Phase II pilot study of pembrolizumab (PEM) and neoadjuvant radiation therapy (nRT) in high-risk soft tissue sarcomas (STS).

11584 Background: Pathologic necrosis (PN) after neoadjuvant therapy in STS has been associated with improved outcomes. We investigated clinicopathologic outcomes of concurrent PEM/nRT in STS. Methods: Adults with localized STS FNCLCC grade 3 ( > 1.5 cm) or grade 2 ( > 3 cm) received 3 doses of PEM (200 mg IV q21 d) concurrently with nRT, followed by surgery. Primary endpoint was the rate of post-treatment complete pathologic necrosis (CPN; ≥90% PN). 26 subjects provided 94% power to detect an increase in CPN rate from 15% to 40%; ≥7 cases with CPN would exclude a 15% CPN rate. Secondary endpoints included toxicity (CTCAE 5.0), response (RECIST 1.1), and event-free survival (EFS). Results: 27 STS patients were enrolled including UPS (10; 37%), DD liposarcoma (8; 30%), myxofibrosarcoma (2; 7%), solitary fibrous tumor (2; 7%), and other STS (5; 19%). 26 patients were evaluable for CPN and 25 for EFS. All except 2 (7%) received 3 planned PEM doses. All completed planned RT (50-50.4 Gy). 2 (7%) with UPS had partial responses prior to surgery. Median tumor size was 10 cm (range 2.1-26 cm). R0 resection was achieved in 92%. 14 (54%) patients had grade 3 tumors; 12 (46%) had grade ≥2. Median post-treatment PN was 55% (range 0-99%) with 5/26 (19%) having CPN. Median follow-up time was 33.4 months (m) from PEM initiation (range 1.6-60 m). 12/25 patients had an EFS event. Among all patients (n = 27), 12 developed only distant metastatic disease, and 1 developed local and distant recurrence. AEs were consistent with anticipated effects of PEM and RT. Two grade 5 events occurred (ischemic colitis, prostate cancer), both judged unrelated to study therapy. 3 patients experienced wound dehiscence, and one had wound infection. EFS at 12 m was 68%; at 57.5 m, it was 52%. Post-treatment PN as a continuous variable was inversely associated with EFS (HR = 22.47, p = 0.004). Increased tumor size was also associated with inferior EFS (HR = 1.09/cm, p = 0.04). In multivariable analyses, both necrosis and tumor size remained independently associated with EFS (HR = 26.52 and 1.09, p = 0.004 and 0.041, respectively). Sex, age, histology, tumor grade/location, and radiation modality were not associated with EFS. Conclusions: PEM did not increase the proportion of patients with post-treatment CPN after RT. Unexpectedly, increased tumoral necrosis after treatment was associated with inferior EFS. It is possible that increased post-treatment tumoral necrosis may identify a subset of STS patients less likely to benefit from PEM/nRT or who have inherently more aggressive tumor biology. These findings warrant additional studies for validation and exploration of the mechanisms and clinical applications of these findings. PN after PEM/nRT might provide a readily available biomarker that could be used to adjust therapy in those unlikely to benefit from PEM/nRT. Correlative analysis using pre- and post-treatment tumor are on-going and will be presented. Clinical trial information: NCT03338959 .