Molecular Markers in the Era of Precision Care in Lung Cancer

Ishan Paranjpe; Alexander I. Salter; Kenneth Chen; Millie Das

doi:10.1055/a-2649-9199

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med
DOI: 10.1055/a-2649-9199

Review Article

Molecular Markers in the Era of Precision Care in Lung Cancer

Ishan Paranjpe^*

¹Department of Medicine, Stanford University School of Medicine, Stanford, California

,

Alexander I. Salter^*

²Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California

,

Kenneth Chen^*

²Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California

,

Millie Das

²Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California

³Division of Oncology, Department of Medicine, Veterans Affairs Palo Alto Health System, Palo Alto, California

› Author Affiliations

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. The past two decades have brought advances in molecular profiling and the advent of therapies that specifically target genetic and/or molecular alterations in NSCLC. There are now many FDA-approved targeted therapies for patients with metastatic lung cancer who harbor oncogenic driver alterations, including those in epidermal growth factor receptor, ALK receptor tyrosine kinase, KRAS proto-oncogene, GTPase, and others. These advances epitomize personalized medicine and improve patient outcomes compared with conventional cytotoxic chemotherapy. This review highlights the current and evolving landscape of targeted therapies in NSCLC, emphasizing key targets, resistance mechanisms, and new approaches poised to improve patient outcomes in the era of precision oncology. The next decade will likely be marked by further improvements in the specificity, duration of action, and toxicity profiles of targeted therapies, allowing patients to live longer and better lives.

