Effect of first-line spartalizumab + dabrafenib + trametinib on immunosuppressive features detected in peripheral blood and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma
Autor: | Hussein Abdul-Hassan Tawbi, Victoria Atkinson, Paul Nathan, Naoya Yamazaki, Radha Ramesh, Daniel Gusenleitner, Paolo A. Ascierto, Céleste Lebbé, Eduard Gasal, Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Jan C. Brase, Keith T. Flaherty, Georgina V. Long, Mario Mandalà, Antoni Ribas, Kelly Biette, Erika Richtig, Ana Arance |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Trametinib
Oncology Cancer Research medicine.medical_specialty business.industry First line Melanoma Mutant Medizin Dabrafenib medicine.disease Peripheral blood 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis Internal medicine medicine In patient business Complete response 030215 immunology medicine.drug |
Popis: | 10034 Background: Spartalizumab + dabrafenib + trametinib has previously shown a high response rate of 78% (28 of 36 pts), with a complete response (CR) rate of 42%. A correlative analysis of gene expression signatures (GES)/pathways using whole-transcriptome RNA-seq data from tissue showed that pts with a CR had significantly lower expression levels of immunosuppressive factors in the tumor microenvironment (TME) at baseline (BL). Here we analyze BL peripheral blood markers in the same cohort of pts to assess whether liquid markers can also predict response and clinical outcome to spartalizumab + dabrafenib + trametinib. Methods: The Phase III COMBI-i study (NCT02967692) is evaluating spartalizumab + dabrafenib + trametinib in pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma. In parts 1 (safety run-in; n = 9) and 2 (biomarker cohort; n = 27), blood and tissue samples were collected at BL, on treatment after 2-3 wk and 8-12 wk, and at disease progression. Lactate dehydrogenase (LDH) and other blood-based markers (including cytokine profiling [n = 45] and blood RNA-seq [114 signatures]) were assessed in all 36 pts. Pts were divided into 2 groups of 24 and 12 pts based on progression-free survival (PFS) of > 1 or < 1 y. Results: In addition to LDH, previously described blood markers such as neutrophil to lymphocyte ratio (NLR) and plasma IL-8 were identified among other neutrophil and immunosuppressive features as top candidates associated with PFS > 1 y. Low plasma IL-8 levels were also associated with CR, and multivariate models suggested that IL-8 may add independent predictive value to LDH and NLR for PFS > 1 y and CR. Pts with high IL-8 levels in the circulation were characterized by high neutrophil chemokine signaling (ρ = 0.553) and high neutrophil markers (ρ = 0.466) in the tumor as measured by RNA-seq GES levels. We observed a decrease in plasma IL-8 levels from BL upon treatment with spartalizumab + dabrafenib + trametinib. Conclusions: Our peripheral blood marker analysis confirmed recent findings from tissue samples that intratumoral immunosuppressive features may preclude a CR and are associated with poor outcomes. High BL plasma IL-8 levels may be associated with an immunosuppressive TME. Further validation is warranted; the randomized placebo-controlled part 3 of COMBI-i is ongoing. Clinical trial information: NCT02967692. |
Databáze: | OpenAIRE |
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