Healio
Healio

 Back to Non-Small Cell Lung Cancer

Lung cancer module OG

Non-Small Cell Lung Cancer

Emerging Therapies and Research

Edward S. Kim, MD, MBA, FACP, FASCO 
Reviewed on December 04, 2024
email icon linkedin twitter facebook

Targeted Therapies and Immunotherapy

The advent of targeted therapy and immunotherapy has radically transformed the approach to the treatment of non-small cell lung cancer (NSCLC). Treatment choices are now primarily biomarker-driven, enabled by next-generation sequencing technologies which can uncover mutations specific to each individual tumor, allowing for more personalized treatment. The fruits of this precision medicine revolution are just beginning to be exploited, and research in NSCLC therapeutics is devoted to both developing new targeted or immunotherapies and exploring their combination with existing therapies.

In targeted therapy, the focus is on developing next-generation agents to overcome resistance and improve response rates. Many new agents targeted against rare mutations are also in the pipeline, including, among other, the epidermal growth factor receptor (EGFR)

exon 20 insertion inhibitors poziotinib, mobocertinib, zipalertinib and amivantamab (a monoclonal antibody (

Targeted Therapies and Immunotherapy

The advent of targeted therapy and immunotherapy has radically transformed the approach to the treatment of non-small cell lung cancer (NSCLC). Treatment choices are now primarily biomarker-driven, enabled by next-generation sequencing technologies which can uncover mutations specific to each individual tumor, allowing for more personalized treatment. The fruits of this precision medicine revolution are just beginning to be exploited, and research in NSCLC therapeutics is devoted to both developing new targeted or immunotherapies and exploring their combination with existing therapies.

In targeted therapy, the focus is on developing next-generation agents to overcome resistance and improve response rates. Many new agents targeted against rare mutations are also in the pipeline, including, among other, the epidermal growth factor receptor (EGFR)

exon 20 insertion inhibitors poziotinib, mobocertinib, zipalertinib and amivantamab (a monoclonal antibody (mAb) recently approved for first- and second-line treatment, now under investigation for expanded use); the mesenchymal-epithelial transition factor (MET) inhibitors savolitinib and glumetinib; and the human epidermal growth factor receptor 2 (HER2) inhibitors poziotinib (which also targets EGFR) and pyrotinib. Combination therapies with inhibitors of the vascularization factor VEGF (eg, bevacizumab) are also being investigated, as are alternative ways of inhibiting the target molecules, such as using microRNA (miRNA) for translational or chromatin-level control of gene expression.

In immunotherapy, the focus is both on testing new combinations of immune checkpoint blockers/inhibitors (ICBs) and other therapies, as well as testing novel drugs and therapeutic strategies. Novel ICBs that target other negative immune checkpoint molecules, such as T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and LAG-3, are being investigated. Adoptive cell therapy, an approach in which the patient’s T cells are expanded and/or modified in vitro, is also being pursued. This involves several strategies: isolating the T cells from the tumor, expanding them and reinfusing them into the tumor (tumor-infiltrating lymphocyte, or TIL, therapy); genetically editing the T cell to express a receptor specific to a surface antigen on cancer cells (chimeric antigen receptor T cell, or CAR-T, therapy); and genetically editing T cells to express a receptor specific for cancer antigens presented on MHC complexes on APCs (engineered T-cell receptor, or TCR, therapy). A promising Phase 1 trial combining TIL therapy with nivolumab raises the prospect of combining novel immunotherapeutic approaches with established therapies. Another approach involves genetically modified viruses that selectively infect and destroy cancer cells (oncolytic viruses). In addition to a cytotoxic application, oncolytic viruses can be used to increase the expression of specific biomarkers in cancer cells, making them better targets for ICBs and targeted therapies. Finally, therapeutic cancer vaccines, which aim to prime antigen-specific T cells and so enhance their response against the tumor, are another form of immunotherapy under investigation for cancer in general, with two products (CV301 and NEO-PV-01) being investigated for NSCLC.

