Background: Neoadjuvant chemo-immunotherapy has become a new standard of care in locally advanced, resectable NSCLC. The SAKK 16/14 trial demonstrated a major improvement in pathological response (pCR), major pathological remission (MPR) and event-free survival (EFS) with the addition of perioperative durvalumab after standard induction chemotherapy (ChT) with cisplatin and docetaxel. Based on data suggesting a potential enhancement of immunotherapy efficacy, the ongoing SAKK 16/18 trial investigates the addition of immune-modulatory radiotherapy (RT) given concurrently with neoadjuvant durvalumab. Methods: In this non-comparative randomized phase II trial patients (pts) with resectable stage IIIA-B(N2) (cT1-3 or T4 due to size N2 M0) NSCLC receive 3 cycles of cisplatin 100mg/m2 and docetaxel 85mg/m2 followed by durvalumab (1500mg) and one of three randomized RT regimens before tumor resection and adjuvant durvalumab for 1 year. RT is delivered to the primary tumor only, using either 20x2 Gy, 5x5 Gy, or 3x8 Gy (deliverd inhomogenously). RT planning is optimized for strict organ at risk and mediastinal lymph node sparing. The primary endpoint is 1-year EFS. We report a preplanned interim analysis of the secondary endpoints safety, surgical outcomes and pathological response after surgery in 25 pts. Results: At data cut-off on Oct 8, 2022, 25 pts had reached post-operative day 30 and a total of 31 pts were included in the safety analysis. Thirty pts (97%) had at least one treatment related adverse events (TRAE). Eighty-eight % were attributed to neoadjuvant ChT (16% G3-4), 4% each to neoadjuvant durvalumab (1% G3) and RT (1% G4), and 8% to surgery (35% G3-4). One fatal TRAE occurred in a pt with COVID-pneumonia during neoadjuvant ChT. No difference in safety was seen between the three RT arms. There was no treatment-related cancellation or delay in surgery and 0% 30-day postoperative mortality. Eighty-one % of pts underwent tumor resection (96% R0). Non-resection was due to death (n = 1), progressive disease (n = 3), or unresectable tumor (n = 2). The pCR-rate was 28%, and MPR (≤10% viable tumor cells) was detected in 76% of all specimens. Details of pathological responses with regard to immune-modulatory RT regimen will be presented at the meeting. Conclusions: The preplanned interim safety analysis of the SAKK 16/18 trial did not show a relevant increase in TRAE due to immune-modulatory RT. Surgical feasibility and safety are confirmed and the trial continues enrolment to a planned total of 90 pts (30 per RT arm). Preliminary pathological responses are promising, and exploratory analyses will study potential differences between the RT regimens, in order to better understand the potential role of immune-modulatory RT in the multimodal treatment of resectable stage III(N2) NSCLC. Clinical trial information: NCT04245514.