Keywords

lung cancer - targeted therapy - non-small cell lung cancer - EGFR mutation

Full Text

References

References
1 Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol 2022; 40 (06) 611-625
2 Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer 2019; 19 (09) 495-509
3 Riely GJ, Wood DE, Ettinger DS. et al. Non-small cell lung cancer, version 4.2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2024; 22 (04) 249-274
4 Shi Y, Au JS, Thongprasert S. et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9 (02) 154-162
5 Borgeaud M, Parikh K, Banna GL. et al. Unveiling the landscape of uncommon EGFR mutations in NSCLC- A systematic review. J Thorac Oncol 2024; 19 (07) 973-983
6 Shepherd FA, Rodrigues Pereira J, Ciuleanu T. et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353 (02) 123-132
7 Paez JG, Jänne PA, Lee JC. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304 (5676): 1497-1500
8 Lynch TJ, Bell DW, Sordella R. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350 (21) 2129-2139
9 Yang JC-H, Schuler M, Popat S. et al. Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases. J Thorac Oncol 2020; 15 (05) 803-815
10 Wu Y-L, Cheng Y, Zhou X. et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18 (11) 1454-1466
11 Park K, Tan EH, O'Byrne K. et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016; 17 (05) 577-589
12 Pang LL, Zhuang WT, Huang YH. et al. Uncommon de novo EGFR-Mutant NSCLC characterized with unique genetic features: clinical response and acquired resistance to the third-generation EGFR-TKIs treatment. Lung Cancer 2024; 190: 107528
13 Soria J-C, Ohe Y, Vansteenkiste J. et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378 (02) 113-125
14 Cross DAE, Ashton SE, Ghiorghiu S. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4 (09) 1046-1061
15 Lu S, Dong X, Jian H. et al. AENEAS: A randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR Exon 19 deletion or L858R mutations. J Clin Oncol 2022; 40 (27) 3162-3171
16 Shi Y, Chen G, Wang X. et al; FURLONG investigators. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med 2022; 10 (11) 1019-1028
17 Lu S, Zhou J, Jian H. et al. Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study. Lancet Respir Med 2023; 11 (10) 905-915
18 Cho BC, Ahn MJ, Kang JH. et al. Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced non-small-cell lung cancer: results from LASER301. J Clin Oncol 2023; 41 (26) 4208-4217
19 Ramalingam SS, Vansteenkiste J, Planchard D. et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020; 382 (01) 41-50
20 Anand K, Ensor J, Trachtenberg B, Bernicker EH. Osimertinib-induced cardiotoxicity: a retrospective review of the FDA adverse events reporting system (FAERS). JACC Cardiooncol 2019; 1 (02) 172-178
21 Ohe Y, Kato T, Sakai F. et al. Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan. Jpn J Clin Oncol 2020; 50 (08) 909-919
22 Planchard D, Jänne PA, Cheng Y. et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 2023; 389 (21) 1935-1948
23 Valdiviezo N, Okamoto I, Hughes BGM. et al. 4O First-line (1L) osimertinib (osi) ± platinum-pemetrexed in EGFR-mutated (EGFRm) advanced NSCLC: FLAURA2 post-progression outcomes. ESMO Open 2024; 9: 102583
24 Cho BC, Lu S, Felip E. et al; MARIPOSA Investigators. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med 2024; 391 (16) 1486-1498
25 Yang J. et al. Amivantamab Plus Lazertinib vs Osimertinib in First-line (1L) EGFR-mutant (EGFRm) Advanced NSCLC: Final Overall Survival (OS) from the Phase 3 MARIPOSA Study presented at European Lung Cancer Congress; March 26–29, 2025; Paris, France
26 Cho BC, Wang Y, Felip E. et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2. J Clin Oncol 2024; 42 (16) 8516
27 Felip E, Cho BC, Gutiérrez V. et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol 2024; 42 (16) 8504
28 Gomatou G, Syrigos N, Kotteas E. Osimertinib resistance: molecular mechanisms and emerging treatment options. Cancers (Basel) 2023; 15 (03) 841
29 Passaro A, Wang J, Wang Y. et al; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024; 35 (01) 77-90
30 Zwierenga F, van Veggel B, Hendriks LEL. et al. High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: results from the phase 2 multicenter POSITION20 trial. Lung Cancer 2022; 170: 133-140
31 Park K, Haura EB, Leighl NB. et al. Amivantamab in EGFR Exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol 2021; 39 (30) 3391-3402
32 Zhou C, Tang KJ, Cho BC. et al; PAPILLON Investigators. Amivantamab plus chemotherapy in NSCLC with EGFR Exon 20 insertions. N Engl J Med 2023; 389 (22) 2039-2051
33 Yang JC-H, Doucet L, Wang M. et al. A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study. J Clin Oncol 2024; 42: 8513-8513
34 Piotrowska Z, Tan DS, Smit EF. et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor Exon 20 insertions. J Clin Oncol 2023; 41 (26) 4218-4225
