NTRK: Larotrectinib
Héctor Callata MD
Clin Cancer Res;24(23); 5807–14
Tropomyosin receptor kinase (TRK) family:
NTRK1, NTRK2 and NTRK3 genes.
Binding of neurotrophins
chr 1 chr 9 chr 15
An Oncogenic NTRK Fusion
Clin Cancer Res;24(23); 5807–14
Oncogenic NTRK fusions
CCR-18-3694, 0.1158/1078-0432.
NTRK(+) adult tumors
NTRK assessment
NTRK testing
NTRK IHC testing
NTRK methodology: FISH
NGS as methodology to detect NTRK
Strategy in high fusion frequency
Strategy in low fusion frequency
The FJD experience1151 cancer cases tested by immunohistochemistry
Tumor type Localization Fusion Assay IHC
Secretory breast carcinoma Breast NTRK3-ETV6 RNA PanCancer Positive
Adenocarcinoma Lung NTRK3-ETV6 RNA PanCancer Positive
Adenocarcinoma Lung NTRK1-TMP3 Oncomine Comprehensive Positive
Papillary carcinoma Thyroid NTRK1-TMP3 Oncomine Comprehensive Positive
Leiomyosarcoma Uterus NTRK3-ETV6 Oncomine Comprehensive Positive
Undifferentiated biphasic tumor of low malignant
potential
Retroperitoneal/small bowel NTRK3-ETV6 Oncomine Comprehensive Positive?
Desmoplastic melanoma Skin NTRK2-VCAN RNA PanCancer Negative
Neuroendocrine carcinoma Lung NTRK1-TMP3 Oncomine Comprehensive Positive
Melanoma Skin NTRK3-ETV6 Oncomine Comprehensive Positive
Serous carcinoma Peritoneal NTRK1-TMP3 Oncomine Comprehensive Positive
Adenocarcinoma Colorectal NTRK1-TMP3 Oncomine Comprehensive Positive
Adenocarcinoma Colorectal NTRK1-LMNA Oncomine Comprehensive Positive
Melanocitosis Skin NTRK2-VCAN RNA PanCancer Negative
Desmoplastic small round cell tumor Retroperitoneal None RNA PanCancer Positive
Neuroendocrine carcinoma Apendix None RNA PanCancer & Oncomine
Comprehensive
Positive
NTRK inhibitors
Clin Cancer Res; 24(23); 5807–14. 2018 AACR.
Larotrectinib Formulations and Dosing
1. Laetsch TW, et al. J Clin Oncol. 2017;35:10510; 2. Laetsch TW, et al. Lancet Oncology. 2018;S1470-2045(18)30119-0; 3. Data on file. Clinical Protocol LOCO-TRK-
15003. Loxo Oncology.
• Larotrectinib formulations and doses1–2
– Liquid formulation (20 mg/mL)
–Hard gelatin capsules • 25 mg
• 100 mg
• Dosing1,2
–Adult: 100 mg BID orally
–Pediatric (1 month to 18 years): 100 mg/m2 BID orally (maximum 100 mg BID)
• Larotrectinib can be taken with or without food, and formulations can be used interchangeably3
Clinical Evidence
A pooled analysis from three larotrectinib
clinical trials was performed1,2
*Confirmation testing was not required or routinely performed. †Assessed by independent radiology review according to RECIST 1.1.
‡According to investigator’s assessment. Tumor assessments were performed at baseline and every 8 weeks for 1 year and every 12 weeks thereafter until disease progression.
BSA, body surface area; CLIA, Clinical Laboratory Improvement Amendments; CTCAE, Common Terminology Criteria for Adverse Events; FISH, fluorescence in situ hybridization; NGS,
next-generation sequencing; PFS, progression-fress survival; RECIST, Response Evaluation Criteria in Solid Tumours.
1. Hyman DM, et al. J Clin Oncol. 2017;35:LBA2501; 2. Drilon A, et al. N Engl J Med. 2018;378:731-739.
Adult phase 1
• Age ≥18 years
• Advanced solid tumors
SCOUT pediatric phase 1/2
• Age ≤21 years
• Advanced solid tumors
NAVIGATE adult/adolescent
phase 2 ‘Basket Trial’
• Age ≥12 years
• Advanced solid tumors
• NTRK gene fusion
N=55Patients harboring
NTRK gene fusions
n=12
TRK fusion status
• Determined by local CLIA (or similarly
accredited) laboratories
• Assessed by NGS (n=50) and FISH
(n=5) in 15 laboratories*
Primary endpoint (combined analysis)
• Overall response rate (ORR)†
Secondary endpoints
• ORR‡
• Duration of response
• PFS
• Safety (CTCAE 4.0)
Dosing
• Adults: 100 mg BID
• Children with BSA <1 m2: 100 mg/m2
BID
• Treatment beyond progression is
permitted if patient continues to benefit
43 adult pts
Adult and paediatric patients with a range of solid tumour
types harbouring NTRK fusions were included
Drilon A et al. N Eng J Med 2018;378:731–9.
Larotrectinib demonstrated a promising overall response rate
Drilon A et al. N Eng J Med 2018;378:731–9.
Change in tumour size across tumour type and age
Drilon A et al. N Eng J Med 2018;378:731–9.
