAK/STAT, MAPK, PKC, PI3K, and PKA pathways.⁶⁵ In 1-2 % of non-small cell lung cancer RET fusion or RET arrangements have been identified. The most common fusion partner of RET is intron 15 of KIF5B.^66,67

MET (mesenchymal-epithelial transition factor)

The MET gene encodes hepatocyte growth factor receptor and the phosphorylation of this results in the stimulation of various cellular signaling pathways which includes PI3K, MAPK, and STAT. The amplification of MET is generally linked with EGFR TKIs resistance.⁶⁸Most common pattern of MET mutations is skipping of MET exon 14, which results in constant stimulation of MET protein.⁶⁹ Crizotinib was recognized for second-line treatment of MET exon 14 skipping positive in patients of non-small cell lung cancer. Tepotinib and capmatinib are MET TKIs used in the treatment of MET exon 14 skipping mutation-positive in progressive non-small cell lung cancer. Various approaches to prevent MET.HGFR-mediated growth is in progress which includes anti-HGFR mAb, HGF antagonists, anti-MET mAb and MET TKIs like cabozantinib (XL184), tivantinib (ARQ197), and crizotinib.^70,71

NTRK

Tropomyosin receptor kinases A, B, and C are encoded by NTRK (Neurotrophic tropomyosin-related kinases) genes 1,2, and 3. 1-2% of non-small cell lung cancer patients show NTRK fusion. Entrectinib,larotrectinib, and repotrectinib were recognized for the treatment of NTRK gene fusion-positive solid tumor which includes non-small cell lung cancer.^72,73

HER2 Human epidermal growth factor 2 (HER2/ErbB2/neu)

HER2 (ERBB2), HER3, and HER4 are part of the ERBB RTK family.⁷⁴ Overexpression of HER2 is relatively seen in 10% of lung cancer. Also, amplification of HER2 is seen in 30% of lung cancer.^75,76 The common mutations seen in HER2 take place in exon 20 by the inclusion of DNA bases. Various targeted agents like antibody-drug conjugates (ADCs), antibodies (transtuzumab and pertuzumab), and small molecular TKIs (dacomitinib,poziotinib, lapatinib,pyrotinib) have been examined in various clinical trials.^77,78Antibody-drug conjugates demonstrates most promising therapeutic effects for HER2 mutation-positive in patients of non-small cell lung cancer.⁷⁹

VEGF/VEGFR

In addition to targeting genomic alterations, the formation of inhibition tumor vasculature by targeting the angiogenic determinants is also a hopeful and characteristic anticancer approach.⁸⁰Microvessels having high density are linked with poor prognosis and metastasis of non-small cell lung cancer.VEGF (vascular endothelial growth factor ) and the communication with its receptors are found to be most effective in controlling angiogenesis and are also capable to intensify the vascular permeability.^81,82

Suppression of tumor angiogenesis is presumed as an encouraging therapeutic approach. The anti-angiogenic treatment for non-small cell lung cancer consists of small molecule TKIs,mAbs, and recombinant human endostatin. Ramucirumab and Bevacizumab are two mAbs accepted for the treatment of non-small cell lung cancer. Bevacizumab is the first antiangiogenic drug that prohibits angiogenesis by neutralizing all isoforms of VEGF.⁸³ Bevacizumab in consolidation with paclitaxel and carboplatin was accepted as the first-line treatment of progressive non-squamous non-small cell lung cancer.⁸⁴ Ramucirumab, a monoclonal antibody, attaches to the extracellular VEGF-binding domain of VEGFR-2, which results in the suppression of angiogenesis.^85,86

TKIs targeting platelet-derived growth factor/receptor (PDGF/PDGFR), c-Kit, VEGF/VEGFR and fibroblast growth factor/ receptor (FGF/FGFR) illustrate the consequence on inhibition angiogenesis including sunitinib, nintedanib, sorafenib, vandetanib and anlotinib.^87-90 Anlotinib suppresses a wide spectrum of targets which includes FGFR1-4, c-Kit, VEGFR2/3, PDGFR ?/?, and Ret, which is expected to have extreme effects on anti-angiogenesis.⁹¹

