Targeted Therapy in NSCLC: A Comprehensive Review of Molecular Drivers and Treatment Strategies

Valeryia Milasheuskaya; Katsiaryna Miraniuk; Mykola Sobchynskyi; Andrii Myrnyi; Dmytro Kowalczuk; Viktoryia Kasianik; Darya Lazitskaya; Kamil Turlej; Iga Kiełbaszewska; Natalia Surosz; Dawid Wiczkowski

doi:10.12775/QS.2025.43.61191

Authors

Valeryia Milasheuskaya Wroclaw Medical University https://orcid.org/0009-0006-4126-2375
Katsiaryna Miraniuk https://orcid.org/0009-0006-1406-9756
Mykola Sobchynskyi https://orcid.org/0009-0008-1804-1114
Andrii Myrnyi https://orcid.org/0009-0006-5592-259X
Dmytro Kowalczuk https://orcid.org/0009-0004-1433-5052
Viktoryia Kasianik https://orcid.org/0009-0004-1540-5227
Darya Lazitskaya https://orcid.org/0009-0007-8680-8826
Kamil Turlej https://orcid.org/0009-0008-2919-284X
Iga Kiełbaszewska https://orcid.org/0009-0004-9892-4769
Natalia Surosz https://orcid.org/0009-0005-1939-151X
Dawid Wiczkowski https://orcid.org/0009-0004-7050-9598

DOI:

https://doi.org/10.12775/QS.2025.43.61191

Keywords

non-small cell lung carcinoma, molecular targeted therapy, tyrosine kinase inhibitors, gene expression profiling

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with its management increasingly guided by molecular profiling and targeted therapies. This review comprehensively examines current treatment standards for NSCLC, focusing on the evolving landscape of targeted therapies tailored to specific oncogenic driver mutations, including EGFR, ALK, ROS1, MET, KRAS, RET, BRAF, NTRK, and HER2. We highlight the efficacy, resistance mechanisms, and clinical trial outcomes of tyrosine kinase inhibitors (TKI) and other targeted agents, emphasizing their impact on progression-free survival (PFS) and overall survival (OS). The integration of these therapies into clinical practice has transformed patient outcomes, particularly in advanced-stage disease. However, challenges such as acquired resistance and toxicity profiles necessitate ongoing research into combination strategies and next-generation inhibitors. This work underscores the importance of precision medicine in NSCLC and outlines future directions for optimizing therapeutic approaches.

References

[1] T. S. Mok et al., “Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma,” New England Journal of Medicine, vol. 361, no. 10, pp. 947–957, Sep. 2009, doi: 10.1056/NEJMOA0810699/SUPPL_FILE/NEJM_MOK_947SA1.PDF.

[2] T. Mitsudomi et al., “Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial,” Lancet Oncol, vol. 11, no. 2, pp. 121–128, Feb. 2010, doi: 10.1016/S1470-2045(09)70364-X.

[3] J. Y. Han et al., “First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung,” Journal of Clinical Oncology, vol. 30, no. 10, pp. 1122–1128, Apr. 2012, doi: 10.1200/JCO.2011.36.8456/SUPPL_FILE/368456.PDF.

[4] W. Z. Zhong et al., “Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial,” J Clin Oncol, vol. 39, no. 7, pp. 713–722, Mar. 2021, doi: 10.1200/JCO.20.01820.

[5] C. Zhou et al., “Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802),” Annals of Oncology, vol. 26, no. 9, pp. 1877–1883, Sep. 2015, doi: 10.1093/annonc/mdv276.

[6] R. Rosell 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, vol. 13, no. 3, pp. 239–246, Mar. 2012, doi: 10.1016/S1470-2045(11)70393-X.

[7] Y. K. Shi et al., “First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study,” Ann Oncol, vol. 28, no. 10, pp. 2443–2450, Oct. 2017, doi: 10.1093/ANNONC/MDX359.

[8] L. V. Sequist et al., “Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations,” J Clin Oncol, vol. 31, no. 27, pp. 3327–3334, Sep. 2013, doi: 10.1200/JCO.2012.44.2806.

[9] Y. L. Wu 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, vol. 15, no. 2, pp. 213–222, Feb. 2014, doi: 10.1016/S1470-2045(13)70604-1.

[10] K. Park 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, vol. 17, no. 5, pp. 577–589, May 2016, doi: 10.1016/S1470-2045(16)30033-X.

[11] J. C. Soria et al., “Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial,” Lancet Oncol, vol. 16, no. 8, pp. 897–907, Aug. 2015, doi: 10.1016/S1470-2045(15)00006-6.

