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

Purpose: Angiosarcoma 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.

Methods: This 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.

Results: Overall, 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.

Conclusion: The 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 number: NCT02834013.

Keywords: Clinical Trials; Combination; Drug Therapy; Immunotherapy; Phase II as Topic; Sarcoma.

Conflict of interest statement

Competing interests: MJW reports scientific advisory income from Adaptimmune and Deciphera. His university received research funding from Athenex, Adaptimmune, Deciphera, GlaxoSmithKline, Incyte, InhibRX. MO reports consulting with Merck, Daiichi Sankyo, Biosight and is on a data safety monitoring board for Celgene and GlycomimeticsSP reports scientific advisory income from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Illumina, Merck, Rakuten, Paradigm, Tempus. Patel’s university receives research funding from Bristol-Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, IovanceCR reports consulting from AstraZeneca, Bristol-Meyer Squibb, Deciphera, Eisai, Exelixis, Janssen. Ryan’s institution received research funding from Bristol-Myers Squibb, Daiichi-Sankyo, Exelixis, Genetech, GlaxoSmithKline/Novartis, Karyopharm Therapeutics, Leducq, Merck, Nektar, Pfizer, and Xynomic. GTB reports honoraria for consulting and speaking from Deciphera. His institution received research support from Ambrx, Roche, Daiichi, TraconAV reports consulting from Foundation medicine and case roundtable for Sanofi. CR reports personal fees from Epizyme, Ipsen, Deciphera; travel/non-financial support from Janssen, Astra Zeneca, Springworks, GSK; Research funding to institution from Plexxicon, AADi, Novartis, Medivation, Advenchen, Epizyme, Springworks, Mundipharma, GSK, Qilu Puget Sound.MA reports consulting or Advisory role with Lilly, Adaptimmune, Regeneron, and AstraZeneca; speakers bureau with Bristol-Myers Squib, Bayer, and Deciphera. His institution received research funding from Exelixis. YKC reports research grants from AbbVie, Bristol‐Myers Squibb, Biodesix, Lexent Bio, and Freenome and consulting fees, payments, and/or honoraria from Roche/Genentech, AstraZeneca, Bristol‐Myers Squibb, Foundation Medicine, Counsyl, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Pfizer, Tempus, Lunit, and Takeda. RK reports consultant and/or speaker fees and/or advisory board for Actuate Therapeutics, Bicara Therapeutics, Biological Dynamics, Neomed, Pfizer, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a cofounder of CureMatch. Her institution receives research funding RK research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance.The other authors made no disclosures.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Outcome of patients with angiosarcoma treated with nivolumab and ipilumumab. (A) RECIST waterfall plot by primary anatomic site (patients not assessable by RECIST marked with hatched bars; RECIST progression (+20%) and PR (−30%) marked with horizontal lines); (B) waterfall plot by cutaneous versus non-cutaneous primary site (patients not assessable by RECIST marked with hatched bars; RECIST progression (+20%) and PR (−30%) marked with horizontal lines); (C) Swimmer’s Plot by primary anatomic site; (D) examples of responses, pictures taken at baseline, 8 weeks, and 16 weeks for both patients. Top part of the figure shows a man in his 80s with cutaneous angiosarcoma of the face and one prior therapy who achieved best response of 89% reduction that has lasted 11+ months and is ongoing in spite of a treatment hold for grade 3 elevation of liver transaminases. Molecular alterations showed an intermediate tumor mutation burden (TMB) 8 mut/mb and PDL1 tumor proportion score of 30% (see also table 2); bottom figure is a woman in her 40s with cutaneous angiosarcoma of the scalp and two prior systemic therapies and prior radiation for treatment who achieved best response of 81% tumor reduction that lasted 5 months. There was grade 3 pneumothorax and hypokalemia. Molecular alterations showed a high TMB of 24 mut/mb (see also table 2). Blue triangle points to a chronic lesion resulting from her prior treatments and is not angiosarcoma. CR, complete response; PR, partial response.

Figure 2

RECIST 1.1 PFS (A) and OS (B) Kaplan-Meier curves. OS, overall survival; PFS, progression-free survival.