Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy.

Autor:	Rose AAN; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada april.rose@mail.mcgill.ca Anna.Spreafico@uhn.ca.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada., Armstrong SM; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Hogg D; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Butler MO; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada.; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Saibil SD; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada.; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Arteaga DP; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada., Pimentel Muniz T; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada., Kelly D; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada., Ghazarian D; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., King I; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Kamil ZS; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Ross K; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Spreafico A; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada april.rose@mail.mcgill.ca Anna.Spreafico@uhn.ca.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada.; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Jan; Vol. 9 (1).
DOI:	10.1136/jitc-2020-001642
Abstrakt:	Purpose: Anti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma. Methods: We performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS). Results: We identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma. Conclusions: In our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype-including NRAS-should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma. Competing Interests: Competing interests: AANR: Immediate family member is an employee of Merck. AS: Consultant/Advisory Board: Merck, Bristol-Myers Squibb, Novartis, Oncorus, Janssen. Grant/Research support from Clinical Trials: Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma. SDS: Consultant/Advisory Board: Novartis, Janssen. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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