CONCLUSION

In the last few decades, meaningful advancement in molecular pathology occurs and it allowed us to explain the basic pathology and considerable heterogeneity of non-small cell lung cancer. Numerous signaling pathways have now been recognized as well as particular oncogenic driver mutations that result in malignant transformations. In current decades, target therapy and immunotherapy have made a notable significant addition to the modernized management of lung cancer. Furthermore, genetic testing and biomarker analysis helps in the special management and treatment of numerous forms of lung cancer

REFERENCE

1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61(4):212-36
2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. doi: 10.3322/caac.20107. Epub 2011 Feb 4. Erratum in: CA Cancer J Clin. 2011 Mar-Apr;61(2):134.
3. Sun, S., Schiller, J. & Gazdar, A. Lung cancer in never smokers — a different disease. Nat Rev Cancer.2007; 7, 778–790.
4. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortalityworldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-E386
5. Smith CJ, Perfetti TA, Rumple MA, Rodgman A, Doolittle DJ. “IARC Group 2A Carcinogens” reported in cigarette mainstream smoke. Food Chem Toxicol. 2000;38(4):371-383
6. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409
7. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550
8. Halmos B. Molecular testing in lung cancer: where to draw the line. Arch Pathol Lab Med. 2018;142(7):787-789.
9. Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20(12):1479-1484.
10. Lam SW, Cleton-Jansen AM, Cleven A, et al. Molecular analysis of gene fusions in bone and soft tissue tumors by anchored multiplex PCR-based targeted next-generation sequencing. J Mol Diagn. 2018;20(5):653-663
11. Davies KD, Le AT, Sheren J, et al. Comparison of molecular testing modalities for detection of ROS1 rearrangements in a cohort of positive patient samples. J Thorac Oncol. 2018;13(10):1474-1482.
12. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
13. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863-870.
14. Vendrell JA, Taviaux S, Beganton B, et al. Detection of known and novel ALK fusion transcripts in lung cancer patients using next-generation sequencing approaches. Sci Rep. 2017;7(1):12510.
15. Trombetta D, Sparaneo A, Fabrizio FP, Muscarella LA. Liquid biopsy and NSCLC. Lung Cancer Manag. 2016;5(2):91-104
16. Marchio C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417-1427.
17. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358
18. Tsao AS, Scagliotti GV, Bunn PA Jr, et al. Scientific advances in lung cancer 2015. J Thorac Oncol. 2016;11(5):613-638.
19. Arteaga CL. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001;19:32S-40S.
20. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127-37.
21. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908-14.
22. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. fKRASN Engl J Med 2009;361:958-67
23. Mendelsohn J, Masui H, Goldenberg A. Anti-epidermal growth factor receptor monoclonal antibodies may inhibit A431 tumor cell proliferation by blocking an autocrine pathway. Trans Assoc Am Physicians. 1987;100:173-178.
24. Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2014;6(4):a020768
25. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339- 346
26. Tsao AS, TangXM, Sabloff B, et al. Clinicopathologic characteristics of the EGFR genemutation in non-small cell lung cancer. J Thorac Oncol. 2006;1(3):231-239
27. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169-181
28. Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer. Lancet Oncol. 2006;7(6):499-507
29. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13(5):539-548.
30. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334.
31. Wu YL, Zhou C, Hu CP, 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(2):213-222.
32. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12(3 Pt 1):839-844
33. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616-1622.
34. Kobayashi S, Boggon TJ, DayaramT, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792
35. Park K, Janne PA, Yu C. 412OA global phase II study of olmutinib (HM61713) in patients with T790M-positive NSCLC after failure of first-line EGFR-TKI. Ann Oncol. 2017;28:mdx671.
36. Wang H, Zhang L, Hu P, et al. Penetration of the blood–brain barrier by avitinib and its control of intra/extra-cranial disease in non-small cell lung cancer harboring the T790M mutation. Lung Cancer. 2018;122:1-6.
37. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700-1709
38. Kim D-W, Tan DSW, Aix SP, et al. Preliminary phase II results of a multicenter, open-label study of nazartinib (EGF816) in adult patients with treatment-naive EGFR-mutant non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36:9094.
39. Husain H, Martins RG, Goldberg SB. 1358PFirst-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLCafter progression on a first-line EGFRTKI. Ann Oncol. 2017;28;mdx380.
40. Wu YL, Ahn MJ, Garassino MC, et al. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018;36(26):2702-2709.
41. Pulford K, Lamant L, Espinos E, et al. The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci. 2004;61(23):2939-2953.
42. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263(5151):1281-1284.
