TY - JOUR
T1 - Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy
AU - Khan, Shaheer
AU - Lutzky, Jose
AU - Shoushtari, Alexander N.
AU - Jeter, Joanne
AU - Marr, Brian
AU - Olencki, Thomas E.
AU - Cebulla, Colleen M.
AU - Abdel-Rahman, Mohamed
AU - Harbour, J. William
AU - Sender, Naomi
AU - Nesson, Alexandra
AU - Singh-Kandah, Shahnaz
AU - Hernandez, Susana
AU - King, Jeanelle
AU - Katari, Manpreet S.
AU - Dimapanat, Lyssa
AU - Izard, Stephanie
AU - Ambrosini, Grazia
AU - Surriga, Oliver
AU - Rai, Alex J.
AU - Chiuzan, Codruta
AU - Schwartz, Gary K.
AU - Carvajal, Richard D.
N1 - Funding Information:
SK reports honoraria from Castle Biosciences. JL reports advisory/consulting fees from Regeneron, Sapience Therapeutics, Agenus, and research funding from Bristol Myers Squibb, Novartis, Agenus, Vyriad, Regeneron, Immunocore, Foghorn, Replimmune, InstilBio, Iovance, InflaRx, and Trisalus. ANS reports advisory/personal fees from Bristol Myers Squibb, Immunocore, Novartis, and research funding from Pfizer, Bristol Myers Squibb, Immunocore, Novartis, Targovax, Polaris, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linneaus Therapeutics, and Prelude Therapeutics. GKS reports stock or other ownership interests in GenCirq, Bionaut Labs, and January Therapeutics; advisory/consulting/personal fees from Bionaut Labs, Ellipses Pharma,GenCirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, OnCusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech Health, and Killys Therapeutics; research funding from Astex Pharmaceuticals, Incyte, Calithera Biosciences, Lilly, Daiichi Sankyo, Fortress Biotech, Karyopharm Therapeutics, Oxford Biotherapeutics, TopAlliance Biosciences, Adaptimmune, Springworks Therapeutics, and TRACON Pharma. RDC reports consulting fees from Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath Systems, Eisai, Jiangsu Hengrui Pharmaceuticals, Ideaya Biosciences, Immunocore, InxMed, Iovance, Merck, Novartis, OncoSec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics, Trisalus and advisory board fees from Aura Biosciences, Chimeron, and Rgenix.
Funding Information:
Drug and funding for this investigator-sponsored research study was provided by Pfizer, Inc (New York, NY, USA). The sponsor had no role in data collection, analysis, interpretation, or in writing of this report.
Publisher Copyright:
Copyright © 2022 Khan, Lutzky, Shoushtari, Jeter, Marr, Olencki, Cebulla, Abdel-Rahman, Harbour, Sender, Nesson, Singh-Kandah, Hernandez, King, Katari, Dimapanat, Izard, Ambrosini, Surriga, Rai, Chiuzan, Schwartz and Carvajal.
PY - 2022/8/29
Y1 - 2022/8/29
N2 - Introduction: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. Materials and Methods: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. Results: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. Conclusions: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.
AB - Introduction: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. Materials and Methods: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. Results: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. Conclusions: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.
KW - adjuvant therapy
KW - crizotinib
KW - extracellular vesicles
KW - high-risk
KW - uveal melanoma
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U2 - 10.3389/fonc.2022.976837
DO - 10.3389/fonc.2022.976837
M3 - Article
C2 - 36106113
AN - SCOPUS:85138080774
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 976837
ER -