Key Strategies in Precision Medicine for Overcoming Resistance in Lung Cancer

Meziem Prince *

Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nsukka, Nigeria.

Eleje Catherine

Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nsukka, Nigeria.

Ezema Somtochukwu

Department of Clinical Pharmacy and Pharmacy Management, University of Nigeria, Nsukka, Nigeria.

Maduka Anulika

Department of Pharmacology and Toxicology, University of Nigeria, Nsukka, Nigeria.

*Author to whom correspondence should be addressed.


Abstract

The burden of lung cancer in Nigeria represents a significant clinical problem due to the high mortality rate. Added to this is the lack of a comprehensive cancer treatment strategy in Nigeria, resulting in underdiagnosis and poor access to treatment. Furthermore, the challenges of chemoresistance represent a major obstacle to lung cancer therapy in Nigeria. These challenges highlight the need for precision medicine that targets specific genetic mutations and can potentially overcome resistance. This review article aimed to provide a comprehensive compilation of studies on the resistance mechanisms in the different types of therapy and current key strategies for overcoming resistance in lung cancer. Herein, we selected significant studies from the Web of Science and PubMed databases by conducting a systematic search for articles published between 2018 and 2024 with the keywords “Precision Medicine”, “Targeted Therapy”, “Overcoming Resistance”, “ Lung cancer”, “Treatment” and any analogies and combinations of the keywords. In summary, resistance mechanisms in lung cancer therapy, such as primary and acquired resistance, and tumor microenvironment changes, were examined and promising strategies to overcome them include; modulating immune checkpoints, enhancing T cell priming, conditioning the gut microbiota, stimulating the immune system, targeting the tumor microenvironment, and developing combination therapies, were provided and discussed.

Keywords: Precision medicine, targeted therapy, overcoming resistance, lung cancer, treatment, personalised medicine, chemoresistance


How to Cite

Prince, Meziem, Eleje Catherine, Ezema Somtochukwu, and Maduka Anulika. 2024. “Key Strategies in Precision Medicine for Overcoming Resistance in Lung Cancer”. International Research Journal of Oncology 7 (1):39-59. https://www.journalirjo.com/index.php/IRJO/article/view/147.

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References

Thandra KC, Barsouk A, Saginala K, Aluru JS, Barsouk A.. Epidemiology of lung cancer. Contemporary oncology (Poznan, Poland). 2021;25(1):45–52. Available: https://doi.org/10.5114/wo.2021.103829

Zappa C, Mousa SA. Non-small cell lung cancer: Current treatment and future advances. Translational Lung Cancer Research. 2016;5(3):288–300. Available: https://doi.org/10.21037/tlcr.2016.06.07

Okonta KE, Baiyewu LA, Jimoh MA. Lung Cancer in Nigeria. Journal of thoracic oncology : Official publication of the International Association for the Study of Lung Cancer. 2023;18(11):1446–1457. Available: https://doi.org/10.1016/j.jtho.2023.08.022

Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, Seth S, Chow CW, Cao Y, Gumbs C, Gold KA, Kalhor N, Little L, Mahadeshwar H, Moran C, Protopopov A, Sun H, Tang J, Wu X, Ye Y , Futreal PA. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science (New York, N.Y.). 2014;346(6206):256–259. Available: https://doi.org/10.1126/science.1256930

Osmani L, Askin F, Gabrielson E, Li QK. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy. Seminars in cancer biology, 52(Pt 1). 2018;103–109. Available: https://doi.org/10.1016/j.semcancer.2017.11.019

McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27(1):15–26. Available: https://doi.org/10.1016/j.ccell.2014.12.001

Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proceedings of the American Thoracic Society. 2009;6(2):201–205. Available: https://doi.org/10.1513/pats.200809-107LC

Hirsch FR, Suda K, Wiens J, Bunn PA, Jr. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet (London, England). 2016;388(10048):1012–1024. Available: https://doi.org/10.1016/S0140-6736(16)31473-8

Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung cancer (Amsterdam, Netherlands). 2011;71(1):3–10. Available: https://doi.org/10.1016/j.lungcan.2010.08.022

