Ipilimumab/Nivolumab Elicits Promising Responses in Patients With Angiosarcoma


Findings from the phase 2 DART trial demonstrated that the combination of ipilimumab and nivolumab may have potential for the treatment of patients with angiosarcoma.

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) demonstrated promising activity in patients with angiosarcoma, including those with cutaneous tumors of the face or scalp, according to the results of the phase 2 DART (SWOG S1609) trial (NCT02834013).

Data from the trial indicated that of the 16 eligible patients, an overall response rate (ORR) of 25% was reported, including 4 confirmed responses (95% CI, 9%-45%). Response durations have ranged from 5 months to over 13 months, with 2 patients experiencing ongoing responses. Additionally, a fifth patient achieved a reduction in tumor size, but disease progression was reported during the follow up confirmatory assessment. Two patients achieved stable disease for over 6 months.

“Larger studies of immune checkpoint inhibitors in sarcoma have included angiosarcoma patients but in small numbers making assessment of efficacy in this specific histology impossible from prior studies,” the investigators stated. “Most angiosarcoma responders to immunotherapy in reports where site of primary tumor is available have cutaneous disease of the face or scalp, consistent with the higher TMB seen in this group. …There [are] limited other published data to suggest whether angiosarcomas of other sites might respond to [immune checkpoint inhibitors]. We, therefore, included all angiosarcomas in this study. To our knowledge, this represents the first prospective trial of immunotherapy in angiosarcoma.

The multicenter, open label, multi cohort study sought to assess the benefit of ipilimumab and nivolumab in several rare malignancies, with angiosarcoma representing 1 of 53 cohorts. Patients received 240 mg of intravenous nivolumab every 2 weeks and 1 mg/kg of intravenous ipilimumab every 6 weeks. Assessments were conducted at baseline and at weeks 8, 16, 24 and every 12 weeks thereafter until tumor progression occurred.

To be enrolled on the study, patients were required to have a confirmed diagnosis of angiosarcoma with evaluable disease by RECIST 1.1 criteria. Additionally, cutaneous disease was allowed only if disease could be measured and photographed. Patients were also required to be 18 years or older with adequate end organ function.

The primary end point of the study was ORR by RECIST 1.1 criteria, with key secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity.

Additional findings from a subgroup analysis indicated that patients with primary cutaneous tumors of the face or scalp achieved a confirmed ORR of 60% (n = 3). Additionally, a patient with breast angiosarcoma who received radiation therapy experienced an objective response. The overall 6-month PFS rate was 38% (95% CI, 20%-71%) and the median OS had not been reached after a median follow-up of 12.1 months.

In terms of safety, 75% of patients experienced any grade adverse effect (AE) and 25% experienced grade 3/4 AEs. Notably, there were no drug-related deaths, although 12.5% (n = 2) of patients experienced toxicities that led to drug discontinuation. Reasons for discontinuation included grade 3 liver toxicity and grade 3 lower limb muscle weakness. Additionally, 2 patients discontinued ipilimumab alone.

The most common AEs included increased alanine aminotransferase (ALT), anemia, increased aspartate aminotransferase (AST), diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash. A total of 68.8% of patients developed immune-related AEs (irAEs), with 12.5% experiencing grade 3/4 irAEs. The most common irAEs included increased ALT, increased AST, diarrhea, hypothyroidism, pneumonitis, pruritus, and rash. Notably, ALT and AST increase and diarrhea were the most common grade 3/4 irAEs.

“Ipilimumab and nivolumab showed activity in angiosarcoma with responses seen in cutaneous angiosarcomas. Correlative studies to better understand the molecular characteristics of these patients utilizing the same centralized platforms are underway. Further study of ipilimumab and nivolumab in angiosarcoma is warranted,” the investigators concluded.


Wagner M, Othus M, Patel SP, et al. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). 2021;9:e002990. doi:10.1136/jitc-2021-002990

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