9507 Background: Standard of care for locally advanced cutaneous SCC (CSCC) consists of extensive and mutilating surgery often with adjuvant radiotherapy (RT). To improve clinical prospects of these patients (pts), we tested efficacy of neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (COMBO) in pts with CSCC with an indication for extensive surgery with or without adjuvant RT. Methods: 40 pts with T1-4N0-3M0 or TxN1-3M0 CSCC and an indication for extensive and/or mutilating surgery were needed to reach the primary objective of this trial. Pts were randomized for ARM A: NIVO (3 mg/kg, weeks 0&2, N = 26) or ARM B: NIVO (3 mg/kg, weeks 0&2) + IPI (1mg/kg, week 0, N = 24) prior to surgery (week 4). Primary objective was pathological response at time of surgery. A major pathological response (MPR) was defined as ≤10% residual viable cancer cells in the surgical resection specimen. Secondary endpoints were tolerability (CTCAE v.5.0), survival, and quality of life (QOL). Key exploratory aim for the trial was the serial collection of pre- and on-treatment tumor samples to investigate immunogenomic features correlating with immunotherapy response. Preliminary results: 50 pts were enrolled at median age 76, of whom 32% with TxN1-3M0 disease. Grade 3-4 irAEs occurred in 6 (12%) pts and were well manageable. 40 pts underwent standard of care surgery w/wo adjuvant RT, of whom 40% and 53% reached an MPR upon NIVO and COMBO, respectively. However, 10 pts withdrew consent to undergo surgery and RT, of whom nine pts declined because of self-reported substantial clinical remission upon neoadjuvant immunotherapy. These clinical responses were confirmed via FDG-PET evaluation in week 4. All these 9 pts are currently cancer free at median FU of 12 months (range 4 to 27) with superior QOL compared to MATISSE pts undergoing standard of care. Overall, we found deep clinical responses in 13/26 (50%) and 14/23 (61%) of pts upon NIVO and COMBO, respectively, being either a MPR at time of surgery or a clinical CR in patients declining surgery. Preliminary conclusions: The MATISSE trial shows deep responses of 50% and 61% upon neoadjuvant NIVO and COMBO, respectively, with well manageable toxicity in this elderly CSCC population. Nine MATISSE patients have proven the concept that organ preservation and durable complete remissions can be achieved after two infusions of neoadjuvant immunotherapy only, without extensive or mutilating curative surgery and/or RT. Clinical trial information: NCT04620200 .