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science (New York, N.Y.). 2018;359(6382):1350–1355. Available: https://doi.org/10.1126/science.aar4060

Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: An overview. Cancers. 2014;6(3):1769–1792. Available: https://doi.org/10.3390/cancers6031769

Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer. 2013;13(10):714–726. Available: https://doi.org/10.1038/nrc3599

Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World Journal of Gastroenterology. 2023;29(6):926–948. Available:https://doi.org/10.3748/wjg.v29.i6.926

Aldea M, Andre F, Marabelle A, Dogan S, Barlesi F, Soria JC. Overcoming resistance to tumor-targeted and immune-targeted therapies. Cancer Discovery. 2021;11(4): 874–899. Available: https://doi.org/10.1158/2159-8290.cd-20-1638

Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. International Immunopharmacology. 2017;46:210–219. Available:https://doi.org/10.1016/j.intimp.2017.03.015

Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K, Capelletti M, Shimamura T, Ercan D, Stumpfova M, Xiao Y, Weremowicz S, Butaney M, Heon S, Wilner K, Jänne PA. A novel Alk Secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Research. 2011;71(18):6051–6060. Available: https://doi.org/10.1158/0008-5472.can-11-1340

Romanidou O, Landi L, Cappuzzo F, Califano R. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer. Therapeutic Advances in Medical Oncology. 2016;8(3):176–187. Available: https://doi.org/10.1177/1758834016631531

Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. Journal of clinical oncology : Official Journal of the American Society of Clinical Oncology. 2013;31(31):3987–3996. Available: https://doi.org/10.1200/JCO.2012.45.2029

Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Translational Lung Cancer Research. 2015;4(1):67–81. Available: https://doi.org/10.3978/j.issn.2218-6751.2014.11.06

Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nature Medicine. 2013;19(11):1389–1400. Available: https://doi.org/10.1038/nm.3388

Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(6):2070–2075. Available:https://doi.org/10.1073/pnas.0709662105

El Kadi N, Wang L, Davis A, Korkaya H, Cooke A, Vadnala V, Brown NA, Betz BL, Cascalho M, Kalemkerian GP, Hassan KA. The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer. Cancer Research. 2018;78(24):6728–6735. Available: https://doi.org/10.1158/0008-5472.CAN-17-3370

Wang F, Wang S, Zhou Q. The Resistance Mechanisms of Lung Cancer Immunotherapy. Frontiers in Oncology. 2020;10:568059. Available: https://doi.org/10.3389/fonc.2020.568059

Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017;168(4):707–723. Available: https://doi.org/10.1016/j.cell.2017.01.017

Schoenfeld AJ, Antonia SJ, Awad MM, Felip E, Gainor J, Gettinger SN, Hodi FS, Johnson ML, Leighl NB, Lovly CM, Mok T, Perol M, Reck M, Solomon B, Soria JC, Tan DSW, Peters S, Hellmann MD. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer. Annals of oncology : Official Journal of the European Society for Medical Oncology. 2021; 32(12):1597–1607. Available: https://doi.org/10.1016/j.annonc.2021.08.2151

Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637): 321–330. Available: https://doi.org/10.1038/nature21349

Frisone D, Friedlaender A, Addeo A, Tsantoulis P. The Landscape of Immunotherapy Resistance in NSCLC. Frontiers in Oncology. 2022;12:817548. Available:https://doi.org/10.3389/fonc.2022.817548

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer. 2012;12(4):252–264. Available: https://doi.org/10.1038/nrc3239

Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nature reviews. Immunology. 2020;20(1): 25–39. Available: https://doi.org/10.1038/s41577-019-0218-4

Attili I, Tarantino P, Passaro A, Stati V, Curigliano G, de Marinis F. Strategies to overcome resistance to immune checkpoint blockade in lung cancer. Lung Cancer (Amsterdam, Netherlands). 2021;154:151–160. Available: https://doi.org/10.1016/j.lungcan.2021.02.035

