<h3>Purpose/Objective(s)</h3> Preoperative radiotherapy (RT) is one of the recommended treatments for primary extremity and trunk soft tissue sarcoma, however, the pathological remission is relatively low, and survival is not improved. We hypothesized that the addition of tyrosine kinase inhibitor (TKI) will improve the pathological remission rate without significant increase of major wound complications (MWCs). <h3>Materials/Methods</h3> Two phase II study were initiated in our center. Primary or recurrent non-metastatic extremity or trunk soft tissue sarcoma was enrolled. Patients received preoperative intensity-modulated radiotherapy (IMRT) of 50Gy in 25 fractions with concurrent and sequential Anlotinib (12 mg QD for 2 weeks, 3 cycles in total) or Apatinib (500 mg QD, 5 days per week, for 9 weeks in total), followed by wide resection. NCI-CTC 5.0, RECIST 1.1 criteria, and EORTC-STBSG criteria was used to evaluate acute toxicities, clinical response and pathological grading. The primary endpoint was defined as MWCs as per the SR2 criteria within 4 months post-surgery. <h3>Results</h3> From Jul 2020 to Dec 2021, 31 patients were enrolled and completed RT. The median onset age is 55 (22-82) years old. There are 26 and 5 patients with primary untreated and locally relapsed disease, respectively. The median tumor size is 10.5 (3.7-19.5) cm, with 23 patients (74.2%) larger than 8cm. Twenty-seven tumors (87.1%) were evaluated as unresectable or borderline resectable, which was defined as impossible or difficult to conserve limb with non-R2 wide resection. There were 21, 9 and 1 patients having Anlotinib, Apatinib and none, respectively. All except 5 took TKI as per protocol, with 4 patients having dose reduction due to Grade 3 toxicities. The observed ≥Grade 3 toxicities are: hypertension in 4 patients (19.1%) in Anlotinib group and 2 patients (22.2%) in Apatinib group, and one Grade 4 hepatotoxicity in Apatinib group (11.1%). There are 14 (14/30, 46.7%) and 16 patients (16/30, 53.3%) who achieved partial response (PR) and SD as per RECIST 1.1 criteria at 1-month post-radiotherapy, respectively. All the patients who had PR had obvious tumor shrink at the first 1 to 2 weeks during radiotherapy. Six out of 24 patients (25%) who underwent wide resection with at least 6 weeks follow-up had MWCs, with all in lower extremity. There were 4 (4/26, 15.4%), 3 (3/26, 11.5%) and 3 (3/26, 11.5%) patients achieving pathological Grade A, B, and C remission as per EORTC-STBSG criteria, respectively. All the 22 patients with unresectable or borderline resectable tumor had non-R2 limb-conserving wide resection, with 18 R0 and only 4 R1 resection. <h3>Conclusion</h3> For patients with non-metastatic extremity or trunk primary sarcoma, the combination of TKI and pre-operative RT is safe and well-tolerated, and achieve favorable clinical and pathological response. The earlier response with addition of TKI made more patients with unresectable or borderline resectable tumor completely resected by limb-conserving wide resection. NCT05167994, NCT05235100