Background: Isolated thoracic recurrences of NSCLC in/near previously irradiated fields present a therapeutic challenge. One treatment option is re-RT with proton beam therapy (PBT) to minimize normal tissue exposure; however, distant failure is common. Herein, we report the first prospective trial of PBT re-RT followed by pembro. Methods: This phase II, single-arm trial (NCT03087760) enrolled patients (pts) with isolated locoregional recurrences of NSCLC in/near previously irradiated fields. Key inclusion were definitive thoracic RT > 6 months (mo) prior, ECOG 0-1, and clinical target volume (CTV) < 250 cc. Key exclusion were extrathoracic metastases, prior grade ≥3 pneumonitis, and prior immunotherapy < 30 days from re-RT start. 4-12 weeks after completion of 60-70 Gy PBT re-RT, pts without progressive disease started pembro 200 mg IV q21 days for up to 12 mo. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and CTCAE v5.0 toxicity. PFS and OS were measured from re-RT start and estimated using Kaplan-Meier method. Results: Between November 2017 and April 2021, 32 pts were consented; 10 were excluded most commonly due to CTV ≥250cc (N = 3) or separate primary (N = 3). 22 were eligible and initiated PBT re-RT. Trial closed early due to slow accrual. Median age was 68 years. All recurrences were biopsy-proven; 8 (36%) were squamous. Recurrences were primary tumor (N = 4), nodal (N = 8), and both (N = 10). 8 pts (36%) received prior durvalumab. Median interval from prior RT end to re-RT start was 20 mo (range 10.2-74.8). Median delivered re-RT dose and dose/fraction were 60 Gy (range 18-70) and 2 Gy (range 1.8-4), respectively; 21 pts (95%) received concurrent chemotherapy. 15 pts (68%) initiated consolidation pembro on trial and received a median of 3 cycles (range 2-17). Pembro was discontinued due to completion of 1 year (N = 3), disease progression (N = 4), toxicity (N = 5; 2 pembro-related [grade 2 pneumonitis after cycle 3 and grade 3 mucositis after cycle 13, the former also re-RT-related]), death without progression (N = 2; NSTEMI and unknown), and pt decision (N = 1). Median follow-up was 38.7 mo. Median PFS and OS were 8.8 mo (95% CI 4.2-23.7) and 22.8 mo (95% CI 6.9-not reached) for all pts, respectively, and 13.5 mo (95% CI 4.2-25.3) and 22.8 mo (95% CI 6.5-not reached) for pts who started pembro. Receipt of > 3 cycles pembro (N = 7) associated with better OS (median 46.7 vs 13.8 mo, log-rank p = 0.007). 10 pts (46%) had grade ≥3 toxicity; 2 were pembro-related (grade 3 lymphopenia and mucositis). 1 pt had grade 5 toxicity (aortic fistula), from re-RT. Conclusions: In the first prospective trial of PBT re-RT + consolidation pembro, treatment proved feasible and PFS was acceptable though the capacity to administer pembro was limited. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC. Clinical trial information: NCT03087760.