Reuben A, Zhang J, Chiou SH, Gittelman RM, Li J, Lee WC, Fujimoto J, Behrens C, Liu X, Wang F, Quek K, Wang C, Kheradmand F, Chen R, Chow CW, Lin H, Bernatchez C, Jalali A, Hu X, Wu CJ, Zhang J. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nature Communications. 2020;11(1):603. Available: https://doi.org/10.1038/s41467-019-14273-0

Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, Wu C, Jiang J. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: A Meta-Analysis. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2015;37(4):1560–1571. Available: https://doi.org/10.1159/000438523

Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook. Molecular Cancer. 2020;19(1): 141. Available: https://doi.org/10.1186/s12943-020-01260-z

Boyero L, Sánchez-Gastaldo A, Alonso M, Noguera-Uclés JF, Molina-Pinelo S, Bernabé-Caro R. Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy. Cancers. 2020;12(12): 3729. Available: https://doi.org/10.3390/cancers12123729

Solimando AG, Summa S, Vacca A, Ribatti D. Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling. Cancers. 2020;12(11):3380. Available: https://doi.org/10.3390/cancers12113380

Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky, MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(43):17561–17566. Available: https://doi.org/10.1073/pnas.1215397109

Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, Lin CC, Flor MJ, Di Nicola M, Alvarez RM, Dussault I, Helwig C, Ojalvo LS, Gulley JL, Cho BC. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial. Journal of thoracic oncology : Official Publication of the International Association for the Study of Lung Cancer. 2020;15(7):1210–1222. Available: https://doi.org/10.1016/j.jtho.2020.03.003

Akhurst RJ. Targeting TGF-β Signaling for Therapeutic Gain. Cold Spring Harbor Perspectives in Biology. 2017;9(10): a022301. Available: https://doi.org/10.1101/cshperspect.a022301

Tauriello DVF, Sancho E, Batlle E. Overcoming TGFβ-mediated immune evasion in cancer. Nature reviews. Cancer. 2022;22(1):25–44. Available: https://doi.org/10.1038/s41568-021-00413-6

Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur, CD, White JM, Kalinke U, Murphy KM, Schreiber RD. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. The Journal of Experimental Medicine. 2011;208(10):1989–2003. Available: https://doi.org/10.1084/jem.20101158

Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. The Journal of Experimental Medicine. 2011;208(10): 2005–2016. Available: https://doi.org/10.1084/jem.20101159

Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, Cho K, Hensley-Alford S, Munkarah A, Liu R, Zou W. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527(7577): 249–253. Available: https://doi.org/10.1038/nature15520

Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte, V, Viola A. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. The Journal of Experimental Medicine. 2011;208(10):1949–1962. Available: https://doi.org/10.1084/jem.20101956

Proost P, Mortier A, Loos T, Vandercappellen J, Gouwy M, Ronsse I, Schutyser E, Put W, Parmentier M, Struyf S, Van Damme J. Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration. Blood. 2007;110(1):37–44. Available: https://doi.org/10.1182/blood-2006-10-049072

Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nature reviews. Immunology. 2015;15(8):486–499. Available: https://doi.org/10.1038/nri3862

Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nature Immunology. 2013;14(10):1014–1022. Available: https://doi.org/10.1038/ni.2703

Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nature reviews. Clinical Oncology. 2017;14(12): 717–734. Available: https://doi.org/10.1038/nrclinonc.2017.101

Zhang H, Conrad DM, Butler JJ, Zhao C, Blay J, Hoskin DW. Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. Journal of Immunology (Baltimore, Md. : 1950). 2004;173(2):932–944. Available: https://doi.org/10.4049/jimmunol.173.2.932

Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K. Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors. Frontiers in Immunology. 2015;5:673. Available: https://doi.org/10.3389/fimmu.2014.00673

Mott KR, Gate D, Matundan HH, Ghiasi YN, Town T, Ghiasi H. CD8+ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1. Journal of Virology. 2016;90(10):5059–5067. Available:https://doi.org/10.1128/JVI.00255-16

Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Wu CJ. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217–221. Available: https://doi.org/10.1038/nature22991