[12] P. M. Ellis et al., “Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): A double-blind, randomised, phase 3 trial,” Lancet Oncol, vol. 15, no. 12, pp. 1379–1388, Nov. 2014, doi: 10.1016/S1470-2045(14)70472-3.

[13] S. S. Ramalingam et al., “Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 30, no. 27, pp. 3337–3344, Sep. 2012, doi: 10.1200/JCO.2011.40.9433/ASSET/70670538-1DC0-4E9D-954F-623D59FD4C34/ASSETS/GRAPHIC/ZLJ9991024750006.JPEG.

[14] S. S. Ramalingam et al., “Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): A randomised, double-blind, phase 3 trial,” Lancet Oncol, vol. 15, no. 12, pp. 1369–1378, Nov. 2014, doi: 10.1016/S1470-2045(14)70452-8.

[15] Y. L. Wu 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, vol. 18, no. 11, pp. 1454–1466, Nov. 2017, doi: 10.1016/S1470-2045(17)30608-3.

[16] V. A. Papadimitrakopoulou et al., “Osimertinib versus platinum–pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis,” Annals of Oncology, vol. 31, no. 11, pp. 1536–1544, Nov. 2020, doi: 10.1016/j.annonc.2020.08.2100.

[17] J.-C. Soria et al., “ Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer ,” New England Journal of Medicine, vol. 378, no. 2, pp. 113–125, Jan. 2018, doi: 10.1056/NEJMOA1713137/SUPPL_FILE/NEJMOA1713137_DISCLOSURES.PDF.

[18] S. S. Ramalingam et al., “ Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC ,” New England Journal of Medicine, vol. 382, no. 1, pp. 41–50, Jan. 2020, doi: 10.1056/NEJMOA1913662/SUPPL_FILE/NEJMOA1913662_DATA-SHARING.PDF.

[19] K. S. Thress et al., “Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M HHS Public Access Author manuscript,” Nat Med, vol. 21, no. 6, pp. 560–562, 2015, doi: 10.1038/nm.3854.

[20] C. Zhou et al., “Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial,” JAMA Oncol, vol. 7, no. 12, pp. 1772–1781, Dec. 2021, doi: 10.1001/JAMAONCOL.2021.4761.

[21] P. A. Jänne et al., “507O EXCLAIM-2: Phase III trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC,” Annals of Oncology, vol. 34, pp. S1663–S1664, Nov. 2023, doi: 10.1016/j.annonc.2023.10.586.

[22] N. Girard et al., “LBA5 Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): Primary results from PAPILLON, a randomized phase III global study,” Annals of Oncology, vol. 34, p. S1304, Oct. 2023, doi: 10.1016/j.annonc.2023.10.060.

[23] K. Park 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,” Journal of Clinical Oncology, vol. 39, no. 30, p. 3391, Oct. 2021, doi: 10.1200/JCO.21.00662.

[24] Y. Y. Elamin et al., “Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity,” Cancer Cell, vol. 40, no. 7, pp. 754-767.e6, Jul. 2022, doi: 10.1016/J.CCELL.2022.06.006.

[25] X. Le et al., “Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial,” Journal of Clinical Oncology, vol. 40, no. 7, pp. 710–718, Mar. 2022, doi: 10.1200/JCO.21.01323/SUPPL_FILE/PROTOCOL_JCO.21.01323.PDF.

[26] S. Sun et al., “26MO Efficacy and safety of poziotinib in treatment-naïve HER2 exon 20 insertion (ex20ins) mutated non-small cell lung cancer (NSCLC): ZENITH20-4,” Annals of Oncology, vol. 33, p. S13, Mar. 2022, doi: 10.1016/j.annonc.2022.01.035.

[27] Y. Xu et al., “Efficacy and safety of sunvozertinib in treatment naïve NSCLC patients with EGFR exon20 insertion mutations.,” Journal of Clinical Oncology, vol. 41, no. 16_suppl, pp. 9073–9073, Jun. 2023, doi: 10.1200/JCO.2023.41.16_SUPPL.9073.

[28] M. Wang et al., “Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial,” Lancet Respir Med, vol. 12, no. 3, pp. 217–224, Mar. 2024, doi: 10.1016/S2213-2600(23)00379-X.

[29] B. Han 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,” Journal of Thoracic Oncology, vol. 18, no. 11, p. S49, Nov. 2023, doi: 10.1016/j.jtho.2023.09.033.

[30] H. Yasuda et al., “A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer,” Lung Cancer, vol. 162, pp. 140–146, Dec. 2021, doi: 10.1016/J.LUNGCAN.2021.10.006.

