Nivolimumab and Ipilimumab in Treating Kaposi Sarcoma: Insights From a Phase II, Single Arm Study

Author: Halen Huessner, BS

Reviewed By: Caden Carver, DO

Published: February 23, 2025

Kaposi sarcoma (KS) is an angioproliferative neoplasm caused by human herpes virus 8 (HHV-8). It is classified into four epidemiological variants: AIDS-associated (found predominantly in men who have sex with men in resource-rich areas, and in heterosexual men and women in resource-poor areas like sub-Saharan Africa), classic (most commonly seen in older adult males of Mediterranean or Central/Eastern European descent), endemic (primarily observed in children and adult men from equatorial Africa before the AIDS epidemic), and iatrogenic (occurring in solid organ transplant recipients and patients undergoing immunosuppressive therapy)1. Unlike the more aggressive AIDS-associated form, classic Kaposi sarcoma (cKS) is usually characterized by a chronic, localized and indolent course, with little impact on overall survival. The cutaneous lesions of cKS are typically confined to the distal extremities, especially the lower legs and feet. Oral mucosa, gastrointestinal tract, and regional lymph node involvement are much less common and typically occur later in the disease course. However, in rare cases, cKS can progress rapidly, leading to widespread visceral involvement, which may result in significant disability and even death. Treatment options for rapidly progressive cKS are currently limited due the relative scarcity of the disease and lack of high-quality evidence on its clinical management. Cytotoxic chemotherapy has traditionally been the mainstay of systemic therapy for cKS, but its effectiveness is often hampered by the short-lived responses, highlighting the need for a tolerable systemic treatment that can effectively manage the disease over a longer period. Checkpoint inhibitor immunotherapy has been shown to induce significant and long-lasting antitumor responses across a broad spectrum of cancers. For example, a dual immunotherapy approach with nivolumab (a Programmed cell death protein 1 [PD-1] inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor) has proven effective and is approved for several advanced, metasatic, or unresectable cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, and hepatocellular carcinoma, among others2. Due to its viral etiology, inflammatory nature, and increased incidence in immunocompromised individuals, it was proposed that a combination therapy with nivolumab and ipilimumab might be an effective and safe treatment option for previously treated progressive cKS.

In March 2022, a study entitled Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS) by Zer et al was published in the Annals of Oncology. The primary goal of the study was to evaluate the efficacy and safety of nivolumab in combination with low dose ipilimumab in patients with previously treated progressive cKS.

Researchers in the study conducted a prospective phase II clinical trial. Eligible patients were identified at six Israeli cancer centers and referred for screening, enrollment, and treatment at a single center. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. They enrolled 18 adult male patients (median age 76.5 years) between April 2018 and December 2020 who met eligibility based on histologically confirmed disease, at least one prior line of systemic therapy, and measurable disease by positron emission tomography-computed tomography (PET/CT) scan and/or physical examination. Patients who had HIV-related Kaposi sarcoma, active hepatitis B or C infection, ongoing immunosuppressive therapy, and active autoimmune disease were not included in the study. All patients had a baseline clinical examination, lesion measurements, and photography of target lesions as well as a baseline PET/CT scan. Patients were evaluated for treatment-related adverse events (AEs) continuously throughout the treatment period and graded according to the NCI Common Terminology Criteria for Adverse Events (NCICTCAE).

The primary endpoint of the study was overall response rate (ORR), determined radiologically by radiologic RESIST v1.1, metabolically via fluorodeoxyglucose (FDG) uptake on a PET/CT, clinically by clinical assessment, and pathologically by review of post-treatment core needle biopsy. Lack of malignant cells in addition to lack of HHV-8 immunohistochemistry (IHC) positivity was defined as pathological complete response (pCR). Secondary endpoints included 6-month progression-free survival (PFS) rate, safety, and tolerability. At a median follow up of 24.4 months, radiologic ORR was 87%, clinical ORR was 78% and metabolic ORR was 62%. Some (6/13) achieved pCR after treatment. In two patients, palliative limb amputation was prevented. Median duration of response was 13.5 months (range 2.1-29.9 months). Median PFS was not reached. The 6-month and 12-month PFS rates were 76.5% and 58.8%, respectively. Immune-related AEs (irAEs) were mostly mild, with all 18 patients experiencing any irAEs and four patients (22%) experiencing grade 3-4 irAEs. Two patients discontinued treatment because of immune-related AEs (irAEs) possibly related to treatment and seven patients discontinued ipilimumab only due to toxicity. Researchers reported no treatment-related deaths.

Key limitations of this study include the lack of randomization and the small sample size, which limits the generalizability and strength of the findings. The lack of a control group makes it difficult to determine the true comparative effectiveness of this combination therapy versus existing therapies. Additionally, there was variability among participants in terms of the number of prior systemic therapies (ranging from 1 to 3 lines of treatment) and the presence of extracutaneous disease. The goal sample size to achieve a statistical power of 0.8 was 20, but this target was not met. In some cases, disease was not detectable on CT scans or FDG-PET but was visible on clinical examination, so post-treatment core-needle biopsies were taken to assess treatment response. However, these biopsies only represented the site sampled, limiting the generalizability of the results.  

This study suggests that the combination of nivolumab and ipilimumab is an effective and relatively safe treatment for patients with advanced and progressive cKS who have received prior systemic therapy. While the study provides valuable preliminary data on this new therapeutic approach, further research is needed. Future studies should focus on identifying clinically practical endpoints specific to cKS, and randomized controlled trials should be conducted to provide more reliable, valid, and generalizable conclusions about the efficacy and safety of this combination therapy.

This article is a summary of: Zer A, Icht O, Yosef L, Avram D, Jacobi O, Fenig E, Kurman N, Peretz I, Shamai S, Merimsky O, Ben-Ami E, Shapira Frommer R, Schwarzbach AE, Bernstine H, Weitzen R, Vornicova O, Bar-Sela G, Stemmer SM, Lotem M. Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS). Ann Oncol. 2022 Jul;33(7):720-727. doi: 10.1016/j.annonc.2022.03.012. Epub 2022 Mar 23. PMID: 35339649.

References

1.     Curtiss P, Strazzulla LC, Friedman-Kien AE. An Update on Kaposi's Sarcoma: Epidemiology, Pathogenesis and Treatment. Dermatol Ther (Heidelb). 2016 Dec;6(4):465-470. doi: 10.1007/s13555-016-0152-3. Epub 2016 Nov 1. PMID: 27804093; PMCID: PMC5120640.

2.     Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, Safaei S, Brunetti O, Racanelli V, Silvestris N, Baradaran B. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials. Int J Mol Sci. 2020 Jun 22;21(12):4427. doi: 10.3390/ijms21124427. PMID: 32580338; PMCID: PMC7352976.