Son CH, Bae JH, Shin DY, Lee HR, Choi YJ, Jo WS, Ho Jung M, Kang CD, Yang K, Park YS. CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. Journal of Immunotherapy (Hagerstown, Md. : 1997). 2014;37(1): 1–7. Available: https://doi.org/10.1097/CJI.0000000000000007

Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, Vaysse T, Marthey L, Eggermont A, Asvatourian V, Lanoy E, Mateus C, Robert C, Carbonnel F. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Annals of oncology : Official Journal of the European Society for Medical Oncology. 2017;28(6):1368–1379. Available: https://doi.org/10.1093/annonc/mdx108

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K , Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science (New York, N.Y.). 2018;359(6371):97–103. Available:https://doi.org/10.1126/science.aan4236

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 2018;359(6371):91–97. Available: https://doi.org/10.1126/science.aan3706

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Molecular and Cellular Endocrinology. 2011;335(1):2–13. Available: https://doi.org/10.1016/j.mce.2010.04.005

Vijayan D, Young A, Teng MWL, Smyth MJ. Targeting immunosuppressive adenosine in cancer. Nature reviews. Cancer. 2017;17(12):765. Available: https://doi.org/10.1038/nrc.2017.110

Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, Kreutz M. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. Frontiers in Immunology. 2017;8:248. Available:https://doi.org/10.3389/fimmu.2017.00248

De Rosa V, Di Rella F, Di Giacomo A, Matarese G. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism. Cytokine & Growth Factor Reviews. 2017;35:15–25. Available: https://doi.org/10.1016/j.cytogfr.2017.04.001

June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy?. Nature Medicine. 2017;23(5):540–547. Available: https://doi.org/10.1038/nm.4321

Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, Li S, Chen T, Poteete A, Estrada-Bernal A, Le AT, Truini A, Nilsson MB, Sun H, Roarty E, Goldberg SB, Brahmer JR, Altan M, Lu C, Papadimitrakopoulou V, Heymach JV. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nature Medicine. 2018;24(5):638–646. Available:https://doi.org/10.1038/s41591-018-0007-9

Romero D. Poziotinib for uncommon ERBB mutations. Nature reviews. Clinical Oncology. 2018;15(7):404. Available: https://doi.org/10.1038/s41571-018-0038-7

Godin-Heymann N, Ulkus L, Brannigan BW, McDermott U, Lamb J, Maheswaran S, Settleman J, Haber DA. The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Molecular Cancer Therapeutics. 2008;7(4):874–879. Available: https://doi.org/10.1158/1535-7163.MCT-07-2387

Van Der Steen N, Giovannetti E, Carbone D, Leonetti A, Rolfo CD, Peters GJ. Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer. Cancer Drug Resistance; 2018. Available: https://doi.org/10.20517/cdr.2018.13

Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, Ladanyi M. Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncology. 2015;1(7):982–984. Available:https://doi.org/10.1001/jamaoncol.2015.1066

Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. Journal of Hematology & Oncology. 2016;9(1):59. Available: https://doi.org/10.1186/s13045-016-0290-1

Yu Z, Boggon TJ, Kobayashi S, Jin C, Ma PC, Dowlati A, Kern JA, Tenen DG, Halmos B. Resistance to an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals novel treatment strategies. Cancer Research. 2007;67(21):10417–10427. Available: https://doi.org/10.1158/0008-5472.CAN-07-1248

Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Jänne PA, Oxnard GR. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nature Medicine. 2015;21(6):560–562. Available: https://doi.org/10.1038/nm.3854

Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research : An Official Journal of the American Association for Cancer Research. 2006;12(21):6494–6501. Available: https://doi.org/10.1158/1078-0432.CCR-06-1570

Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clinical cancer research : An official Journal of the American Association for Cancer Research. 2008;14(22):7519–7525. Availble:https://doi.org/10.1158/1078-0432.CCR-08-0151

Costa DB, Schumer ST, Tenen DG, Kobayashi S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2008;26(7):1182–1186. Available:https://doi.org/10.1200/JCO.2007.14.9039