43. Soda M, Choi YL, EnomotoM, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-566.
44. Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res. 2015;21(10):2227-2235.
45. Christensen JG, Zou HY, ArangoME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12 Pt1):3314-3322.
46. Gainor JF, Ou SH, Logan J, Borges LF, Shaw AT. The central nervous system as a sanctuary site in ALK-positive non-small cell lung cancer. J Thorac Oncol. 2013;8(12):1570-1573.
47. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662-673.
48. Wang Y, Yang N, Zhang Y, et al. Effective treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and cis-C797S triple mutations by brigatinib and cetuximab combination therapy. J Thorac Oncol. 2020;15(8):1369- 1375.
49. Kim DW, Tiseo M, Ahn MJ, 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(22):2490-2498
50. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029
51. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistantmutations. J Med Chem. 2014;57(11):4720-4744.
52. Baglivo S, Ricciuti B, Ludovini V, et al. Dramatic response to lorlatinib in a heavily pretreated lung adenocarcinoma patient harboring G1202R mutation and a synchronous novel R1192P ALK point mutation. J Thorac Oncol. 2018;13(8):e145-e147
53. Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta. 2009;1795(1):37-52.
54. Facchinetti F,Rossi G, Bria E, et al.Oncogene addiction in nonsmall cell lung cancer: focus on ROS1 inhibition. Cancer Treat Rev. 2017;55:83-95.
55. Birchmeier C, Sharma S, WiglerM. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A. 1987;84(24):9270-9274.
56. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131(6):1190-1203
57. ShawAT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971
58. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020;21(2):261-270.
59. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29(15):2046-2051.
60. Cardarella S, Ogino A, Nishino M, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19(16):4532- 4540.
61. Dankner M, Rose A, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183-3199.
62. Takashima A, Faller DV. Targeting the RAS oncogene. Expert Opin Ther Targets. 2013;17(5):507-531.
63. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: metaanalyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24(9):2371-2376
64. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006
65. Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16(4-5):441-467
66. Michels S, Scheel AH, Scheffler M, et al. Clinicopathological characteristics of RET rearranged lung cancer in European patients. J Thorac Oncol. 2016;11(1):122-127.
67. 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(1):27-45.
68. LiuD, Zhong M, ZhanD, Zhang Y, Liu S.Roles of theHGF/Met signaling in head and neck squamous cell carcinoma: focus on tumor immunity (Review). Oncol Rep. 2020;44(6):2337-2344.
69. Kong-Beltran M, Seshagiri S, Zha J, et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 2006;66(1):283-289
70. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51.
71. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14- mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957
72. Doebele RC, Davis LE, Vaishnavi A, 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(10):1049-1057.
73. Marcus L, Donoghue M, Aungst S, et al. FDA approval summary: entrectinib for the treatment of NTRK gene fusion solid tumors. Clin Cancer Res. 2021;27(4):928-932
74. Pillai RN, Behera M, Berry LD, et al. HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium. Cancer. 2017;123(21):4099-4105.
75. Wang SE, Narasanna A, Perez-Torres M, et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell. 2006;10(1):25-38.
76. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380
77. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65(5):1642-1646.
78. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(15):9504.
79. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532-2537
80. Herbst RS, Fidler IJ. Angiogenesis and lung cancer: potential for therapy. Clin Cancer Res. 2000;6(12):4604-4606.
81. Meert AP, PaesmansM,Martin B, et al. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2002;87(7):694-701.
82. Ferrara N, GerberHP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669-676
83. Presta LG, Chen H, O’Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593-4599
84. SandlerA,Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550
85. Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J ClinOncol. 2010;28(5):780-787.
86. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for secondline treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673
87. Hall RD, Le TM, Haggstrom DE, Gentzler RD. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2015;4(5):515-523.
88. Paz-Ares L, Hirsh V, Zhang L, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: a phase III, multicenter, placebocontrolled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015;10(12):1745-1753.
89. Baggstrom MQ, Socinski MA, Wang XF, et al. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study-CALGB 30607 (Alliance). J Thorac Oncol. 2017;12(5):843-849.
90. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010;11(7):619-626.
91. Sun Y, Niu W, Du F, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 2016;9(1):105.