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)

Abstract

PurposeAngiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study.MethodsThis is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used.ResultsOverall, there were 16 evaluable patients. Median age was 68 years (range, 25–81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3–4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR.ConclusionThe combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma.Trial registration numberNCT02834013.

Emerging mechanisms of immunotherapy resistance in sarcomas

“…Additionally, these sarcomas showed high expression of early immune response signatures, including MHC-I. Close to 80% of the sarcomas had a low or heterogeneous immune signature expression, supporting clinical observations of checkpoint inhibitors inducing a response in only about 20% of patients [4][5][6][7][8][9][10] . A subsequent paper utilized the CIBERSORT algorithm to query microarray expression data in 253 soft tissue sarcomas [synovial sarcoma, myxoid liposarcoma, non-translocation sarcomas with more complex genomic profiles, and gastrointestinal stromal tumor (GIST)] and identified immune signatures that were largely clustered within the histologic subtype.…”

“…In sarcomas, the success of checkpoint inhibitors alone is limited for most subtypes, with responses ranging consistently less than 20% [9,52] . Exceptions to those responses have been observed in a few histologies such as UPS, dLPS, ASPS, and cutaneous angiosarcoma [4,5,9,52] . Since ICIs are now the most commonly tested immunotherapy strategy for sarcoma patients, the majority of our knowledge on immunotherapy resistance mechanisms stems from these trial results.…”

“…Some evidence exists that perhaps genetic abnormalities not picked up with standard WGS, such as fusions without an RNA product, or indels, may help to drive responses. We previously reported whole-exome and RNA sequencing results for a patient with cutaneous angiosarcoma who had a complete response to very low dose cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) inhibition on a phase 1 clinical trial [5] . While many cutaneous angiosarcomas have been shown to have high TMB with an ultraviolet radiation damage signature resembling melanoma [26] , our patient had a very low TMB at 0.09 mutations/Mb.…”

“…With the modern revolution in cancer immunotherapy, interest in exploring novel treatment approaches such as immune checkpoint inhibitors and adoptive cellular therapies has rebounded for sarcomas, with numerous clinical trials being conducted in a wide variety of sarcoma subtypes (See Table 1 for representative trials). While there have been a few promising signals of activity, such as engineered T cell therapy targeting cancer/testis antigens in synovial sarcomas, and remarkable responses to checkpoint inhibitors in alveolar soft part sarcoma (ASPS) and cutaneous angiosarcomas, responses to immunotherapy for most sarcoma subtypes have remained modest [4][5][6][7][8][9][10] . To further improve the activity of immune-modulating therapies in sarcomas, it is critical that we learn from the extensive work in other cancers aimed to explore mechanisms of response and resistance, and better understand the barriers existing in the sarcoma tumor and immune microenvironment.…”

Malignant Vascular Tumors of the Head and Neck—Which Type of Therapy Works Best?

“…In a prospective phase II trial, PD-1 inhibition had limited activity in 57 patients with soft tissue sarcomas, including one patient with angiosarcoma [ 49 ]. In a cohort of patients with metastatic or unresectable angiosarcoma, dual anti-CTLA-4 and anti PD-1- blockade demonstrated an overall response rate of 25%, with three of five patients with cutaneous tumors of the scalp or face responding to treatment [ 42 ].…”