References

  • Araghi M, Mannani R, Heidarnejad Maleki A, et al. Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023;23(1):162.
  • Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-199.
  • Brazel D, Nagasaka M. The development of amivantamab for the treatment of non-small cell lung cancer. Respir Res. 2023;24(1):256.
  • Bryan DS, Donington JS. Surgically Resectable Disease. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Cabanero M, Prodipto P, Ming-Sound T. Diagnosis and Treatment of Anaplastic Lymphoma Kinase (ALK) Rearranged Non-Small Cell Lung Cancer. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Cabanero M, Prodipto P, Ming-Sound T. Histology and Molecular Testing. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Cabanero M, Prodipto P, Ming-Sound T. Other Molecular Cohorts Including ROS1, BRAF, HER2, MET, NTRK, RET, KRAS. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2027-2039.
  • Capella MP, Pang SA, Magalhaes MA, Esfahani K. A Review of Immunotherapy in Non-Small-Cell Lung Cancer. Curr Oncol. 2024;31(6):3495-3512.
  • Cascetta P, Marinello A, Lazzari C, et al. KRAS in NSCLC: State of the Art and Future Perspectives. Cancers (Basel). 2022;14(21):5430.
  • Chabner BA, Roberts TG Jr. Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer. 2005;5(1):65-72.
  • Chi A, Fang W, Sun Y, Wen S. Comparison of Long-term Survival of Patients With Early-Stage Non-Small Cell Lung Cancer After Surgery vs Stereotactic Body Radiotherapy. JAMA Netw Open. 2019;2(11):e1915724.
  • Chun SG, Hu C, Choy H, et al. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J Clin Oncol. 2017;35(1):56-62.
  • Ciardiello F, Tortora G. EGFR antagonists in cancer treatment [published correction appears in N Engl J Med. 2009 Apr 9;360(15):1579]. N Engl J Med. 2008;358(11):1160-1174.
  • Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27(8):1410-1418.
  • D'Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol. 2005;23(13):2926-2936.
  • Fan T, Zhang M, Yang J, Zhu Z, Cao W, Dong C. Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduct Target Ther. 2023
  • Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092.
  • Goss GD, Cobo M, Lu S, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial. EClinicalMedicine. 2021;37:100940.
  • Gou Q, Gou Q, Gan X, Xie Y. Novel therapeutic strategies for rare mutations in non-small cell lung cancer. Sci Rep. 2024;14(1):10317.
  • Hendriks LEL, Remon J, Faivre-Finn C, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2024;10(1):71.
  • Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120-131.
  • Johnson ML, Cho BC, Luft A, et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023;41(6):1213-1227.
  • Lazcluze [package insert]. Horsham, PA: Janssen Biotech, Inc; 8/2024.
  • Lee SH. Chemotherapy for Lung Cancer in the Era of Personalized Medicine. Tuberc Respir Dis (Seoul). 2019;82(3):179-189.
  • Lim TKH, Skoulidis F, Kerr KM, et al. KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing. Lung Cancer. 2023;184:107293.
  • Liu T, He Z, Dang J, Li G. Comparative efficacy and safety for different chemotherapy regimens used concurrently with thoracic radiation for locally advanced non-small cell lung cancer: a systematic review and network meta-analysis. Radiat Oncol. 2019;14(1):55.
  • Ma J, Li X, Zhao S, Wang J, Zhang W, Sun G. Robot-assisted thoracic surgery versus video-assisted thoracic surgery for lung lobectomy or segmentectomy in patients with non-small cell lung cancer: a meta-analysis. BMC Cancer. 2021;21(1):498.
  • Nobel TB, Antonoff MB. Surgical Considerations in Lung Cancer Treatment. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311(7010):899-909.
  • Novello S, Califano R, Reinmuth N, Tamma A, Puri T. RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape. Oncologist. 2023;28(5):402-413.
  • Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2021 Mar;22(3):e92. doi: 10.1016/S1470-2045(21)00082-6]. Lancet Oncol. 2021;22(2):198-211.
  • Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829-838.
  • Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021;6(5):100260.
  • Rybrevant [package insert]. Horsham, PA: Janssen Biotech, Inc; 9/2024.
  • Saadeddin A. Radiotherapy for NSCLC: review of conventional and new treatment techniques. J Infect Public Health. 2012;5 Suppl 1:S45-S49.
  • Santarpia M, Massafra M, Gebbia V, et al. A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations. Transl Lung Cancer Res. 2021;10(3):1536-1556.
  • Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020;383(21):2018-2029.
  • Shemanski KA, David EA. Oligometastatic Disease. In: Gillaspie EA, Cass AS, Horn L, eds. Lung Cancer: An Evidence-Based Approach to Multidisciplinary Management. Elsevier; 2024.
  • Sihoe ADL. Video-assisted thoracoscopic surgery as the gold standard for lung cancer surgery. Respirology. 2020;25 Suppl 2:49-60.
  • Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021;384(25):2371-2381.
  • Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.
  • Stanley R, Flanagan S, Reilly DO, Kearney E, Naidoo J, Dowling CM. Immunotherapy through the Lens of Non-Small Cell Lung Cancer. Cancers (Basel). 2023;15(11):2996.
  • Vinod SK, Hau E. Radiotherapy treatment for lung cancer: Current status and future directions. Respirology. 2020;25 Suppl 2:61-71.
  • Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454-1466.
  • Xiao Y, Liu P, Wei J, Zhang X, Guo J, Lin Y. Recent progress in targeted therapy for non-small cell lung cancer. Front Pharmacol. 2023;14:1125547.
  • Yan N, Guo S, Zhang H, Zhang Z, Shen S, Li X. BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective. Front Oncol. 2022;12:863043.
  • Zia V, Lengyel CG, Tajima CC, de Mello RA. Advancements of ALK
More in Non-Small Cell Lung Cancer
 Previous Treatment Options and Emerging Therapies
Next  Treatment Guidelines: NCCN, ASCO, IASLC and ESMO Guidelines