[31] A. B. Cortot et al., “First-Line Afatinib plus Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study,” Clin Cancer Res, vol. 27, no. 15, pp. 4168–4176, Aug. 2021, doi: 10.1158/1078-0432.CCR-20-4604.

[32] C. Aggarwal and S. V. Liu, “Zipalertinib in EGFR Exon 20-Mutant Non-Small-Cell Lung Cancer: Drug Development in a Rare but Crowded Setting,” Journal of Clinical Oncology, vol. 41, no. 26, pp. 4200–4203, Sep. 2023, doi: 10.1200/JCO.23.00958/ASSET/01C1E80E-AA63-4BBB-B6AB-5773941C756F/ASSETS/IMAGES/LARGE/JCO.23.00958T1.JPG.

[33] J. Guan et al., “FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase,” Elife, vol. 4, no. September 2015, Sep. 2015, doi: 10.7554/ELIFE.09811.

[34] A. Addeo, F. Tabbò, T. Robinson, L. Buffoni, and S. Novello, “Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario,” Crit Rev Oncol Hematol, vol. 122, pp. 150–156, Feb. 2018, doi: 10.1016/J.CRITREVONC.2017.12.015.

[35] A. Friedlaender, G. Banna, S. Patel, and A. Addeo, “Diagnosis and Treatment of ALK Aberrations in Metastatic NSCLC,” Curr Treat Options Oncol, vol. 20, no. 10, pp. 1–17, Oct. 2019, doi: 10.1007/S11864-019-0675-9/METRICS.

[36] B. J. Solomon et al., “ First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer ,” New England Journal of Medicine, vol. 371, no. 23, pp. 2167–2177, Dec. 2014, doi: 10.1056/NEJMOA1408440/SUPPL_FILE/NEJMOA1408440_DISCLOSURES.PDF.

[37] B. J. Solomon et al., “Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in alk-mutation-positive non–small-cell lung cancer,” Journal of Clinical Oncology, vol. 36, no. 22, pp. 2251–2258, Aug. 2018, doi: 10.1200/JCO.2017.77.4794/ASSET/654FB27C-4D49-47B6-9389-381E1F17B14E/ASSETS/IMAGES/LARGE/JCO.2017.77.4794TA1.JPG.

[38] S.-H. Ignatius Ou et al., “JOURNAL OF CLINICAL ONCOLOGY Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study,” J Clin Oncol, vol. 34, pp. 661–668, 2015, doi: 10.1200/JCO.2015.63.9443.

[39] D. W. Kim et al., “Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial,” Journal of Clinical Oncology, vol. 35, no. 22, pp. 2490–2498, Aug. 2017, doi: 10.1200/JCO.2016.71.5904/SUPPL_FILE/PROTOCOL_2016.715904.PDF.

[40] D. W. Kim 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, vol. 17, no. 4, pp. 452–463, Apr. 2016, doi: 10.1016/S1470-2045(15)00614-2.

[41] S. Peters et al., “ Alectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer ,” New England Journal of Medicine, vol. 377, no. 9, pp. 829–838, Aug. 2017, doi: 10.1056/NEJMOA1704795/SUPPL_FILE/NEJMOA1704795_DISCLOSURES.PDF.

[42] J. C. Soria 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,” The Lancet, vol. 389, no. 10072, pp. 917–929, Mar. 2017, doi: 10.1016/S0140-6736(17)30123-X.

[43] A. T. Shaw et al., “Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial,” Lancet Oncol, vol. 18, no. 7, pp. 874–886, Jul. 2017, doi: 10.1016/S1470-2045(17)30339-X.

[44] E. Felip et al., “Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study,” J Thorac Oncol, vol. 15, no. 3, pp. 392–403, Mar. 2020, doi: 10.1016/J.JTHO.2019.10.006.

[45] M. S. Lara et al., “Phase 1 Study of Ceritinib Combined With Trametinib in Patients With Advanced ALK- or ROS1-Positive NSCLC,” JTO Clin Res Rep, vol. 3, no. 12, Dec. 2022, doi: 10.1016/J.JTOCRR.2022.100436.

[46] D. R. Camidge et al., “Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial,” Journal of Thoracic Oncology, vol. 16, no. 12, pp. 2091–2108, Dec. 2021, doi: 10.1016/J.JTHO.2021.07.035.

[47] J. J. Lin et al., “Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors,” Journal of Thoracic Oncology, vol. 15, no. 2, pp. 258–265, Feb. 2020, doi: 10.1016/J.JTHO.2019.10.014.