35 Han B, Zhou C, Zheng W. et al. OA03.04 A phase 1b study of furmonertinib, an oral, brain penetrant, selective EGFR inhibitor, in patients with advanced NSCLC with EGFR Exon 20 insertions. J Thorac Oncol 2023; 18: S49
36 Tsuboi M, Herbst RS, John T. et al; ADAURA Investigators. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 2023; 389 (02) 137-147
37 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
38 Desai A, Mohammed T, Rakshit S, Krull J. 21P The landscape of ALK alterations in non-small cell lung cancer. J Thorac Oncol 2021; 16: S707
39 Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011; 17 (08) 2081-2086
40 Shaw AT, Yeap BY, Mino-Kenudson M. et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009; 27 (26) 4247-4253
41 Schneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target. Nat Cancer 2023; 4 (03) 330-343
42 Ou SI, Zhu VW, Nagasaka M. Catalog of 5′ fusion partners in ALK-positive NSCLC circa 2020. JTO Clin Res Rep 2020; 1 (01) 100015
43 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
44 Wu Y-L, Lu S, Lu Y. et al. Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol 2018; 13 (10) 1539-1548
45 Shaw AT, Kim DW, Nakagawa K. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368 (25) 2385-2394
46 Solomon BJ, Mok T, Kim DW. et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371 (23) 2167-2177
47 Solomon BJ, Kim DW, Wu YL. et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol 2018; 36 (22) 2251-2258
48 Kim D-W, Mehra R, Tan DSW. et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016; 17 (04) 452-463
49 Felip E, Orlov S, Park K. et al. Phase 2 study of ceritinib in ALKi-naïve patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC): whole body responses in the overall pt group and in pts with baseline brain metastases (BM). Ann Oncol 2016; 27: vi416
50 Soria J-C, Tan DSW, Chiari R. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017; 389 (10072): 917-929
51 Hotta K, Hida T, Nokihara H. et al. Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer. ESMO Open 2022; 7 (04) 100527
52 Peters S, Camidge DR, Shaw AT. et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017; 377 (09) 829-838
53 Hida T, Nokihara H, Kondo M. et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017; 390 (10089): 29-39
54 Mok T, Camidge DR, Gadgeel SM. et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020; 31 (08) 1056-1064
55 Zhou C, Lu Y, Kim SW. et al. Alectinib versus crizotinib in Asian patients with treatment-naïve advanced ALK-positive NSCLC: Five-year update from the phase 3 ALESIA study. JTO Clin Res Rep 2024; 5 (09) 100700
56 Camidge DR, Kim HR, Ahn MJ. et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018; 379 (21) 2027-2039
57 Camidge DR, Kim HR, Ahn MJ. et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L Trial. J Thorac Oncol 2021; 16 (12) 2091-2108
58 Horn L, Wang Z, Wu G. et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial: a randomized clinical trial. JAMA Oncol 2021; 7 (11) 1617-1625
59 Gadgeel S, Peters S, Mok T. et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018; 29 (11) 2214-2222
60 Solomon BJ, Liu G, Felip E. et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol 2024; 42 (29) 3400-3409
61 Shaw AT, Bauer TM, de Marinis F. et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020; 383 (21) 2018-2029
62 Jia K, Ren S. Neurocognitive adverse events of lorlatinib: on the way to precise prediction?. J Thorac Oncol 2023; 18 (01) 26-28
63 Shaw AT, Solomon BJ, Besse B. et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol 2019; 37 (16) 1370-1379
64 Gainor JF, Dardaei L, Yoda S. et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016; 6 (10) 1118-1133
65 Wu Y-L, Dziadziuszko R, Ahn JS. et al; ALINA Investigators. Alectinib in resected ALK-positive non-small-cell lung cancer. N Engl J Med 2024; 390 (14) 1265-1276
66 Drilon AE. et al. 1253O Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours. Ann Oncol 2024; 35: S802-S803
67 Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511 (7511): 543-550
68 Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther 2021; 6 (01) 386
69 Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013; 503 (7477): 548-551
70 de Langen AJ, Johnson ML, Mazieres J. et al; CodeBreaK 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS^G12C mutation: a randomised, open-label, phase 3 trial. Lancet 2023; 401 (10378): 733-746
71 Mok TSK, Yao W, Duruisseaux M. et al. KRYSTAL-12: phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS^G12C mutation. J Clin Oncol 2024; 42: LBA8509
72 Ijichi H. Targeting mutated KRAS in the first-line therapy. Clin Transl Discov 2024; 4: e291
73 Jänne PA, Bigot F, Papadopoulos K. et al. Abstract PR014: preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment. Mol Cancer Ther 2023; 22: PR014
74 Arbour KC, Punekar S, Garrido-Laguna I. et al. 652O preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Ann Oncol 2023; 34: S458