Zheng D, Hu M, Bai Y, Zhu X, Lu X, Wu C, Wang J, Liu L, Wang Z, Ni J, Yang Z, Xu J. EGFR G796D mutation mediates resistance to osimertinib. Oncotarget. 2017;8(30):49671–49679. Available: https://doi.org/10.18632/oncotarget.17913

Oxnard G, Hu Y, Mileham K, Tracy P, Feeney N, Sholl L, Paweletz C, Thress K, Jänne P. OA 09.02 osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms. Journal of Thoracic Oncology. 2017;12(11). Available:https://doi.org/10.1016/j.jtho.2017.09.376

Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Letters. 2017;385:51–54. Available:https://doi.org/10.1016/j.canlet.2016.11.008

Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Pao W. Met amplification occurs with or without t790m mutations in egfr mutant lung tumors with acquired resistance to gefitinib or Erlotinib. Proceedings of the National Academy of Sciences. 2007;104(52):20932–20937. Available: https://doi.org/10.1073/pnas.0710370104

Roberts PJ, Stinchcombe TE. kras mutation: Should we test for it, and does it matter? Journal of Clinical Oncology. 2013;31(8):1112–1121. Available: https://doi.org/10.1200/jco.2012.43.0454

Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK, Choi YJ, Choi CM, Kim SW, Jang SJ, Park YS, Kim WS, Lee DH, Lee JS, Miller VA, Arcila M, Bivona TG. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics. 2012; 44(8):852–860. Available: https://doi.org/10.1038/ng.2330

Moasser MM, Basso A, Averbuch SD, Rosen N. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Research. 2001;61(19):7184–7188.

Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clinical cancer research : An Official Journal of the American Association for Cancer Research. 2007;13(9):2795–2803. Available: https://doi.org/10.1158/1078-0432.CCR-06-2077

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch, TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Engelman JA. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science Translational Medicine. 2011;3(75):75ra26. Available:https://doi.org/10.1126/scitranslmed.3002003

Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2011;17(23):7337–7346. Available: https://doi.org/10.1158/1078-0432.CCR-11-1667

Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. Journal of Cancer Research Updates. 2013;2(4):265–282. Available: https://doi.org/10.6000/1929-2279.2013.02.04.5

Ashrafi A, Akter Z, Modareszadeh P, Modareszadeh P, Berisha E, Alemi PS, Chacon Castro MDC, Deese AR, Zhang L. Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance. Cancers. 2022;14(19):4562. Available:https://doi.org/10.3390/cancers14194562

Young LC, Campling BG, Cole SP, Deeley RG, Gerlach JH. Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: Correlation of protein levels with drug response and messenger RNA levels. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2001;7(6):1798–1804.

Gomez-Casal R, Epperly MW, Wang H, Proia DA, Greenberger JS, Levina V. Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition. Oncotarget. 2015;6(42):44306–44322. Available: https://doi.org/10.18632/oncotarget.6248

Tan S, Yi P, Wang H, Xia L, Han Y, Wang H, Zeng B, Tang L, Pan Q, Tian Y, Rao S, Oyang L, Liang J, Lin J, Su M, Shi Y, Liao Q, Zhou Y. RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer. Frontiers in Oncology. 2020;10:649. Available:https://doi.org/10.3389/fonc.2020.00649

Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: The framework of malignant behavior. Molecular Biology Reports. 2020;47(6):4587–4629. Available: https://doi.org/10.1007/s11033-020-05435-1

Li L, Li Y, Zou H. A novel role for apatinib in enhancing radiosensitivity in non-small cell lung cancer cells by suppressing the AKT and ERK pathways. PeerJ. 2021; 9:e12356. Available:https://doi.org/10.7717/peerj.12356

Ushijima H, Suzuki Y, Oike T, Komachi M, Yoshimoto Y, Ando K, Okonogi N, Sato H, Noda SE, Saito J, Nakano T. Radio-sensitization effect of an mTOR inhibitor, temsirolimus, on lung adenocarcinoma A549 cells under normoxic and hypoxic conditions. Journal of Radiation Research. 2015;56(4):663–668. Available: https://doi.org/10.1093/jrr/rrv021