[48] B. J. Solomon et al., “Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study,” Lancet Respir Med, vol. 11, no. 4, pp. 354–366, Apr. 2023, doi: 10.1016/S2213-2600(22)00437-4.

[49] A. T. Shaw et al., “ First-Line Lorlatinib or Crizotinib in Advanced ALK -Positive Lung Cancer ,” New England Journal of Medicine, vol. 383, no. 21, pp. 2018–2029, Nov. 2020, doi: 10.1056/NEJMOA2027187/SUPPL_FILE/NEJMOA2027187_DATA-SHARING.PDF.

[50] B. J. Solomon et al., “Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study,” J Clin Oncol, vol. 40, pp. 3593–3602, 2022, Accessed: Apr. 16, 2025. [Online]. Available: https://doi.org/10.

[51] L. Horn et al., “MINI01.02: Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (pts) with ALK+ NSCLC,” Journal of Thoracic Oncology, vol. 11, no. 11, pp. S256–S257, Nov. 2016, doi: 10.1016/j.jtho.2016.09.017.

[52] Y. Ma et al., “First-in-human phase I study of TQ-B3139 (CT-711) in advanced non-small cell lung cancer patients with ALK and ROS1 rearrangements,” Eur J Cancer, vol. 173, pp. 238–249, Sep. 2022, doi: 10.1016/J.EJCA.2022.06.037.

[53] A. T. Shaw et al., “ Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F ,” New England Journal of Medicine, vol. 374, no. 1, pp. 54–61, Jan. 2016, doi: 10.1056/NEJMOA1508887/SUPPL_FILE/NEJMOA1508887_DISCLOSURES.PDF.

[54] J. F. Gainor et al., “Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer,” Cancer Discov, vol. 6, no. 10, pp. 1118–1133, Oct. 2016, doi: 10.1158/2159-8290.CD-16-0596.

[55] J. J. Lin, G. J. Riely, and A. T. Shaw, “Targeting ALK: Precision Medicine Takes on Drug Resistance,” Cancer Discov, vol. 7, no. 2, pp. 137–155, Feb. 2017, doi: 10.1158/2159-8290.CD-16-1123.

[56] B. J. Solomon et al., “Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study,” Lancet Oncol, vol. 19, no. 12, pp. 1654–1667, Dec. 2018, doi: 10.1016/S1470-2045(18)30649-1.

[57] J. J. Lin et al., “Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC,” J Thorac Oncol, vol. 13, no. 10, pp. 1530–1538, Oct. 2018, doi: 10.1016/J.JTHO.2018.06.005.

[58] S. H. I. Ou et al., “Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study,” J Clin Oncol, vol. 34, no. 7, pp. 661–668, Mar. 2016, doi: 10.1200/JCO.2015.63.9443.

[59] J. J. Lin et al., “ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer,” Journal of Thoracic Oncology, vol. 12, no. 5, pp. 872–877, May 2017, doi: 10.1016/J.JTHO.2017.01.004.

[60] S. H. I. Ou and V. W. Zhu, “Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020,” JTO Clin Res Rep, vol. 1, no. 2, p. 100037, Jun. 2020, doi: 10.1016/J.JTOCRR.2020.100037.

[61] T. Patil et al., “The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non–Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib,” Journal of Thoracic Oncology, vol. 13, no. 11, pp. 1717–1726, Nov. 2018, doi: 10.1016/J.JTHO.2018.07.001.

[62] A. T. Shaw et al., “ Crizotinib in ROS1 -Rearranged Non–Small-Cell Lung Cancer ,” New England Journal of Medicine, vol. 371, no. 21, pp. 1963–1971, Nov. 2014, doi: 10.1056/NEJMOA1406766/SUPPL_FILE/NEJMOA1406766_DISCLOSURES.PDF.

[63] A. T. Shaw et al., “Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001,” Annals of Oncology, vol. 30, no. 7, pp. 1121–1126, Jul. 2019, doi: 10.1093/ANNONC/MDZ131.

[64] A. Drilon et al., “Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials,” Lancet Oncol, vol. 21, no. 2, pp. 261–270, Feb. 2020, doi: 10.1016/S1470-2045(19)30690-4.

[65] A. T. Shaw et al., “Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1–2 trial,” Lancet Oncol, vol. 20, no. 12, pp. 1691–1701, Dec. 2019, doi: 10.1016/S1470-2045(19)30655-2.