75 Cregg J, Edwards AV, Chang S. et al. Discovery of daraxonrasib (RMC-6236), a potent and orally bioavailable RAS(ON) multi-selective, noncovalent Tri-complex inhibitor for the treatment of patients with multiple RAS-addicted cancers. J Med Chem 2025; 68 (06) 6064-6083
76 Patnaik A, Pelster M, Hong DS. et al. A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRAS^G12D mutation. J Clin Oncol 2024; 42 (16) TPS3172
77 Engelman JA, Zejnullahu K, Mitsudomi T. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316 (5827): 1039-1043
78 Coleman N, Hong L, Zhang J, Heymach J, Hong D, Le X. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open 2021; 6 (06) 100319
79 Schrock AB, Frampton GM, Suh J. et al. Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations. J Thorac Oncol 2016; 11 (09) 1493-1502
80 Wolf J, Seto T, Han JY. et al; GEOMETRY mono-1 Investigators. Capmatinib in MET Exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med 2020; 383 (10) 944-957
81 Paik PK, Felip E, Veillon R. et al. Tepotinib in non-small-cell lung cancer with MET Exon 14 skipping mutations. N Engl J Med 2020; 383 (10) 931-943
82 Jaiyesimi IA, Leighl NB, Ismaila N. et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, version 2023.3. J Clin Oncol 2024; 42 (11) e1-e22
83 Waqar SN, Redman MW, Arnold SM. et al. A phase II study of telisotuzumab vedotin in patients with c-MET-positive stage IV or recurrent squamous cell lung cancer (LUNG-MAP sub-study S1400K, NCT03574753). Clin Lung Cancer 2021; 22 (03) 170-177
84 DaSilva JO, Yang K, Surriga O. et al. A biparatopic antibody-drug conjugate to treat MET-expressing cancers, including those that are unresponsive to MET pathway blockade. Mol Cancer Ther 2021; 20 (10) 1966-1976
85 Bergethon K, Shaw AT, Ou SH. et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30 (08) 863-870
86 Shaw AT, Ou SH, Bang YJ. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371 (21) 1963-1971
87 Lin JJ, Choudhury NJ, Yoda S. et al. Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion-positive lung cancer. Clin Cancer Res 2021; 27 (10) 2899-2909
88 Chun SG, Choe KS, Iyengar P, Yordy JS, Timmerman RD. Isolated central nervous system progression on crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?. Cancer Biol Ther 2012; 13 (14) 1376-1383
89 Drilon A, Siena S, Dziadziuszko R. et al; trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020; 21 (02) 261-270
90 Drilon A, Chiu CH, Fan Y. et al. Long-term efficacy and safety of entrectinib in ROS1 fusion-positive NSCLC. JTO Clin Res Rep 2022; 3 (06) 100332
91 Dingemans A-MC, Griesinger F, Paz-Ares L. et al. A randomized phase 3 study of entrectinib versus crizotinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC with or without baseline CNS metastases (mets). J Clin Oncol 2022; 40: TPS9141-TPS9141
92 Drilon A, Camidge DR, Lin JJ. et al; TRIDENT-1 Investigators. Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer. N Engl J Med 2024; 390 (02) 118-131
93 Pérol M, Li W, Pennell NA. et al. 1289P Pooled efficacy and safety from 2 pivotal phase II trials of taletrectinib in patients (Pts) with advanced or metastatic ROS1+ non-small cell lung cancer (NSCLC). Ann Oncol 2024; 35: S821
94 Drilon A, Horan JC, Tangpeerachaikul A. et al. NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations. Cancer Discov 2023; 13 (03) 598-615
95 Besse B, Drilon AE, Cho BC. et al. 1256MO Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours. Ann Oncol 2024; 35: S804-S805
96 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
97 Xia L, Yu Y, Lan F. et al. Case report: tumor microenvironment characteristics in a patient with HER2 mutant lung squamous cell carcinoma harboring high PD-L1 expression who presented hyperprogressive disease. Front Oncol 2021; 11: 760703
98 Gao Y, Zheng A, Zhu X, Song J, Xue Q. Clinical benefit from afatinib in an advanced squamous cell lung carcinoma patient harboring HER2 S310Y mutation: a case report. OncoTargets Ther 2018; 11: 8705-8710
99 Yu X, Ji X, Su C. HER2-altered non-small cell lung cancer: biology, clinicopathologic features, and emerging therapies. Front Oncol 2022; 12: 860313
100 Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open 2021; 6 (05) 100260
101 Li BT, Smit EF, Goto Y. et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 2022; 386 (03) 241-251
102 Goto K, Goto Y, Kubo T. et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol 2023; 41 (31) 4852-4863
103 Janne PA. et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): final analysis results of DESTINY-Lung02. J Clin Oncol 2024; 42: 8543
104 Li BT, Planchard D, Goto K. et al. 1321MO trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic non–small cell lung cancer (NSCLC) with and without brain metastases (BMs): pooled analyses from DESTINY-Lung01 and DESTINY-Lung02. Ann Oncol 2023; 34: S762-S763
