PEMBROCABOSARC: A phase II trial combining pembrolizumab and cabozantinib in patients with advanced undifferentiated pleomorphic sarcoma.

11514 Background: There is a growing rationale for combining immunotherapy and VEGF inhibitors in sarcoma. We report results of an open-label multicentre phase 2 study assessing the anti-PD-1 antibody pembrolizumab (pembro) in combination with cabozantinib (cabo) in patients (pts) with advanced undifferenciated pleomorphic sarcoma (UPS). Methods: Pts aged > 18 years old, with advanced or metastatic UPS who received no more than three previous lines and no previous history of exposure to anti PD1/L1 or cabozantinib were included to receive cabo 40 mg daily and pembro 200 mg IV q21 days. The primary endpoint was 6-month non-progression (NP) per RECIST v1.1. This trial used a 2-stage optimal Simon’s design needing 8 NP at 6 months observed among 29 evaluable pts to be considered positive. Results: 33 pts were enrolled from December 27th, 2022 to September 25th, 2024, 32 were assessable for safety and 31 for efficacy. Overall, 13 (40.6%) pts had at least one dose reduction of cabo and 5 (15.6%) stopped treatment for a drug-related adverse event (3 related to cabo, 1 to pembro and 1 to both drugs). The most frequent adverse events related to treatment were asthenia, diarrhea, palmo-plantar syndrom and aminotransferase increase. There was no new emerging toxicity with the combination. One grade 5 pneumothorax was considered possibly related to cabozantinib by the investigator. At a median follow up of 13.8 months [95% CI: 12 – 17.2], 8 pts out of the first 29 evaluable pts were NP at 6 months (27.6% [95% CI: 12.7%-47.2%]). Among the efficacy population, 14 pts experienced tumor shrinkage resulting in a partial response (PR) in 8 (25.8%). Responses were long-lasting. The median overall survival was not reached. Conclusions: Combining VEGF and PD-1 inhibition showed favorable activity in unselected UPS compared to available evidence for each treatment in monotherapy. Correlative studies of immune biomarkers on paired tumor biopsies and plasma samples done at baseline and on-treatment are on-going to decipher biomarkers of response and resistance to treatment. Clinical trial information: NCT05182164 . Number of patients with at least one Grade 3 to 5 adverse event related to treatment. Adverse Event Grade 3 Grade 5 Diarrhea 2 (6.2%) 0 Palmo-plantar syndrom 2 (6.2%) 0 Aminotransferase increase 2 (6.2%) 0 Hypertension 1 (3.1%) 0 Headache 1 (3.1%) 0 Dysgeusia 1 (3.1%) 0 Skin rash 1 (3.1%) 0 Pyoderma 1 (3.1%) 0 Left ventricular dysfunction 1 (3.1%) 0 Pneumothorax 1 (3.1%) 1 (3.1%)