[66] B. C. Cho et al., “Open-label, multicenter, phase II Study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement,” Journal of Clinical Oncology, vol. 35, no. 23, pp. 2613–2618, Aug. 2017, doi: 10.1200/JCO.2016.71.3701/ASSET/01878D7D-5391-4357-8DDE-E62FDAC3FC99/ASSETS/IMAGES/LARGE/JCO.2016.71.3701TA8.JPG.

[67] M. R. Yun et al., “Repotrectinib exhibits potent antitumor activity in treatment-naïve and solvent-front-mutant ROS1-rearranged non-small cell lung cancer,” Clinical Cancer Research, vol. 26, no. 13, pp. 3287–3295, Jul. 2020, doi: 10.1158/1078-0432.CCR-19-2777/358848/P/REPOTRECTINIB-EXHIBITS-POTENT-ANTITUMOR-ACTIVITY.

[68] R. C. Doebele et al., “TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.,” Journal of Clinical Oncology, vol. 38, no. 15_suppl, pp. TPS9637–TPS9637, May 2020, doi: 10.1200/JCO.2020.38.15_SUPPL.TPS9637.

[69] J. Watanabe, N. Furuya, and Y. Fujiwara, “Appearance of a BRAF Mutation Conferring Resistance to Crizotinib in Non–Small Cell Lung Cancer Harboring Oncogenic ROS1 Fusion,” Journal of Thoracic Oncology, vol. 13, no. 4, pp. e66–e69, Apr. 2018, doi: 10.1016/j.jtho.2017.11.125.

[70] J. J. Lin et al., “Resistance to lorlatinib in ROS1 fusion-positive non-small cell lung cancer.,” Journal of Clinical Oncology, vol. 38, no. 15_suppl, pp. 9611–9611, May 2020, doi: 10.1200/JCO.2020.38.15_SUPPL.9611.

[71] J. Remon et al., “MET alterations in NSCLC—Current Perspectives and Future Challenges,” Journal of Thoracic Oncology, vol. 18, no. 4, pp. 419–435, Apr. 2023, doi: 10.1016/J.JTHO.2022.10.015/ATTACHMENT/0E76C4D4-A8A3-4690-BBEF-4C732117809C/MMC1.DOCX.

[72] J. Wolf et al., “Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial,” Lancet Oncol, vol. 25, no. 10, pp. 1357–1370, Oct. 2024, doi: 10.1016/S1470-2045(24)00441-8.

[73] P. K. Paik et al., “ Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations ,” New England Journal of Medicine, vol. 383, no. 10, pp. 931–943, Sep. 2020, doi: 10.1056/NEJMOA2004407/SUPPL_FILE/NEJMOA2004407_DATA-SHARING.PDF.

[74] S. Lu et al., “Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).,” Journal of Clinical Oncology, vol. 38, no. 15_suppl, pp. 9519–9519, May 2020, doi: 10.1200/JCO.2020.38.15_SUPPL.9519.

[75] A. Drilon et al., “Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration,” Nature Medicine 2020 26:1, vol. 26, no. 1, pp. 47–51, Jan. 2020, doi: 10.1038/s41591-019-0716-8.

[76] L. Landi et al., “Crizotinib in MET-deregulated or ROS1-rearranged pretreated non–small cell lung cancer (METROS): A phase II, prospective, multicenter, two-arms trial,” Clinical Cancer Research, vol. 25, no. 24, pp. 7312–7319, Dec. 2019, doi: 10.1158/1078-0432.CCR-19-0994/74330/AM/CRIZOTINIB-IN-MET-DEREGULATED-OR-ROS1-REARRANGED.

[77] D. Moro-Sibilot et al., “Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial,” Annals of Oncology, vol. 30, no. 12, pp. 1985–1991, Dec. 2019, doi: 10.1093/ANNONC/MDZ407.

[78] D. R. Camidge et al., “Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).,” Journal of Clinical Oncology, vol. 38, no. 15_suppl, pp. 9510–9510, May 2020, doi: 10.1200/JCO.2020.38.15_SUPPL.9510.

[79] A. E. Drilon et al., “A phase 1/2 study of REGN5093-M114, a METxMET antibody-drug conjugate, in patients with mesenchymal epithelial transition factor (MET)-overexpressing NSCLC.,” Journal of Clinical Oncology, vol. 40, no. 16_suppl, pp. TPS8593–TPS8593, Jun. 2022, doi: 10.1200/JCO.2022.40.16_SUPPL.TPS8593.

[80] “Elzovantinib (TPX-0022) | Available Agents | NCI Formulary.” Accessed: May 03, 2025. [Online]. Available: https://nciformulary.cancer.gov/available_agents/Elzovantinib.htm

[81] G. Recondo et al., “Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC,” Clin Cancer Res, vol. 26, no. 11, pp. 2615–2625, Jun. 2020, doi: 10.1158/1078-0432.CCR-19-3608.

