In:
Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 181-181
Kurzfassung:
Background:PD-1 and PD-L1/PD-L2 are expressed by malignant T-cells in mycosis fungoides (MF) and Sézary syndrome (SS). PD-1 is additionally expressed by tumor-infiltrating cytotoxic T-cells and PD-L1 is expressed by macrophages and other stromal components of the tumor microenvironment in these diseases. Moreover, reports of 9p24.1/PD-L2 translocation and CTLA4-CD28 fusion events in MF/SS support a genomic basis for immune evasion. Here, we explore the clinical activity of pembrolizumab, an immune checkpoint inhibitor of the PD-1/PD-L1 axis, in MF/SS. Methods:Patients (pts) with MF/SS stages IB-IV treated with at least 1 prior systemic therapy were enrolled in this phase 2, single-arm study coordinated by the Cancer Immunotherapy Trials Network (CITN). A Simon two-stage design was applied where stage 2 is initiated if 1 of 9 pts had an objective response. An additional 15 pts were planned in stage 2. Pembrolizumab was administered at 2 mg/kg every 3 weeks and treatment was allowed up to 2 years. The primary endpoint was overall response rate (ORR) as determined by the consensus global response criteria. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative biomarker studies included immunohistochemistry (IHC) staining for PD-L1, PD-L2, and multiple immune subsets as well as serum analysis of 62 cytokines and chemokines. Phenotypic and functional profiling of malignant and non-malignant immune cells will be performed by flow cytometry and mass cytometry (CyTOF). Results: The study completed enrollment and all 24 patients received at least one dose of pembrolizumab. Median age was 67 (range 44-85); 18 were male. Patients were advanced stage with 23 patients (96%) stage IIB or higher, including 15 patients (63%) with stage IVA SS. Most pts were heavily treated with a median of 4 prior systemic therapies (range 1-11). The median follow-up time was 40 weeks (range 9-60 weeks). The objective response rate (ORR) was 38% with 1 complete response (CR) and 8 partial responses (PR). Of the responding pts, 6 pts had 90% or greater improvement in skin disease as measured by mSWAT. An additional 9 pts (38%) had stable disease (SD). The median TTR was 11 weeks (range 8-41 weeks). Responses were durable with 8 of 9 (89%) responses currently ongoing at a median of 32 weeks of duration (4-46). The median PFS has not yet been reached, and the one-year PFS was 69%. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), and number of prior therapies, nor with skin tissue expression of PD-1, PD-L1, PD-L2, or infiltrating CD8+ T-cells as determined by IHC. Planned additional correlatives including CyTOF profiling, gene expression profiling, T cell receptor high throughput sequencing, multiplexed ion beam imaging (MIBI), and whole exome sequencing will explore potential predictive biomarkers of response. Adverse events (AE) were consistent with those seen in prior studies of pembrolizumab with the exception of an immune-mediated skin flare reaction seen in 6 pts (2 grade 2 and 4 grade 3). Skin flares occurred exclusively in patients with SS (6/15; 40%) and were associated with lower serum levels of the cytokines IL-7 and SCF prior to pembrolizumab treatment (p=0.01 and p=0.02 respectively, n.s. by Bonferroni correction). Pts with the skin flare reaction experienced increases in serum IFN-gamma, IL-12p40, IL-15, LIF, G-CSF, and CCL4 following treatment. There were two treatment related serious adverse events (SAE), both immune related. One pt experienced grade 2 pneumonitis which resolved with systemic corticosteroids. Another patient experienced grade 3 diarrhea secondary to steroid-refractory duodenitis. Conclusions: Pembrolizumab has significant clinical activity in pts with previously treated MF/SS. Responses were durable and were not associated with any identifiable clinical or pathologic characteristics. Treatment was well tolerated with a toxicity profile consistent with prior pembrolizumab studies, though 40% of pts with SS developed a notable skin flare reaction. These findings support further study of PD-1 blockade in the treatment of MF and SS. A phase 2 trial of pembrolizumab in combination with interferon-gamma is being developed based on these results. Disclosures Porcu: Millenium: Other: investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Foss:Celgene: Consultancy, Research Funding, Speakers Bureau; Eisai: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Consultancy. Moskowitz:Bristol Myers Squibb: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding. Sokol:Seattle Genetics: Consultancy; Spectrum: Consultancy. Yearley:Merck: Employment. Chartash:Merck: Employment. Townson:Merck: Employment. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Kim:Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Neumedicine: Consultancy; Soligenix: Consultancy; Galderma: Consultancy; Genentech: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Millenium: Consultancy, Other: Investigator in a clinical trial; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; MiRagen: Consultancy; Horizon: Consultancy.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V128.22.181.181
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2016
ZDB Id:
1468538-3
ZDB Id:
80069-7