50
40
30
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100
Soft-tissue sarcoma
93.2
Lung tumour
Gastrointestinal stromal
tumour
Thyroid tumour
Colon tumour
Melanoma
Salivary-gland tumour
Cholangiocarcinoma
Pancreatic tumour
Appendix tumour
Infantile fibrosarcoma
Breast tumor
Efficacy by Tumor Type
Efficacy by Adult vs. Pediatric50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
93.2
Adult patients
Pediatric patients
Change in tumour size by NTRK gene and fusion partner
Drilon A et al. N Eng J Med 2018;378:731–9.
Efficacy by NTRK Gene50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
93.2
NTRK1
NTRK2
NTRK3
Efficacy by Fusion Partner50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
TPM3
93.2
TPM4
LMNA
STRN
ETV6
TRIM63TPRNTRK1
NTRK2
NTRK3
PDE4DIPCTRC IRF2BP2 SQSTM1 PPL
Durable responses to larotrectinib were achieved
Drilon A et al. N Eng J Med 2018;378:731–9.
Durable responses to larotrectinib were achieved
Drilon A et al. N Eng J Med 2018;378:731–9.
55 31 12 7 2 0No. at risk
Pa
tie
nts
with
re
sp
on
se
(%
)
100
50
25
0
0
75
6 12 18 24 30
Months since start of response
73
Progression-free survival
44 22 10 5 1 0No. at risk
Pa
tie
nts
with
re
sp
on
se
(%
)
100
50
25
0
0
75
6 12 18 24 30
Months since start of response
83
Duration of response
• Median duration of response and PFS had not been reached after 1 year
• At a median follow-up time of 9.4 months, 86% of the patients with a response were continuing treatment or
had surgery with curative intent
55% of patients
progression free
71% of responses ongoing
Larotrectinib has an encouraging safety profile
Drilon A et al. N Eng J Med 2018;378:731–9.
AEs (%)
Grade 1 Grade 2 Grade 3 Grade 4 All grades
ALT/AST increased 31 4 7 0 42
Fatigue 20 15 2 0 36
Vomiting 24 9 0 0 33
Dizziness 25 4 2 0 31
Nausea 22 7 2 0 31
Anemia 9 9 11 0 29
Diarrhea 15 13 2 0 29
Constipation 24 4 0 0 27
Cough 22 4 0 0 25
Weight increased 11 5 7 0 24
Dyspnea 9 9 0 0 18
Headache 13 4 0 0 16
Pyrexia 11 2 2 2 16
Arthralgia 15 0 0 0 15
Back pain 5 9 0 0 15
Neutrophil count decreased 0 7 7 0 15
• Clinically significant AEs were uncommon
• 93% of all AEs were Grade 1 or 2
• The most common Grade 3 or 4 AEs were
– Anemia (11%)
– ALT/AST increase (7%)
– Weight increase (7%)
– Neutrophil count decreased (7%)
Larotrectinib has an encouraging safety profile
TRAE, treatment-related adverse events
Treatment-Related Adverse Events Occurring in ≥2% of Patients
Drilon A et al. N Eng J Med 2018;378:731–9.
• No Grade 4 or 5 TRAEs
• No Grade 3 TRAEs occurred in ≥5%
of patients
• 15% of patients (8/55) required dose reductions
– All patients maintained best response at the lower dose
– No responding patients discontinued treatment due to an AE
Patients with TRK fusion cancer: Supplementary dataset
Lassen-U, ESMO 2018
Patients with TRK fusion cancer: Supplementary dataset
Lassen-U, ESMO 2018
Patients with TRK fusion cancer: Supplementary dataset
Lassen-U, ESMO 2018
Supplementary dataset:
Larotrectinib efficacy consistent with primary dataset
Lassen-U, ESMO 2018
Supplementary dataset:
Larotrectinib efficacy consistent with primary dataset
Lassen-U, ESMO 2018
Integrated dataset: Larotrectinib is efficacious regardless of age
Lassen-U, ESMO 2018
Integrated dataset: Duration of larotrectinib treatment
Lassen-U, ESMO 2018
Sustained responses with larotrectinib (DOR)
Lassen-U, ESMO 2018
Adverse events with larotrectinib: ≥15% in safety database (n=207)
Lassen-U, ESMO 2018
Larotrectinib in adult patients with solid tumours:
a multi-centre open-label phase I
Larotrectinib in adult patients with solid tumours:
a multi-centre open-label phase I
Larotrectinib in adult patients with solid tumours:
a multi-centre open-label phase I
Resistance mechanisms
Where have been detected these mutations?
Clin Cancer Res; 24(23); 5807–14. 2018 AACR.
Larotrectinib: clinical summary
Drilon A, et al. N Engl J Med. 2018;378:731-739.
Detection of TRK fusions will be needed to identify
patients who may benefit from larotrectinib
Larotrectinib is a potent, highly selective TRK inhibitor that induced early, durable
antitumour responses in children and adults with TRK fusion solid tumoursEfficacy
The safety profile of larotrectinib indicates suitability for long-term administration
• Adverse events requiring dose modifications were rare
• No patient discontinued treatment due to a drug-related adverse event
Safety
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