[82] J. Rotow and T. G. Bivona, “Understanding and targeting resistance mechanisms in NSCLC,” Nat Rev Cancer, vol. 17, no. 11, pp. 637–658, 2017, doi: 10.1038/NRC.2017.84.

[83] G. Recondo et al., “Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC,” Clin Cancer Res, vol. 26, no. 11, pp. 2615–2625, Jun. 2020, doi: 10.1158/1078-0432.CCR-19-3608.

[84] T. K. H. Lim et al., “KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing,” Lung Cancer, vol. 184, Oct. 2023, doi: 10.1016/J.LUNGCAN.2023.107293/ATTACHMENT/21EC0143-3DF6-4BB3-8DFF-47EFBF3B90B6/MMC1.PDF.

[85] F. Skoulidis et al., “ Sotorasib for Lung Cancers with KRAS p.G12C Mutation ,” New England Journal of Medicine, vol. 384, no. 25, pp. 2371–2381, Jun. 2021, doi: 10.1056/NEJMOA2103695/SUPPL_FILE/NEJMOA2103695_DATA-SHARING.PDF.

[86] A. J. de Langen et al., “Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial,” The Lancet, vol. 401, no. 10378, pp. 733–746, Mar. 2023, doi: 10.1016/S0140-6736(23)00221-0.

[87] S. Pant et al., “KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation.,” Journal of Clinical Oncology, vol. 41, no. 36_suppl, pp. 425082–425082, Apr. 2023, doi: 10.1200/JCO.2023.41.36_SUPPL.425082.

[88] M. C. Garassino et al., “1394TiP KRYSTAL-7: A phase III study of first-line adagrasib plus pembrolizumab versus pembrolizumab alone in patients with advanced NSCLC with KRASG12C mutation,” Annals of Oncology, vol. 35, pp. S872–S873, Sep. 2024, doi: 10.1016/J.ANNONC.2024.08.1449.

[89] T. S. K. Mok 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 KRASG12C mutation.,” Journal of Clinical Oncology, vol. 42, no. 17_suppl, pp. LBA8509–LBA8509, Jun. 2024, doi: 10.1200/JCO.2024.42.17_SUPPL.LBA8509.

[90] T. Koga et al., “KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments,” Journal of Thoracic Oncology, vol. 16, no. 8, pp. 1321–1332, Aug. 2021, doi: 10.1016/j.jtho.2021.04.015.

[91] M. B. Ryan et al., “KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy,” Cell Rep, vol. 39, no. 12, p. 110993, Jun. 2022, doi: 10.1016/J.CELREP.2022.110993.

[92] Y. Adachi et al., “Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer,” Clinical Cancer Research, vol. 26, no. 22, pp. 5962–5973, Nov. 2020, doi: 10.1158/1078-0432.CCR-20-2077/77536/AM/EPITHELIAL-TO-MESENCHYMAL-TRANSITION-IS-A-CAUSE-OF.

[93] R. Ferrara, N. Auger, E. Auclin, and B. Besse, “Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer,” Journal of Thoracic Oncology, vol. 13, no. 1, pp. 27–45, Jan. 2018, doi: 10.1016/J.JTHO.2017.10.021.

[94] A. Drilon et al., “Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial,” J Clin Oncol, vol. 41, pp. 385–394, 2022, doi: 10.1200/JCO.22.

[95] A. Drilon et al., “ Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer ,” New England Journal of Medicine, vol. 383, no. 9, pp. 813–824, Aug. 2020, doi: 10.1056/NEJMOA2005653/SUPPL_FILE/NEJMOA2005653_DATA-SHARING.PDF.

[96] F. Griesinger et al., “Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial,” Annals of Oncology, vol. 33, no. 11, pp. 1168–1178, Nov. 2022, doi: 10.1016/J.ANNONC.2022.08.002.

[97] S. Popat et al., “AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.,” Journal of Clinical Oncology, vol. 40, no. 16_suppl, pp. TPS9159–TPS9159, Jun. 2022, doi: 10.1200/JCO.2022.40.16_SUPPL.TPS9159.

[98] A. Drilon 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, vol. 17, no. 12, pp. 1653–1660, Dec. 2016, doi: 10.1016/S1470-2045(16)30562-9.

[99] A. Drilon et al., “TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers,” Annals of Oncology, vol. 30, pp. v190–v191, Oct. 2019, doi: 10.1093/annonc/mdz244.068.

