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Treatment with Nivolumab and Low-Dose Ipilimumab is Effective and Tolerable in Patients with Previously Treated Progressive Classical Kaposi Sarcoma

Findings from the single-arm phase II study
08 Apr 2022
Cancer Immunology and Immunotherapy;  Sarcomas

In a prospective, phase II study that assessed the efficacy of nivolumab in combination with low-dose ipilimumab in patients with previously treated classical Kaposi sarcoma, the study team observed high response rates and prolonged duration of response with tolerable toxicity. The overall response rate (ORR) reported in this study is higher than for other systemic agents in HIV or classical Kaposi sarcoma. Molecular analyses suggested immune-cold phenotype. The findings are published by Dr. Alona Zer of the Division of Oncology, Rambam Health Care Campus in Haifa, Israel and colleagues on 23 March 2022 in the Annals of Oncology.

Kaposi sarcoma is a cutaneous angio-proliferative mesenchymal neoplasm of endothelial origin, caused by human herpesvirus 8, a double stranded DNA virus. Four subtypes have been described: the classical Kaposi sarcoma usually affecting men of Jewish or Mediterranean origin, with peak incidence in the sixth decade of life, the endemic subtype in Sub-Saharan indigenous Africans, the HIV-related subtype, and an iatrogenic subtype in immunosuppressed patients.

Although classical Kaposi sarcoma often has a chronic and indolent course, in some cases the disease may progress and involve viscera and lymph nodes causing severe disability. While anti-retroviral therapy is the standard first line therapy in HIV-related Kaposi sarcoma, treatment strategies for classical Kaposi sarcoma are less established, and randomised clinical trials are scarce. Just recently, in May 2020, the US Food and Drug Administration expanded the indication of pomalidomide to include Kaposi sarcoma. It is the first new option for HIV-negative Kaposi sarcoma in more than 20 years.

For treatment of mild and local disease either observation or local therapy (surgical removal, radiotherapy) are optional. However, there is no consensus regarding the indications for systemic therapy and it is often reserved for patients with widespread or rapidly progressing Kaposi sarcoma and for patients with visceral and mucosal involvement. Vinblastine, etoposide or pegylated liposomal doxorubicin have been the mainstay of systemic therapy in classical Kaposi sarcoma, with response rates of 50-70%. Despite the relative chemosensitivity of classical Kaposi sarcoma, duration of response is limited which, in an indolent disease such as this unique tumour, it is a major hurdle.

Little is known on the effect of immunotherapy for the treatment of classical Kaposi sarcoma. While recombinant interferon alfa is approved for treatment of HIV-associated Kaposi sarcoma in the US, there is only limited experience with classical Kaposi sarcoma suggesting this agent is active, but toxic. Due to the viral aetiology, the inflammatory nature of the disease and the increased incidence in immune compromised individuals, the study team hypothesised that immune checkpoint inhibitors might be effective in classical Kaposi sarcoma.

In this study, patients with classical Kaposi sarcoma with progressive disease after at least 1 line of systemic therapy and measurable disease by PET-CT and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The study primary endpoint was ORR. Secondary endpoints included 6-months progression-free survival (PFS) rate and safety.

Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (exome capture transcriptome) of tumour specimens and matched blood.

Between April 2018 and December 2020, the study team enrolled 18 male patients with median age of 76.5 years. At a median follow-up of 24.4 months, the ORR by RECIST v1.1 was 87%. Median duration of response was 13.5 months (range, 2.1-29.9). Metabolic complete response as assessed by PET-CT was observed in 8 of 13 evaluable patients (62%). Six of 13 patients achieved pathological complete response post treatment. In two patients, palliative limb amputation was prevented.

Median PFS was not reached. The 6-months and 12-months PFS rate was 76.5% and 58.8%, respectively.

Only 4 patients (22%) experienced grade 3-4 adverse events. The proportion of grade 3 treatment-related adverse events reported in this study for nivolumab plus ipilimumab is comparable to that of chemotherapeutic agents in this setting. 

The most frequent genomic alteration was biallelic copy number loss of FOX1A gene. The majority of tumours carried a low tumour mutational burden, were microsatellite stable, MMR proficient, did not express PD-L1 and displayed only low lymphocytic infiltrates, rendering them immunologically cold.

These findings are clinically meaningful when placed in the context of currently available treatment options for patients with classical Kaposi sarcoma. The options are limited given the relative scarcity of the disease, the advanced age of many affected individuals, and the frequent presence of comorbidities.

The authors commented that their study outlines the need to identify clinically practical endpoints in classical Kaposi sarcoma studies and the challenge in assessing response to therapy in Kaposi sarcoma, a disease often involving large areas of the skin with associated oedema, both difficult to measure.

The authors found it was hard to achieve reproducible, quantitative assessment of multiple skin lesions even when obtaining photographs, since it is hard to capture changes in lesions nodularity and colour. They included FDG-PET scans to better assess disease burden; however, in some patients, disease was not evident on CT or FDG avid, while response was obvious on clinical examination and could only be confirmed by a biopsy. Thus, in the first interim analysis they adjusted the protocol to include an on-treatment biopsy as another method for response assessment. Nevertheless, as these were core-needle biopsies, they only represent the site sampled, limiting the interpretation of results.

While recent reports suggest some efficacy of immune checkpoint blockade in other sarcoma subtypes, this study provides the first evidence in classical Kaposi sarcoma. A phase I study of pembrolizumab in patients with HIV and advanced cancers included 6 patients with HIV-related Kaposi sarcoma, reported no responses, but prolonged stabilisation. An ongoing phase II study of pembrolizumab in classical and endemic Kaposi sarcoma has been reported at ESMO 2020 Congress with preliminary promising responses achieved.

The authors reasoned how can the presence of an immune-cold profile co-exist with robust efficacy of immune checkpoint inhibitors. They stated that viral carcinogenesis represents a complex process involving multiple pathways in the infected and surrounding cells. Oncogenic viruses disable both the host antiviral and anticancer mechanisms, priming the infected cells for cancerous transformation. This is also why some viral cancers are more prevalent in immune-compromised patients. Nevertheless, the recognition of viral genes by host cells initiates DNA damage response which may increase genetic instability and oncogenic alterations, rendering viral-induced cancers a potential target to immunotherapy.

The authors reported receipt of the research grant from BMS.

Reference

Zer A, Icht O, Yosef L, et al. Phase 2 single arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi Sarcoma (cKS). Annals of Oncology; Published online 23 March 2022. DOI: https://doi.org/10.1016/j.annonc.2022.03.012

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