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