PROJECT SUMMARY Lung cancer is the deadliest cancer in American war Veterans. Due to limited uptake in lung cancer screening, one third of patients present locally advanced (Stage III) non-small cell lung cancer (NSCLC) at diagnosis, and the overwhelming majority have unresectable disease. The addition of adjuvant immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (CRT) has resulted in significant improvements in overall survival at five years for unresectable Stage III NSCLC. Unfortunately, up to a quarter of Veterans with Stage III lung cancer are unable to tolerate this trimodality therapy. An equal proportion of Veterans discontinue therapy secondary to treatment progression, highlighting the need for both more effective and better tolerated treatment strategies. In resectable NSCLC, neoadjuvant immunotherapy can induce major pathologic responses (MPR) in up to half of patients. Neoadjuvant therapy is better tolerated in many solid malignancies including locally advanced rectal cancer. Moreover, neoadjuvant immunotherapy more than halves the recurrence rate as compared to adjuvant immunotherapy in locally advanced melanoma. We hypothesize that 1.) neoadjuvant chemoimmunotherapy will improve the progression-free survival of patients with unresectable Stage III NSCLC, 2.) PET-adaptive radiotherapy after neoadjuvant chemoimmunotherapy will reduce radiation field sizes and will enhance the treatment tolerance and outcomes in Veterans with unresectable NSCLC. We will test this hypothesis in two aims: Specific Aim 1: Conduct a multi-site single arm open label Phase II clinical trial to assess if neoadjuvant chemoimmunotherapy followed by adaptive radiotherapy is effective in Veterans with unresectable Stage III NSCLC. Up to thirty Veterans with unresectable Stage III NSCLC with ≥ 1% PD-L1 expression will be enrolled across seven VAs. Three cycles of neoadjuvant chemoimmunotherapy will be given followed by PET-adaptive radiotherapy and adjuvant nivolumab. The primary endpoint of the trial will be the median progression-free survival. Secondary endpoints will include treatment tolerance, completion of planned courses of therapy, best overall response rate, and overall survival. Matched controls will be drawn from a contemporaneous cohort of Veterans with unresectable Stage III NSCLC enrolled on an observational prospective study. We anticipate that completion of this work will identify that neoadjuvant chemoimmunotherapy will improve patient outcomes and treatment tolerance. Specific Aim 2: Examine whether baseline and on-treatment factors are indicative of anti- tumor immunity and clinical benefit from chemoimmunotherapy in Veterans with unresectable Stage III NSCLC. Preliminary data suggests that tissue immunophenotype may be predictive of benefit from ICI in the metastatic setting. We will perform correlative exploratory analyses of tissue samples of patients enrolled in this trial to extend these findings to Stage III NSCLC. In Aim ...