[100] M. F. Chen, M. Repetto, C. Wilhelm, and A. Drilon, “RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future,” Drugs, vol. 84, no. 9, p. 1035, Sep. 2024, doi: 10.1007/S40265-024-02040-5.

[101] S. K. Nelson-Taylor et al., “Resistance to RET-inhibition in RET-rearranged NSCLC is mediated by reactivation of RAS/MAPK signaling,” Mol Cancer Ther, vol. 16, no. 8, pp. 1623–1633, Aug. 2017, doi: 10.1158/1535-7163.MCT-17-0008/86959/AM/RESISTANCE-TO-RET-INHIBITION-IN-RET-REARRANGED.

[102] A. Leonetti et al., “BRAF in non-small cell lung cancer (NSCLC): Pickaxing another brick in the wall,” Cancer Treat Rev, vol. 66, pp. 82–94, May 2018, doi: 10.1016/J.CTRV.2018.04.006.

[103] D. Planchard, R. E. Sanborn, M. V. Negrao, A. Vaishnavi, and E. F. Smit, “BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape,” NPJ Precis Oncol, vol. 8, no. 1, Dec. 2024, doi: 10.1038/S41698-024-00552-7.

[104] M. Sereno et al., “A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation,” Anticancer Drugs, vol. 26, no. 9, pp. 1004–1007, Sep. 2015, doi: 10.1097/CAD.0000000000000277.

[105] D. Planchard et al., “Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial,” Lancet Oncol, vol. 17, no. 7, pp. 984–993, Jul. 2016, doi: 10.1016/S1470-2045(16)30146-2.

[106] D. Planchard et al., “Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study.,” Journal of Clinical Oncology, vol. 35, no. 15_suppl, pp. 9075–9075, May 2017, doi: 10.1200/JCO.2017.35.15_SUPPL.9075.

[107] G. J. Riely et al., “Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients with BRAF V600-Mutant Metastatic Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology, vol. 41, no. 21, pp. 3700–3711, Jul. 2023, doi: 10.1200/JCO.23.00774/ASSET/F5333EC2-D009-4DE5-A7F8-CF4976593EE0/ASSETS/IMAGES/LARGE/JCO.23.00774TA6.JPG.

[108] I. Dagogo-Jack and A. T. Shaw, “Tumour heterogeneity and resistance to cancer therapies,” Nat Rev Clin Oncol, vol. 15, no. 2, pp. 81–94, Feb. 2018, doi: 10.1038/NRCLINONC.2017.166.

[109] M. Repetto et al., “NTRK gene fusion testing and management in lung cancer,” Cancer Treat Rev, vol. 127, p. 102733, Jun. 2024, doi: 10.1016/J.CTRV.2024.102733.

[110] R. C. Doebele et al., “Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials,” Lancet Oncol, vol. 21, no. 2, pp. 271–282, Feb. 2020, doi: 10.1016/S1470-2045(19)30691-6.

[111] D. S. Hong et al., “Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials,” Lancet Oncol, vol. 21, no. 4, pp. 531–540, Apr. 2020, doi: 10.1016/S1470-2045(19)30856-3.

[112] E. Cocco, M. Scaltriti, and A. Drilon, “NTRK fusion-positive cancers and TRK inhibitor therapy,” Nat Rev Clin Oncol, vol. 15, no. 12, pp. 731–747, Dec. 2018, doi: 10.1038/S41571-018-0113-0.

[113] Y. Yu, Y. Yang, H. Li, and Y. Fan, “Targeting HER2 alterations in non-small cell lung cancer: Therapeutic breakthrough and challenges,” Cancer Treat Rev, vol. 114, p. 102520, Mar. 2023, doi: 10.1016/J.CTRV.2023.102520.

[114] B. T. Li et al., “ Trastuzumab Deruxtecan in HER2 -Mutant Non–Small-Cell Lung Cancer ,” New England Journal of Medicine, vol. 386, no. 3, pp. 241–251, Jan. 2022, doi: 10.1056/NEJMOA2112431/SUPPL_FILE/NEJMOA2112431_DATA-SHARING.PDF.

[115] K. Goto 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, vol. 41, no. 31, pp. 4852–4863, Nov. 2023, doi: 10.1200/JCO.23.01361.

[116] B. T. Li et al., “Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04).,” Journal of Clinical Oncology, vol. 40, no. 16_suppl, pp. TPS9137–TPS9137, Jun. 2022, doi: 10.1200/JCO.2022.40.16_SUPPL.TPS9137.

