November 13, 2020 - The combination of nivolumab and ipilimumab elicited an objective response rate of 25% and was found to be well tolerated in patients with advanced or unresectable angiosarcoma, according to cohort findings of the phase 2 DART trial.
Michael J. Wagner, MD
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) elicited an objective response rate (ORR) of 25% and was found to be well tolerated in patients with advanced or unresectable angiosarcoma, according to cohort findings of the phase 2 DART trial (NCT02834013) that were presented during the virtual SITC 2020 Annual Meeting.1
Of the 16 patients enrolled on this cohort, 4 responded to the combination regimen. Responses were achieved in 3 patients with cutaneous disease of the scalp/face (60%) as well as in 1 patient with radiation-associated breast angiosarcoma.
“Ipilimumab and nivolumab are well tolerated and were safe when given to patients with angiosarcoma,” lead study author Michael J. Wagner, MD, assistant professor at University of Washington School of Medicine, assistant member of Fred Hutchinson Cancer Research Center, and physician with Seattle Cancer Care Alliance, said in a virtual press briefing ahead of the meeting. “Even though this was a very small study, the results are really exciting and encouraging, especially given that this is such a rare cancer. It really warrants a further study of ipilimumab and nivolumab in angiosarcoma.”
Angiosarcoma is a rare, aggressive cancer of endothelial cells associated with a high mortality rate that affects approximately 500 people in the United States per year, Wagner explained. The current standard of care is chemotherapy.
Additionally, some angiosarcomas are reported to have high tumor mutational burden and UV light exposure DNA mutational signature. Smaller prior datasets have shown that immune checkpoint inhibition can elicit activity in this patient population.
The multicenter, prospective DART trial is run by SWOG and is examining the combination of nivolumab/ipilimumab across >50 rare cancer subtypes. In this cohort, labeled as cohort 51, patients with advanced or unresectable angiosarcoma were run through the SWOG Early Therapeutics and Rare Cancers Committee. Nivolumab was administered at 240 mg every 2 weeks along with 1 mg/kg of ipilimumab every 6 weeks. The study comprised a 2-stage design and included 6 patients in the first stage followed by an additional 10 patients in the second stage.
The primary end point is ORR as assessed by RECIST v1.1 criteria, including measurable cutaneous disease that is able to be followed via photography. Secondary end points are progression-free survival (PFS), overall survival, 6-month stable disease rate, and toxicity.
Sixteen patients were enrolled at the time of data cutoff. The median age was 68 years (range, 25-81), and the median lines of prior therapy was 2 (range, 0-5). Moreover, 9 patients had cutaneous primary tumors of any cutaneous site, while 7 patients had non-cutaneous primary tumors.
Results also showed that an additional patient with primary liver visceral angiosarcoma—a subset that is thought to be resistant to chemotherapy—had a greater than 30% reduction in tumor size. However, this patient did progress on a confirmatory follow-up scan, Wagner said.
The 6-month PFS rate was 38%. Two of the 4 patients who responded are still on study at nearly 1 year, suggesting that these responses are durable, he added.
“There are actually 2 other patients who had prolonged stable disease,” said Wagner. “The person who has been on study treatment for the longest did not have a RECIST response, but [they] had stable disease, which is not something we would expect to see with angiosarcoma.”
Regarding safety, adverse events (AEs) were reported in 75% (n = 12) of patients, 25% (n = 4) of whom experienced a grade 3/4 AE. Immune-related AEs (irAEs) occurred in 68.8% of patients, 12.5% (n = 2) of whom developed grade 3/4 irAEs, including increases in alanine aminotransferase and aspartate aminotransferase levels, as well as diarrhea. No grade 5 toxicities occurred.
Based on these data, Wagner said there should be a larger study of nivolumab and ipilimumab conducted in this patient population.
Other malignancies included in other cohorts of the DART study include epithelial tumors of the nasal cavity, sinuses, and nasopharynx; epithelial tumors of major salivary glands; undifferentiated carcinoma of the gastrointestinal tract; adenocarcinoma with variants of small intestine; and spindle cell carcinoma of the kidney, pelvis, and ureter, among other cancer types. Overall, the trial has 51 cohorts.
Wagner M, Othus M, Patel S, et al. A 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). J Immuno Cancer. 2020;8(3). doi:10.1136/jitc-2020-SITC2020.0795