(P 207) A MULTICENTER PHASE II STUDY OF CABOZANTINIB PLUS NIVOLUMAB FOR PATIENTS WITH ADVANCED ANGIOSARCOMA PREVIOUSLY TREATED WITH A TAXANE: ALLIANCE A091902

Objective: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes.Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes.

Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO).

Results: 22 eligible pts [median age 67 yrs (32-92), 11 female] received ≥1 dose of C+N. Primary disease sites: 13 cutaneous (scalp/face), 1 liver, 4 breast, 2 other. All pts received prior taxanes (11/22=50% as adjuvant therapy) and 5/22 (23%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 22 pts achieved OR (11 partial response, 2 complete), for ORR 59% (95%CI: 36-79%). Responses were seen in pts with primary cutaneous disease 7/13 (54%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.4-NR), and OS has not been reached. Off treatment reasons include: progressive disease (15), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension (HTN) was the only possibly treatment related AE (TRAE) occurring in >10%. Two G 4/5 TRAE were reported: HTN and dyspnea. PRO results are being analyzed.

Conclusion: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses will be presented.

Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org. U10CA180868; U10CA180888.