Next Generation of Advanced Non-Small Cell Lung Cancer Therapy: Targeted and Immuno-Therapies
Keywords:immunotherapy, EGFR tyrosine kinase inhibitor, Molecular Targeted Therapy, Non-Small-Cell Lung Carcinoma, Lung neoplasms
Lung cancer is one of the deadliest cancers in the world. Current clinical trials are focused on developing the next generation of therapies that target novel anti-cancer mechanisms. One approach is to prime the immune system, as the cancer has been known to suppress immune cells in the tumour microenvironment. Using pharmacotherapy, the immune system can be unleashed and suppress the cancer’s growth. Another pathway is targeting known oncogenic genes that are important for the cancer’s growth and survival. In lung cancer, the epidermal growth factor receptor and several other mutated proteins are targets of small-molecule inhibitors that have been shown to drastically improve patient survival and quality of life. Discussed in this review are broad highlights of the different immunotherapies and small molecule targeted therapies that have been studied in the latest clinical trials for lung cancer.
Ferlay J. Estimating the global cancer incidence and mortality in 2018 : GLOBOCAN sources and methods. 2018;1–13.
Inamura K. Lung Cancer : Understanding its Molecular Pathology and the 2015 wHO Classification. 2017;7(August):1–7.
Brule S. Second Line and Maintenance Therapy for Advanced Non-Small Cell Lung Cancer without Driver Mutation: An Evolving Paradigm. Int J Cancer Clin Res [Internet]. 2016 Jun 30 [cited 2018 Jul 31];3(3). Available from: https://clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-3-055.php?jid=ijccr
Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5(SUPPL.4):2–9.
Miura Y, Sunaga N. Role of immunotherapy for oncogene-driven non-small cell lung cancer. Cancers (Basel). 2018;10(8).
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer [Internet]. 2018 Dec 23 [cited 2018 Jul 31];6(1):8. Available from: https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0316-z
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2015 Jul 9 [cited 2018 Jul 19];373(2):123–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26028407
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Non-squamous Non-small Cell Lung Cancer. 2015 Oct 22 [cited 2018 Jul 19];373(17). Available from: http://www.ncbi.nlm.nih.gov/pubmed/26412456
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2017 Jun 22 [cited 2018 Jul 19];376(25):2415–26. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1613493
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet (London, England) [Internet]. 2017 Jan 21 [cited 2019 Feb 9];389(10066):255–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27979383
Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (London, England) [Internet]. 2016 Apr 9 [cited 2018 Jul 26];387(10027):1540–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26712084
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2016 Nov 10 [cited 2018 Jul 19];375(19):1823–33. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1606774
Lopes G, Wu Y-L, Kudaba I, Kowalski D, Cho BC, Castro G, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. In: Journal of Clinical Oncology [Internet]. American Society of Clinical Oncology; 2018 [cited 2019 Feb 10]. p. LBA4–LBA4. Available from: http://ascopubs.org/doi/10.1200/JCO.2018.36.18_suppl.LBA4
Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ [Internet]. 2014 Jan 21 [cited 2018 Jul 26];21(1):15–25. Available from: http://www.nature.com/articles/cdd201367
Ogawara D, Soda H, Iwasaki K, Suyama T, Taniguchi H, Fukuda Y, et al. Remarkable response of nivolumab-refractory lung cancer to salvage chemotherapy. Thorac Cancer [Internet]. 2018 Jan [cited 2018 Jul 26];9(1):175–80. Available from: http://doi.wiley.com/10.1111/1759-7714.12543
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2018 May 31 [cited 2018 Jul 26];378(22):2078–92. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1801005
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2018 Nov 22 [cited 2019 Mar 10];379(21):2040–51. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1810865
Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med [Internet]. 2018;NEJMoa1801946. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1801946
Jotte RM, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodriguez Abreu D, Hussein MA, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol [Internet]. 2018 Jun 20 [cited 2019 Feb 10];36(18_suppl):LBA9000–LBA9000. Available from: http://ascopubs.org/doi/10.1200/JCO.2018.36.18_suppl.LBA9000
Cappuzzo F, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. IMpower130: Progression-free survival (PFS) and safety analysis from a randomised phase III study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. In: Annals of Oncology [Internet]. Oxford University Press; 2018 [cited 2019 Feb 11]. Available from: https://academic.oup.com/annonc/article/doi/10.1093/annonc/mdy424.065/5142051
Chae YK, Arya A, Iams W, Cruz MR, Chandra S, Choi J, et al. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer [Internet]. 2018 Dec 16 [cited 2019 Feb 9];6(1):39. Available from: https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0349-3
Bristol-Myers Squibb Provides Update on the Ongoing Regulatory Review of Opdivo Plus Low-Dose Yervoy in First-Line Lung Cancer Patients with Tumor Mutational Burden ≥10 mut/Mb | BMS Newsroom [Internet]. [cited 2019 Feb 19]. Available from: https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-provides-update-ongoing-regulatory-review
Rizvi NA, Chul Cho B, Reinmuth N, Lee KH, Ahn M-J, Luft A, et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. In: Annals of Oncology [Internet]. Oxford University Press; 2018 [cited 2019 Feb 19]. Available from: https://academic.oup.com/annonc/article/doi/10.1093/annonc/mdy511.005/5238043
Mok T, Schmid P, Arén O, Arrieta O, Gottfried M, Jazieh AR, et al. 192TiP: NEPTUNE: A global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy versus standard of care (SoC) platinum-based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic NSCLC. J Thorac Oncol [Internet]. 2016 Apr 1 [cited 2019 Feb 19];11(4):S140–1. Available from: https://linkinghub.elsevier.com/retrieve/pii/S155608641630301X
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol [Internet]. 2018 Jun 10 [cited 2019 Feb 19];36(17):1714–68. Available from: http://ascopubs.org/doi/10.1200/JCO.2017.77.6385
Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. International Journal of Cancer. 2006.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;
Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 2005;
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239–46.