105 Smit EF, Felip E, Uprety D. et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol 2024; 25 (04) 439-454
106 Center for Drug Evaluation & Research. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. U.S. Food and Drug Administration. (2024). Accessed July 10, 2025 at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
107 Meric-Bernstam F, Makker V, Oaknin A. et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 2024; 42 (01) 47-58
108 Yoshino T, Di Bartolomeo M, Raghav K. et al; DESTINY-CRC01 investigators. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun 2023; 14 (01) 3332
109 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
110 Iwama E, Zenke Y, Sugawara S. et al. Trastuzumab emtansine for patients with non-small cell lung cancer positive for human epidermal growth factor receptor 2 exon-20 insertion mutations. Eur J Cancer 2022; 162: 99-106
111 Thavaneswaran S, Lin F, Grady JP. et al. A signal-seeking phase 2 study of trastuzumab emtansine in tumours harbouring HER2 amplification or mutation. NPJ Precis Oncol 2024; 8 (01) 195
112 Jhaveri KL, Wang XV, Makker V. et al. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q. Ann Oncol 2019; 30 (11) 1821-1830
113 Sweeney CJ, Hainsworth JD, Bose R. et al. MyPathway human epidermal growth factor receptor 2 basket study: pertuzumab + trastuzumab treatment of a tissue-agnostic cohort of patients with human epidermal growth factor receptor 2-altered advanced solid tumors. J Clin Oncol 2024; 42 (03) 258-265
114 Mazieres J, Lafitte C, Ricordel C. et al. Combination of trastuzumab, pertuzumab, and docetaxel in patients with advanced non-small-cell lung cancer harboring HER2 mutations: results from the IFCT-1703 R2D2 trial. J Clin Oncol 2022; 40 (07) 719-728
115 Kris MG, Camidge DR, Giaccone G. et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol 2015; 26 (07) 1421-1427
116 Li B, Gandhi L, Besse B. et al. FP14.15 neratinib-based combination therapy in HER2-mutant lung adenocarcinomas: findings from two international phase 2 studies. J Thorac Oncol 2021; 16: S234
117 Dziadziuszko R, Smit EF, Dafni U. et al. Afatinib in NSCLC with HER2 mutations: results of the prospective, open-label phase II NICHE trial of European thoracic oncology platform (ETOP). J Thorac Oncol 2019; 14 (06) 1086-1094
118 Fan Y, Chen J, Zhou C. et al. Afatinib in patients with advanced non-small cell lung cancer harboring HER2 mutations, previously treated with chemotherapy: a phase II trial. Lung Cancer 2020; 147: 209-213
119 Zhou C, Li X, Wang Q. et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm, phase II study. J Clin Oncol 2020; 38 (24) 2753-2761
120 Gao G, Li X, Wang Q. et al. Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation. J Clin Oncol 2019; 37: 9089
121 Wang Y, Jiang T, Qin Z. et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol 2019; 30 (03) 447-455
122 Liu SM, Tu HY, Wei XW. et al. First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial. Nat Med 2023; 29 (08) 2079-2086
123 Huang Y, Zhao Y, Huang Y. et al. Phase 1b trial of anti-HER2 antibody inetetamab and pan-HER inhibitor pyrotinib in HER2-positive advanced lung cancer. MedComm 2024; 5 (05) e536
124 Cornelissen R, Prelaj A, Sun S. et al. Poziotinib in treatment-naïve non-small-cell lung cancer harboring HER2 Exon 20 mutations: ZENITH20–4, a multicenter, multicohort, open-label phase 2 trial (cohort 4). J Thorac Oncol 2023; 18 (08) 1031-1041
125 Socinski MA, Cornelissen R, Garassino MC. et al. LBA60 ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Ann Oncol 2020; 31: S1188
126 Prelaj A, Bottiglieri A, Proto C. et al. Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: results from the expanded access program. Eur J Cancer 2021; 149: 235-248
127 Elamin YY, Robichaux JP, Carter BW. et al. Poziotinib for patients with HER2 Exon 20 mutant non-small-cell lung cancer: results from a phase II trial. J Clin Oncol 2022; 40 (07) 702-709
128 Jiang W, Yang Y, Yang G, Xu H, Wang Y. 1297P A phase II study of pyrotinib combined with apatinib in first-line treatment of advanced non-small cell lung cancer patients with primary HER-2 mutations/amplification. Ann Oncol 2024; 35: S826
129 Heymach JV, Opdam F, Barve M. et al. HER2-selective tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with advanced/metastatic solid tumors with HER2 alterations: a phase Ia dose-escalation study. J Clin Oncol 2025; 43 (11) 1337-1347
130 Johnson ML, Soo RA, Wu Y-L. et al. Beamion LUNG-2: a phase III randomized controlled trial of zongertinib (BI 1810631) versus standard of care (SoC) in patients with locally advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) mutations. J Clin Oncol 2024; 42 (16) TPS8654
131 Le X, Girard N, Jänne PA. et al. PL04.03 safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: expansion cohort from the phase I/II SOHO-01 study. J Thorac Oncol 2024; 19: S4