Chen N, Wu L, Yuan H, Wang J. ROS/Autophagy/Nrf2 Pathway Mediated Low-Dose Radiation Induced Radio-Resistance in Human Lung Adenocarcinoma A549 Cell. International Journal of Biological Sciences. 2015; 11(7):833–844. Available:https://doi.org/10.7150/ijbs.10564

Binkley MS, Jeon YJ, Nesselbush M, Moding EJ, Nabet BY, Almanza D, Kunder C, Stehr H, Yoo, C H, Rhee S, Xiang M, Chabon JJ, Hamilton E, Kurtz DM, Gojenola L, Owen SG, Ko RB, Shin JH, Maxim PG, Lui NS, Diehn M. KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition. Cancer Discovery. 2020;10(12):1826–1841. Available:https://doi.org/10.1158/2159-8290.CD-20-0282

Taghvimi S, Vakili O, Soltani Fard E, Khatami SH, Karami N, Taheri-Anganeh M, Salehi M, Negahdari B, Ghasemi H, Movahedpour A. Exosomal microRNAs and long noncoding RNAs: Novel mediators of drug resistance in lung cancer. Journal of Cellular Physiolog. 2022;237(4):2095–2106. Available:https://doi.org/10.1002/jcp.30697

Whiteside TL, Demaria S, Rodriguez-Ruiz ME, Zarour HM, Melero I. Emerging Opportunities and Challenges in Cancer Immunotherapy. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2016;22(8):1845–1855. Available: https://doi.org/10.1158/1078-0432.CCR-16-0049

Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Ramalingam SS. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. The New England Journal of Medicine. 2019; 381(21):2020–2031. Available:https://doi.org/10.1056/NEJMoa1910231

Gul A, Stewart TF, Mantia CM, Shah NJ, Gatof ES, Long Y, Allman KD, Ornstein MC, Hammers HJ, McDermott DF, Atkins MB, Hurwitz M, Rini BI. Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;38(27):3088–3094. Available:https://doi.org/10.1200/JCO.19.03315

Curigliano G, Gelderblom H, Mach N, Doi T, Tai WM, Forde P, Sarantopoulos J, Bedard PL, Lin CC, Hodi S, Wilgenhof S, Santoro A, Sabatos-Peyton C, Longmire T, Wan K, Nikolopoulos P, Manenti L, Naing A. Abstract CT183: Phase (PH) I/II study of MBG453± spartalizumab (PDR001) in patients (PTS) with advanced malignancies. Cancer Research, 79(13_Supplement); 2019. Available: https://doi.org/10.1158/1538-7445.am2019-ct183

Yao S, Zhu Y, Chen L. Advances in targeting cell surface signalling molecules for immune modulation. Nature reviews. Drug Discovery. 2013;12(2):130–146. Available: https://doi.org/10.1038/nrd3877

Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer. Nature reviews. Drug Discovery. 2018;17(7): 509–527. Available:https://doi.org/10.1038/nrd.2018.75

Solomon BJ, Beavis PA, Darcy PK. Promising Immuno-Oncology Options for the Future: Cellular Therapies and Personalized Cancer Vaccines. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting. 2020;40:1–6. Available:https://doi.org/10.1200/EDBK_281101.

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene, M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 2018;359(6371):91–97. Available:https://doi.org/10.1126/science.aan3706.

Zappasodi R, Sirard C, Li Y, Budhu S, Abu-Akeel M, Liu C, Yang X, Zhong H, Newman W, Qi J, Wong P, Schaer D, Koon H, Velcheti V, Hellmann MD, Postow MA, Callahan MK, Wolchok JD, Merghoub T. Rational design of anti-GITR-based combination immunotherapy. Nature Medicine. 2019;25(5):759–766. Available: https://doi.org/10.1038/s41591-019-0420-8

Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Reply: Immunosuppressive cell death in cancer. Nature reviews. Immunology. 2017;17(6):402. Available:https://doi.org/10.1038/nri.2017.48

Zhao L, Ma B, Yang Y, Li T, Han L, Gao Q. Chemotherapy Reverses Anti-PD-1 Resistance in One Patient With Advanced Non-small Lung Cell Cancer. Frontiers in Oncology. 2020;10:507. Available:https://doi.org/10.3389/fonc.2020.00507.

Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: A beneficial liaison?. Nature reviews. Clinical Oncology. 2017;14(6):365–379. Avaiolable:https://doi.org/10.1038/nrclinonc.2016.211.

Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Research. 2020;30(6):507–519. Available: https://doi.org/10.1038/s41422-020-0337-2

Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology. 2022;11(1):2120676. Available:https://doi.org/10.1080/2162402X.2022.2120676

Xu M, Xie Y, Ni S, Liu H. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). Annals of Translational Medicine. 2015;3(7):96. Available:https://doi.org/10.3978/j.issn.2305-5839.2015.03.60

Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Research. 2016;76(6): 1591–1602. Available: https://doi.org/10.1158/0008-5472.CAN-15-2581

Park K, Lee JS, Lee KH, Kim JH, Cho BC, Min YJ, Cho JY, Han JY, Kim BS , Kim JS, Lee DH, Kang JH, Cho EK, Kim HG, Lee KH, Kim HK, Jang IJ, Kim HY, Son J Kim DW. Bi 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: Efficacy and Safety at the RP2D. Journal of Clinical Oncology. 2016;34(15_suppl):9055–9055. Available: https://doi.org/10.1200/jco.2016.34.15_suppl.9055

Husain H, Martins R, Goldberg S, Senico P, Ma W, Masters J, Pathan N, Kim DW, Socinski M, Goldberg Z, Cho BC. P3.02B-001 Phase 1 dose escalation of PF-06747775 (EGFR-T790M inhibitor) in patients with advanced EGFRM (DEL 19 or L858R+/-T790M) NSCLC. Journal of Thoracic Oncology. 2017;12(1). Available: https://doi.org/10.1016/j.jtho.2016.11.1668

Desai A, Lovly CM. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: A narrative review. Translational Lung Cancer Research. 2023;12(3):615–628. Available: https://doi.org/10.21037/tlcr-22-708

Dagogo-Jack I, Yoda S, Lennerz JK, Langenbucher A, Lin JJ, Rooney MM, Prutisto-Chang K, Oh A, Adams NA, Yeap BY, Chin E, Do A, Marble HD, Stevens SE, Digumarthy SR, Saxena A, Nagy RJ, Benes CH, Azzoli CG, Lawrence MS, Hata AN. MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2020;26(11):2535–2545. Available: https://doi.org/10.1158/1078-0432.CCR-19-3906

Sivakumar S, Moore JA, Montesion M, Sharaf R, Lin DI, Colón CI, Fleishmann Z, Ebot EM, Newberg JY, Mills JM, Hegde PS, Pan Q, Dowlati A, Frampton GM, Sage J, Lovly CM. Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation. Cancer Discovery. 2023; 13(7):1572–1591. Available: https://doi.org/10.1158/2159-8290.CD-22-0620

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M, IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. The New England Journal of Medicine. 2018;378(24):2288–2301. Available; https://doi.org/10.1056/NEJMoa1716948

Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter, JD, Volak LP, Lipford JR. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781): 217–223. Available: https://doi.org/10.1038/s41586-019-1694-1

Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue Y, Gatto S, Fernandez-Banet J Pavlicek A, Velastagui K, Chao RC, Christensen JG. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discovery. 2020;10(1);54–71. Available: https://doi.org/10.1158/2159-8290.CD-19-1167

Désage AL, Léonce C, Swalduz A, Ortiz-Cuaran S. Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies. Frontiers in Oncology. 2022;12:796832. Available: https://doi.org/10.3389/fonc.2022.796832

West H, Cappuzzo F, Reck M, Mok T, Jotte RM, NishioM, Kim E, Morris S, Shankar G, Zou W, Shames D, McCleland M, Socinski MA. 1265p IMPOWER150: A post hoc analysis of efficacy outcomes in patients with KRAS, STK11 and KEAP1 mutations. Annals of Oncology. 2020;31. Available:https://doi.org/10.1016/j.annonc.2020.08.1579

