Advances in Multimodality Management of Localized Non-Small Cell Lung Cancer

Abstract

Lung cancer represents the most common cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) comprising the vast majority of cases. Outcomes for stage II–III NSCLC remain suboptimal due to late presentation, biological heterogeneity, and limited efficacy of traditional therapies. Recent advances have reshaped the therapeutic landscape, with immunotherapy and targeted treatments now integrated into the management of resectable NSCLC. Landmark trials such as CheckMate 816 demonstrated improved event-free and overall survival with neoadjuvant chemoimmunotherapy approaches. Similarly, adjuvant targeted therapies such as osimertinib and alectinib have shown benefit in patients with EGFR and ALK alterations, respectively. This review provides an overview of evolving diagnostic strategies, highlights pivotal clinical trials, and explores multidisciplinary treatment approaches across stages I to III NSCLC. We also address key challenges including optimal treatment sequencing, patient selection, and duration of therapy. As clinical trial data continue to mature, personalized multimodal strategies guided by molecular and clinical features remain central to improving long-term outcomes in resectable NSCLC.

Keywords

neoadjuvant immunotherapy - non-small cell lung carcinoma - multimodality treatment

Publication History

Received: 30 May 2025

Accepted: 02 October 2025

Accepted Manuscript online:
03 October 2025

Article published online:
23 October 2025

• References

• 1 Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021; 71 (01) 7-33
• 2 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
• 3 Waser N, Vo L, McKenna M, Penrod JR, Goring S. Real-world treatment patterns in resectable (stages I-III) non-small-cell lung cancer: a systematic literature review. Future Oncol 2022; 18 (12) 1519-1530
• 4 Goldstraw P, Chansky K, Crowley J. et al; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions, International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11 (01) 39-51
• 5 Spigel DR, Faivre-Finn C, Gray JE. et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung Cancer. J Clin Oncol 2022; 40 (12) 1301-1311
• 6 Pignon J-P, Tribodet H, Scagliotti GV. et al; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26 (21) 3552-3559
• 7 Gandhi L, Rodríguez-Abreu D, Gadgeel S. et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378 (22) 2078-2092
• 8 Paz-Ares L, Luft A, Vicente D. et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018; 379 (21) 2040-2051
• 9 Soria J-C, Ohe Y, Vansteenkiste J. et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378 (02) 113-125
• 10 Antonia SJ, Villegas A, Daniel D. et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018; 379 (24) 2342-2350
• 11 Tsuboi M, Herbst RS, John T. et al; ADAURA Investigators. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 2023; 389 (02) 137-147
• 12 Wu Y-L, Dziadziuszko R, Ahn JS. et al; ALINA Investigators. Alectinib in resected ALK-positive non-small-cell lung cancer. N Engl J Med 2024; 390 (14) 1265-1276
• 13 Silvestri GA, Gonzalez AV, Jantz MA. et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (5, suppl): e211S-e250S
• 14 Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 2003; 123 (1, suppl): 137S-146S
• 15 Herth FJF, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006; 61 (09) 795-798
• 16 Varela-Lema L, Fernández-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur Respir J 2009; 33 (05) 1156-1164
• 17 De Leyn P, Dooms C, Kuzdzal J. et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014; 45 (05) 787-798
• 18 Mayer N, Boschetti L, Scarci M. et al. Brain imaging in patients with non-small cell lung cancer-a systematic review. J Clin Med 2025; 14 (03) 708
• 19 Brockelsby C, Maconachie R, Navani N. et al. Brain imaging in lung cancer staging: a real-world, multi-centre study of prevalence of brain metastases, impact on treatment and re-modelling of the NICE health economic analysis. Lung Cancer 2023; 178: 145-150
• 20 Heymach JV, Harpole D, Mitsudomi T. et al; AEGEAN Investigators. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med 2023; 389 (18) 1672-1684
• 21 Cascone T, Awad MM, Spicer JD. et al; CheckMate 77T Investigators. Perioperative nivolumab in resectable lung cancer. N Engl J Med 2024; 390 (19) 1756-1769
• 22 Heymach J. et al. Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): an exploratory subgroup analysis of AEGEAN. JCO 2024; 42: 8011-8011
• 23 Rami-Porta R, Osarogiagbon RU, Asamura H. The TNM system is adequate for making treatment decisions and prognostication in lung cancer. J Thorac Oncol 2022; 17 (11) 1255-1257
• 24 Mazieres J, Drilon A, Lusque A. et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019; 30 (08) 1321-1328
• 25 Schoenfeld AJ, Arbour KC, Rizvi H. et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019; 30 (05) 839-844
• 26 Sorin M, Prosty C, Ghaleb L. et al. Neoadjuvant chemoimmunotherapy for NSCLC: a systematic review and meta-analysis. JAMA Oncol 2024; 10 (05) 621-633