132 Goto K, Brase JC, Xu J. et al. EP.12H.08 SOHO-02: phase III trial of BAY 2927088 in patients with locally advanced or metastatic NSCLC with HER2-activating mutations. J Thorac Oncol 2024; 19: S660
133 Sheikine Y, Pavlick D, Klempner SJ. et al. BRAF in lung cancers: analysis of patient cases reveals recurrent BRAF mutations, fusions, kinase duplications, and concurrent alterations. JCO Precis Oncol 2018; 2: 00172
134 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
135 Planchard D, Sanborn RE, Negrao MV, Vaishnavi A, Smit EF. BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape. NPJ Precis Oncol 2024; 8: 1-13
136 Planchard D, Besse B, Groen HJM. et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: Updated 5-year survival rates and genomic analysis. J Thorac Oncol 2022; 17 (01) 103-115
137 Planchard D, Smit EF, Groen HJM. et al. Dabrafenib plus trametinib in patients with previously untreated BRAF^V600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017; 18 (10) 1307-1316
138 Riely GJ, Ahn M-J, Clarke J. et al. LBA56 updated efficacy and safety from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). Ann Oncol 2024; 35: S1246-S1247
139 Planchard D, Mazieres J, Mascaux C. et al. 1259MO encorafenib plus binimetinib in patients (pts) with previously untreated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): an open-label, multicenter phase II trial (IFCT-1904 ENCO-BRAF). Ann Oncol 2024; 35: S806-S807
140 Swalduz A, Beau-Faller M, Planchard D. et al. Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): results from the IFCT-2004 BLaDE cohort. Lung Cancer 2025; 199: 108038
141 Heinzerling L, Eigentler TK, Fluck M. et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open 2019; 4 (03) e000491
142 Lazar R, Fischbach C, Schott R, Somme L. Outcomes of non-small cell lung cancer patients with non-V600E BRAF mutations: a series of case reports and literature review. Front Oncol 2024; 14: 1307882
143 Dagogo-Jack I, Martinez P, Yeap BY. et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res 2019; 25 (01) 158-165
144 ClinicalTrials.gov. Accessed July 10, 2025 at: https://clinicaltrials.gov/study/NCT06563999
145 ClinicalTrials.gov. Accessed July 10, 2025 at: https://clinicaltrials.gov/study/NCT04302025
146 Subbiah V, Baik C, Kirkwood JM. Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer 2020; 6 (09) 797-810
147 Su F, Viros A, Milagre C. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366 (03) 207-215
148 Novello S, Califano R, Reinmuth N, Tamma A, Puri T. RET fusion-positive non-small cell lung cancer: the evolving treatment landscape. Oncologist 2023; 28 (05) 402-413
149 Drilon A, Lin JJ, Filleron T. et al. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol 2018; 13 (10) 1595-1601
150 Gautschi O, Milia J, Filleron T. et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017; 35 (13) 1403-1410
151 Drilon A, Rekhtman N, Arcila 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 (12) 1653-1660
152 Lee S-H, Lee JK, Ahn MJ. 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 (02) 292-297
153 Drilon A, Oxnard GR, Tan DSW. et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 2020; 383 (09) 813-824
154 Gainor JF, Curigliano G, Kim DW. et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 2021; 22 (07) 959-969
155 Zhou C, Solomon B, Loong HH. et al; LIBRETTO-431 Trial Investigators. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med 2023; 389 (20) 1839-1850
156 Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15 (12) 731-747
157 Drilon A, Siena S, Ou SI. 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 (04) 400-409
158 Paz-Ares L, Doebele RC, Farago AF. et al. Entrectinib in NTRK fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of patients (pts) enrolled in STARTRK-2, STARTRK-1 and ALKA-372–001. Ann Oncol 2019; 30 (Suppl. 02) ii48-ii49
159 Drilon A, Laetsch TW, Kummar S. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018; 378 (08) 731-739
160 Solomon BJ, Drilon A, Lin JJ. et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I/II TRIDENT-1 trial. Ann Oncol 2023; 34: S787-S788
161 Gupta B, Wu S, Ou S-H I. et al. NRG1 fusions in solid tumors. J Clin Oncol 2023; 41: 3132-3132
162 Nagasaka M, Ou SI. NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis. Trends Cancer 2022; 8 (03) 242-258
163 Benayed R, Offin M, Mullaney K. et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res 2019; 25 (15) 4712-4722
164 Drilon A, Duruisseaux M, Han JY. et al. Clinicopathologic features and response to therapy of NRG1 fusion-driven lung cancers: The eNRGy1 global multicenter registry. J Clin Oncol 2021; 39 (25) 2791-2802
165 Geuijen CAW, De Nardis C, Maussang D. et al. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. Cancer Cell 2021; 39 (08) 1163-1164
166 Schram AM, Goto K, Kim DW. et al; eNRGy Investigators. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Engl J Med 2025; 392 (06) 566-576