Results from a phase 2 study revealed nivolumab plus ipilimumab to demonstrate promising clinical activity and manageable safety signals in previously treated patients with classical Kaposi sarcoma who had disease progression.
The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed promising clinical activity and manageable safety signals in previously treated patients with classical Kaposi sarcoma (cKS) who had disease progression, according to study results published in the Annals of Oncology.1
Results from a prospectively designed phase 2, single-arm study (NCT03219671) reached the primary end point of overall response rate (ORR) in the clinic at 78% and was bolstered by radiologic ORR, assessed by RECIST v1.1, at 87%.
Moreover, metabolic ORR was 93% with 8 out of 13 patients obtaining a metabolic complete response (CR) compared with 1 patient obtaining a radiologic CR, and 2 obtaining a clinical CR. Partial response to the combination treatment were seen in 80% (n = 15) of patients assessed by RECIST v1.1 data and 13% of patients had stable disease.
Median follow-up of patients was 24.4 months with a median time to clinical response at 1.6 months (range, 0.7-2.8 months). The median duration of treatment was 18.3 months (range, 2.1-29.9 months). Among the responders, palliative limb amputation was prevented in 2 patients.
Secondary end points of the trial included 6-month progression-free survival (PFS), safety, and tolerability, but median PFS was not reached. However, the 6-month PFS rate among patients was 76.5%, and a 58.8% 1-year PFS rate was observed. At the time of data cutoff, 5 patients completed 2 years of therapy and were continuing treatment, with 9 responses ongoing at the time of analysis.
“These findings are clinically meaningful when placed in the context of currently available treatment options for patients with classical Kaposi sarcoma,” the researchers explained in the discussion of their study. “The options are limited given the relative scarcity of the disease, the advanced age of many affected individuals, and the frequent presence of comorbidities.”
In 8 patients on the study, exploratory biomarkers were observed prior to treatment with most genomic alterations detected. In the observed cohort, there were copy number losses of the FOXA1 gene in 57% of samples, followed by CFTR, RAD51C, and the NOTCH2 gene. All 8 patients had a low tumor mutational burden ranging from 0-1.3 mutations per megabase and were microsatellite stable. Just 2 patients had low PD-L1 protein expression on both their tumor cells and tumor-associated immune cells.
According to the researchers, these data confirmed other studies which suggest PD-L1 expression is low or absent on Kaposi’s mesenchymal cells but is often found in the tumor microenvironment. Moreover, they observed that overexpression of immune-related genes and immunotherapy targets, including 4-1BB, CTLA4, CD40, CD27, OX40, GITR, LAG3, TIM3, PD-1, and PD-L1 (CD274), suggest there may be a post-transcriptional regulation of expression associated with the benefit from immune checkpoint blockade therapy.
“We undertook a challenge of enrolling only patients with measurable (hence advanced) classical Kaposi sarcoma after prior systemic therapy,” the researchers explained. “We chose this very narrow population to be able to clarify the effect of immune checkpoint inhibitors in this specific sarcoma subtype.”
Overall, 18 male patients (median age, 76.5 years) were enrolled in the trial and given 240 mg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab intravenously for 6 weeks in a 6-week cycle. All patients had at least 1 line of systemic therapy with most patients given chemotherapy (89%), followed by palliative radioptherapy (67%), interferon-α (22%), and pazopanib (6%).
Extracutaneous extension of patients Kaposi Sarcoma was observed in 11 patients (61%) lymph nodes, 1 patient’s lung, 1 in their adrenal gland, 1 patient’s muscle, and 7 patients had no extracutaneous extension of their Kaposi Sarcoma.
Treatment was continued for up to 2 years or until either withdrawal of consent, intolerable toxicity, or disease progression, excluding 4 patients who benefited from therapy that were allowed to continue treatment beyond their disease progression.
All patients received at least 1 cycle of treatment, but 2 patients discontinued treatment due to immune-related adverse events (irAEs). Seven patients discontinued just ipilimumab due to toxicities, and 2 patients also discontinued ipilimumab due to a delayed dosing of >12 weeks during the COVID-19 pandemic.
Six patients discontinued due to disease progression, however, there were no treatment related deaths. One patient was hospitalized due to a transient ischemic attack and another due to COVID-19, but the researchers believe they were unlikely related to treatment.
All patients experienced any grade irAEs with 4 patients experiencing grade 3-4 irAEs amylase/lipase elevation (n = 2), colitis/diarrhea (n = 1), and pneumonia (n = 1). The most common irAEs were pruritis (67%), amylase/lipase elevation (44%), hypothyroidism (39%), colitis/diarrhea (28%), aspartate aminotransferase/alanine aminotransferase elevation (28%), and fatigue (28%).
“In conclusion, this phase 2 clinical trial indicates that treatment with nivolumab and ipilimumab is effective and tolerable in patients with classical Kaposi sarcoma,” the researchers wrote. “This study provides a new and promising treatment option for managing [patients with] classical Kaposi sarcoma.”