[117] Z. Li et al., “Trastuzumab rezetecan, a HER2-directed antibody–drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study,” Lancet Oncol, vol. 26, no. 4, pp. 437–446, Apr. 2025, doi: 10.1016/S1470-2045(25)00012-9.

[118] C. Zhou et al., “Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma after Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study,” Journal of Clinical Oncology, vol. 38, no. 24, pp. 2753–2761, Aug. 2020, doi: 10.1200/JCO.20.00297/SUPPL_FILE/PROTOCOL_JCO.20.00297.PDF.

[119] G. Yang et al., “Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2),” BMC Med, vol. 20, no. 1, pp. 1–9, Dec. 2022, doi: 10.1186/S12916-022-02470-6/FIGURES/4.

[120] W. Jiang, Y. Yang, G. Yang, H. Xu, and Y. Wang, “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,” Annals of Oncology, vol. 35, p. S826, Sep. 2024, doi: 10.1016/J.ANNONC.2024.08.1354.

[121] Y. Y. Elamin et al., “Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial,” Journal of Clinical Oncology, vol. 40, no. 7, pp. 702–709, Mar. 2022, doi: 10.1200/JCO.21.01113/ASSET/5BE3EDD4-CA77-4E83-A2E9-D98521ADAEFD/ASSETS/IMAGES/LARGE/JCO.21.01113TA2.JPG.

[122] J. Heymach et al., “OA01.01 Beamion LUNG-1: Phase Ia/b Trial of HER2 Tyrosine Kinase Inhibitor Zongertinib (BI 1810631) in Patients with HER2 Aberration-Positive Solid Tumors,” Journal of Thoracic Oncology, vol. 19, no. 7, p. e1, Jul. 2024, doi: 10.1016/j.jtho.2024.05.199.

[123] A. M. Schram et al., “Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer,” N Engl J Med, vol. 392, no. 6, p. 566, Feb. 2025, doi: 10.1056/NEJMOA2405008.

[124] R. Dziadziuszko et al., “Afatinib in NSCLC With HER2 Mutations: Results of the Prospective, Open-Label Phase II NICHE Trial of European Thoracic Oncology Platform (ETOP),” Journal of Thoracic Oncology, vol. 14, no. 6, pp. 1086–1094, Jun. 2019, doi: 10.1016/J.JTHO.2019.02.017.

[125] M. Aujay et al., “Abstract 4019: Preclinical activity of ELVN-002: A potent, selective, and irreversible HER2 and pan-HER2 mutant small molecule inhibitor for the treatment of HER2 driven malignancies,” Cancer Res, vol. 83, no. 7_Supplement, pp. 4019–4019, Apr. 2023, doi: 10.1158/1538-7445.AM2023-4019.

[126] D. M. Hyman et al., “HER kinase inhibition in patients with HER2- and HER3-mutant cancers,” Nature 2018 554:7691, vol. 554, no. 7691, pp. 189–194, Jan. 2018, doi: 10.1038/nature25475.

[127] X. Le et al., “Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial,” Journal of Clinical Oncology, vol. 40, no. 7, pp. 710–718, Mar. 2022, doi: 10.1200/JCO.21.01323/SUPPL_FILE/PROTOCOL_JCO.21.01323.PDF.

[128] M. G. Kris 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,” Annals of Oncology, vol. 26, no. 7, pp. 1421–1427, Jul. 2015, doi: 10.1093/ANNONC/MDV186.

[129] K. Zhu, X. Yang, H. Tai, X. Zhong, T. Luo, and H. Zheng, “HER2-targeted therapies in cancer: a systematic review,” Biomarker Research 2024 12:1, vol. 12, no. 1, pp. 1–17, Feb. 2024, doi: 10.1186/S40364-024-00565-1.

[130] “Managing Treatment Challenges in HER2-Directed Therapies.” Accessed: May 03, 2025. [Online]. Available: https://www.ajmc.com/view/managing-treatment-challenges-in-her2-directed-therapies.

Targeted Therapy in NSCLC: A Comprehensive Review of Molecular Drivers and Treatment Strategies

Authors

DOI:

Keywords

Abstract

References

Downloads

Published

How to Cite

Issue

Section

License

Stats

Search

Browse

User

Current Issue

Information

Newsletter

Tags

Quality in Sport

Targeted Therapy in NSCLC: A Comprehensive Review of Molecular Drivers and Treatment Strategies

Authors

DOI:

Keywords

Abstract

References

Downloads

Published

How to Cite

Issue

Section

License

Stats

Search

Browse

User

Current Issue

Information

Newsletter

Tags