Wang S, Peng L, Li J, Zeng X, Ouyang L, Tan C, et al. A Trial-Based Cost-Effectiveness Analysis of Erlotinib Alone versus Platinum-Based Doublet Chemotherapy as First-Line Therapy for Eastern Asian Nonsquamous Non-Small-Cell Lung Cancer. PLoS One. 2013;8 (3) (no(e55917).
Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;
Wu Y-L, Lee JS, Thongprasert S, Yu C-J, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777–86.
Miller VA, Hirsh V, Cadranel J, Chen Y-M, Park K, Kim S-W, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528–38.
Soria J-C, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, 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. 2015 Aug;16(8):897–907.
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;
Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med. 2017 Nov;378(2):113–25.
Le T, Gerber DE. ALK alterations and inhibition in lung cancer. Semin Cancer Biol. 2016/09/13. 2017 Feb;42:81–8.
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer. Cell. 2007;
Wilner KD, Riely GJ, Iyer S, Ahn M-J, Moro-Sibilot D, Nakagawa K, et al. Crizotinib versus Chemotherapy in Advanced ALK -Positive Lung Cancer . N Engl J Med. 2013;
Solomon BJ, Reisman A, Mok T, Wilner KD, Paolini J, Blackhall F, et al. First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer . N Engl J Med. 2014;
Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, 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;
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim D-W, et al. Alectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2017;
Camidge DR, Kim HR, Ahn M-J, Yang JC-H, Han J-Y, Lee J-S, et al. Brigatinib versus Crizotinib in ALK -Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2018;
Herbst RS, Davies MJ, Neal JW, Sagorsky S, Gandhi L, Antonia SJ, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):1–15.
Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin C-C, Soo RA, et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol [Internet]. 2019 Jun 1 [cited 2019 Nov 23];37(16):1370–9. Available from: http://ascopubs.org/doi/10.1200/JCO.18.02236
Shaw AT, Solomon BJ, Chiari R, Riely GJ, Besse B, Soo RA, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol [Internet]. 2019 Oct 25 [cited 2019 Nov 23];0(0). Available from: http://www.ncbi.nlm.nih.gov/pubmed/31669155
Drilon A, Sankhala KK, Liu S V., Cho BC, Blakely C, Chee CE, et al. Abstract CT060: STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions. In: Clinical Trials [Internet]. American Association for Cancer Research; 2017 [cited 2019 Nov 23]. p. CT060–CT060. Available from: http://cancerres.aacrjournals.org/lookup/doi/10.1158/1538-7445.AM2017-CT060
How to Cite
Authors who publish with this journal agree to the following terms:
- The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
- Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
- The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
- Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site; with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
- The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
- Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
- The Author represents and warrants that:
- the Work is the Author’s original work;
- the Work is not pending review or under consideration by another publisher;
- the Work has not previously been published;
- the Work contains no libel, invasion of privacy, or other unlawful matter.
- The Author agrees to indemnify and hold Publisher harmless from the Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.
Enforcement of copyright
The IJMS takes the protection of copyright very seriously.
If the IJMS discovers that you have used its copyright materials in contravention of the license above, the IJMS may bring legal proceedings against you seeking reparation and an injunction to stop you using those materials. You could also be ordered to pay legal costs.
If you become aware of any use of the IJMS' copyright materials that contravenes or may contravene the license above, please report this by email to email@example.com
If you become aware of any material on the website that you believe infringes your or any other person's copyright, please report this by email to firstname.lastname@example.org