Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease.1 Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies.2 In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy.3 In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed.4 Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented.5 Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result in a survival benefit in RTOG 0612.6 There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al7 reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade.8 Updated information on these trials and relevant preclinical data will be presented. 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590-9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. 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 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95. radiation sensitization, Stage III NSCLC, concurrent chemoradiotherapy