• 27 Spicer J. et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). JCO 2021; 39: 8503-8503
• 28 Forde PM, Spicer J, Lu S. et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022; 386 (21) 1973-1985
• 29 Chang JY, Mehran RJ, Feng L. et al; STARS Lung Cancer Trials Group. Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Lancet Oncol 2021; 22 (10) 1448-1457
• 30 Moghanaki D. et al. Protocol for the veterans affairs cooperative studies program study number 2005. CHEST Pulm 2023; 1: 100024
• 31 Ambrogi MC, Fanucchi O, Cioni R. et al. Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study. J Thorac Oncol 2011; 6 (12) 2044-2051
• 32 Moore W, Talati R, Bhattacharji P, Bilfinger T. Five-year survival after cryoablation of stage I non-small cell lung cancer in medically inoperable patients. J Vasc Interv Radiol 2015; 26 (03) 312-319
• 33 Detterbeck FC, Woodard GA, Bader AS. et al. The proposed ninth edition TNM classification of lung cancer. Chest 2024; 166 (04) 882-895
• 34 NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014; 383 (9928): 1561-1571
• 35 Liu J, Blake SJ, Yong MC. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 2016; 6 (12) 1382-1399
• 36 Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020; 367 (6477): eaax0182
• 37 Spicer J. et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816. JCO 2024; 42: LBA8010-LBA8010
• 38 Chaft JE, Oezkan F, Kris MG. et al; LCMC study investigators. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nat Med 2022; 28 (10) 2155-2161
• 39 Shu CA, Gainor JF, Awad MM. et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020; 21 (06) 786-795
• 40 Cascone T, William Jr WN, Weissferdt A. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 2021; 27 (03) 504-514
• 41 Cascone T, Leung CH, Weissferdt A. et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med 2023; 29 (03) 593-604
• 42 Wakelee H, Liberman M, Kato T. et al; KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 2023; 389 (06) 491-503
• 43 Spicer JD, Garassino MC, Wakelee H. et al; KEYNOTE-671 Investigators. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2024; 404 (10459): 1240-1252
• 44 Provencio Pulla M. et al. LBA50 Perioperative nivolumab (NIVO) v placebo (PBO) in patients (pts) with resectable NSCLC: clinical update from the phase III CheckMate 77T study. Ann Oncol 2024; 35: S1239-S1240
• 45 Provencio M, Nadal E, González-Larriba JL. et al. Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer. N Engl J Med 2023; 389 (06) 504-513
• 46 Felip E, Altorki N, Zhou C. et al; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021; 398 (10308): 1344-1357
• 47 Felip E, Altorki N, Zhou C. et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023; 34 (10) 907-919
• 48 O'Brien M, Paz-Ares L, Marreaud S. et al; EORTC-1416-LCG/ETOP 8-15–PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022; 23 (10) 1274-1286
• 49 van de Haar J, Mankor JM, Hummelink K. et al. Combining genomic biomarkers to guide immunotherapy in non-small cell lung cancer. Clin Cancer Res 2024; 30 (07) 1307-1318
• 50 Wu Y-L, Tsuboi M, He J. et al; ADAURA Investigators. Osimertinib in Resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 2020; 383 (18) 1711-1723
• 51 Le Pechoux C, Pourel N, Barlesi F. et al. Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial. Lancet Oncol 2022; 23 (01) 104-114
• 52 Forde PM, Spicer J, Girard N. Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816; 2023.
• 53 Ramnath N, Dilling TJ, Harris LJ. et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (5, suppl): e314S-e340S
• 54 Curran Jr WJ, Paulus R, Langer CJ. et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011; 103 (19) 1452-1460
• 55 Senan S, Brade A, Wang LH. et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2016; 34 (09) 953-962
• 56 Takayama K, Inoue K, Tokunaga S. et al. Phase II study of concurrent thoracic radiotherapy in combination with weekly paclitaxel plus carboplatin in locally advanced non-small cell lung cancer: LOGIK0401. Cancer Chemother Pharmacol 2013; 72 (06) 1353-1359
• 57 Belani CP, Ramalingam S, Perry MC. et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 2008; 26 (03) 468-473
• 58 Deek MP, Kim S, Beck R. et al. Variations in initiation dates of chemotherapy and radiation therapy for definitive management of inoperable non-small cell lung cancer are associated with decreases in overall survival. Clin Lung Cancer 2018; 19 (04) e381-e390
• 59 Bradley JD. et al. PACIFIC-2: phase 3 study of concurrent durvalumab and platinum-based chemoradiotherapy in patients with unresectable, stage III NSCLC. JCO 2019; 37: TPS8573-TPS8573
• 60 Bryant AK, Sankar K, Zhao L. et al. De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. Eur J Cancer 2022; 171: 55-63
• 61 Lu S, Kato T, Dong X. et al; LAURA Trial Investigators. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med 2024; 391 (07) 585-597
• 62 Nassar AH, Jayakrishnan R, Feng J. et al. Consolidation ALK tyrosine kinase inhibitors versus durvalumab or observation after chemoradiation in unresectable stage III ALK-positive NSCLC. J Thorac Oncol 2025; 20 (01) 109-118