1 Characterization of TRK fusions and therapeutic response to TRK inhibition in hematologic malignancies Taylor J, 1 Yoshimi A 1 , Marcelus C 1 , Pavlick D 2 , Benayed R 1 , Cocco E 1 , Durham BH 1 , Hechtman JF 1 , Bitner L 1 , Chung YR 1 , Mulaney K 1 , Watts JM 3 , Diamond EL 1 , Albacker LA 2 , Mughal T 2 , Ebata K 4 , Tuch B 4 , Ku N 4 , Scaltriti M 1 , Arcila ME 1 , Ali S 2 , Hyman DM 1 , Abdel-Wahab O, 1 Park JH 1 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Foundation Medicine, Inc., Cambridge, MA; 3 University of Miami Miller School of Medicine, Miami, FL; 4 Loxo Oncology, Inc., San Francisco, CA
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Characterization of TRK fusions and therapeutic response to TRK inhibition in hematologic malignancies
1Memorial Sloan Kettering Cancer Center, New York, NY; 2Foundation Medicine, Inc., Cambridge, MA; 3 University of Miami Miller School of Medicine, Miami, FL; 4 Loxo Oncology, Inc., San Francisco, CA
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TRK fusions were among the first kinase fusions discovered
Neurotrophin family of receptors
TRKA (NTRK1) Pain, thermoregulation
TRKB (NTRK2) Movement, memory, mood, appetite, body weight
TRK fusions now described across diverse cancer types
cBioPortal.org
Occur exclusively to other activating kinase fusions
Stransky et al. Nat Commun 2014
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TRK fusions are targetable alterations
The frequency of TRK fusions in hematologic malignancies is unknown &there are no reports of TRK inhibition in patients with hematologic malignancies
93.2
-100-90-80-70-60-50
Max
imum
cha
nge
in tu
mor
size
(%)
-40-30-20-10
01020304050
# #
IFSBreastSalivary glandCholangiocarcinomaPancreas
ThyroidColonMelanomaSoft tissue sarcoma LungGIST
Appendix
# Pathologic complete response
Response to larotrectinib
Hyman et al. J Clin Oncol 2017
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The frequency and characteristics of TRK fusions in hematologic malignancies are unknown
Case reports of TRK fusions in hematologic malignancies:• ETV6-NTRK3 described in AML in 1999 (Eguchi et al. Blood 1999)• ETV6-NTRK3 described in Ph-like ALL in 2014 (Roberts et al. NEJM 2014)
We performed targeted DNA and RNA sequencing across 7311 patients with hematologic malignancies:1201 AML744 MDS659 ALL23 Histiocytic neoplasms1859 MM3345 Other (NHL & HL)
Collaborationwith Foundation
Medicine Inc.
Identified N=8patients with NTRK1, 2, or 3 fusions (0.1%)
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TRK fusions in hematologic malignancies
TPR NTRK1
LMNA NTRK1
TFG NTRK1
ETV6 NTRK2
ETV6 NTRK3
UBE2R2 NTRK3
HNRNPA2B1 NTRK3
Diverse 5’Fusion
Partners
Kinase DomainRetained
in Each Case
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TRK fusions in hematologic malignanciesInterdigitating dendritic
cell sarcoma
Erdheim-Chesterdisease
AML
B-ALL
Multiple myeloma
Not previouslydescribed
Notpreviouslyfunctionallyevaluated
TPR NTRK1
LMNA NTRK1
TFG NTRK1
ETV6 NTRK2
ETV6 NTRK3
UBE2R2 NTRK3
HNRNPA2B1 NTRK3
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TRK fusions transform hematopoietic cells
Different TRKfusions have distinct potency on signaling
Myeloid (32D)
TRK fusiontransformingactivity may bedependent oncell lineage/geneticbackground
Lymphoid (Ba/F3) Myeloid (32D)
Lymphoid (Ba/F3)
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TRK fusion+ Ba/F3 cells are sensitive to TRK inhibition with larotrectinib
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Generation of an ETV6-NTRK2 AML patient-derived xenograft (PDX)
ETV6-NTRK2 expressed in AML only; not CLL
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Generation of an ETV6-NTRK2 AML patient-derived xenograft (PDX)
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ETV6-NTRK2 AML PDX sensitive to TRK inhibition with larotrectinib
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Clinical response to larotrectinib in ETV6-NTRK2 AML
• Received larotrectinib 100 mg BID under FDA expanded access program• Achieved partial remission• Relapsed due to clone bearing ETV6-MECOM fusion
Periods on larotrectinib
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Clinical response to larotrectinib in ETV6-NTRK2 AML
Clearance of TRK+ blasts but persistence of TRK fusion-negative blasts
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Conclusions
• TRK fusions occur across a variety of hematologic malignancies at low frequencies
• As in solid tumors, TRK fusions are targetable drivers in hematologic malignancies
• There is a need for systematic evaluation for TRK fusions across patients with hematologic malignancies
• Further research is necessary to determine response rates to TRK inhibition in hematologic malignancies
• Further studies need to evaluate the clonality of TRK fusions across cancers and whether this is predictive of therapeutic response to TRK inhibition