Yuan M, Huang LL, Chen JH, Wu J, Xu Q. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduction and Targeted Therapy. 2019;4:61. Available: https://doi.org/10.1038/s41392-019-0099-9

Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng, S. Y., Bischoff, H. G., Peled, N., Grossi, F. Jennens, R. R., Reck, M., Garon, E. B., Novello, S., Rubio-Viqueira, B., Boyer, M., Garassino, M. C. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. Journal of Clinical oncology : Official Journal of the American Society of Clinical Oncology. 2020; 38(14):1505–1517. Available: https://doi.org/10.1200/JCO.19.03136

Paz-Ares L, Luft A., Vicente, D., Tafreshi, A., Gümüş, M., Mazières J., Hermes, B, Çay Şenler, F., Csőszi T., Fülöp, A., Rodríguez-Cid, J, Wilson, J., Sugawara, S, Kato, T., Lee, K. H., Cheng, Y., Novello, S., Halmos, B., Li, X., Lubiniecki, G. M. KEYNOTE-407 Investigators Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. The New England Journal of Medicine. 2018;379(21):2040–2051. Available: https://doi.org/10.1056/NEJMoa1810865

West H, McCleod M, Hussein M., Morabito, A., Rittmeyer, A., Conter, H. J., Kopp, H. G., Daniel, D., McCune, S., Mekhail, T., Zer, A., Reinmuth, N., Sadiq, A., Sandler, A., Lin, W., Ochi Lohmann, T., Archer, V., Wang, L., Kowanetz, M., Cappuzzo, F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A Multicentre, Randomised, open-label, phase 3 trial. The Lancet. Oncology. 2019;20(7):924–937. Available: https://doi.org/10.1016/S1470-2045(19)30167-6

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis, F., Domine, M., Clingan, P., Hochmair, M. J., Powell, S. F., Cheng, S. Y., Bischoff, H. G., Peled, N., Grossi, F., Jennens, R. R., Reck, M., Hui, R., Garon E. B., Boyer, M., Rubio-Viqueira, B. KEYNOTE-189 Investigators Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. The New England Journal of Medicine. 2018;378(22):2078–2092. Available:https://doi.org/10.1056/NEJMoa1801005

Reck M, Ciuleanu TE, Dols MC, Schenker M, Zurawski B, Menezes J, Richardet E Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Yan J, Paz-Ares LG. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (TX) for stage IV/recurrent non-small cell lung cancer (NSCLC): Checkmate 9la. Journal of Clinical Oncology. 2020;38(15_suppl):9501–9501. Available: https://doi.org/10.1200/jco.2020.38.15_suppl.9501

Galffy G, Lugowska I, Poddubskaya E, Cho BC, Ahn MJ, Han JY, Su WC, Hauke R, Dyar S, Lee, DH, Serwatowski P, Estelles DL, Holden V, Kim YJ, Vladimirov V, Horvath Z, Ghose A, Goldman, A , Pietro A di, Laskov M. 281 javelin medley VEGF: Phase 2 study of avelumab + axitinib in patients with previously treated non-small cell lung cancer (NSCLC) or treatment naive, cisplatin-ineligible urothelial cancer (UC). Regular and Young Investigator Award Abstracts; 2020. Available: https://doi.org/10.1136/jitc-2020-sitc2020.0281

Theelen WSME, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts JGJV, Dumoulin DW, Bahce I, Niemeijer AN, de Langen AJ, Monkhorst K, Baas P. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA oncology. 2019;5(9):1276–1282. Available:https://doi.org/10.1001/jamaoncol.2019.1478

Insinga RP, Feliciano JL, Qiao N, Vandormael K, Zhang Y. Cost-effectiveness of pembrolizumab + chemotherapy versus chemotherapy and pembrolizumab monotherapy in first line treatment of NSCLC in the US - updated analyses with additional trial follow-up. Journal of Medical Economics. 2021;24(1):792–805. Available:https://doi.org/10.1080/13696998.2021.1937188