Cancers digestifs NTRK réarrangés –Larotrectinib

Cancers digestifs NTRK réarrangés –Larotrectiniba New TRans-tumor Kid on the block ?

Pr Antoine ItalianoGustave Roussy, VillejuifInstitut Bergonié, BordeauxUniversité de Bordeaux

TRK Biology

TRK Receptors Mediate Neurotrophin Signaling• Neurotrophins are important growth factors that promote sympathetic nervous

system development1,2

• Neurotrophin signaling occurs through activation of the TRK receptor family1,2

Neurotrophin Family of Receptors1–6

TRK Receptor

Gene (Chromosomal

Location)

Functions

Natural LigandsDevelopmental Adult

TRKA NTRK1 (1q23.1) Cellular differentiation/sensory neuron subtype specification and development of pain and thermoregulation modalities1,3

Pain signaling, thermoregulation

Nerve growth factor (NGF), neurotrophin-3 (NT-3)

TRKB NTRK2 (9q21.33) Development of sensory neurons in the brain1,3

Regulation of movement, memory, mood, appetite, body weight

Brain-derived neurotrophic factor (BDNF), neurotrophin-3/4/5 (NT-3/4/5)

TRKC NTRK3 (15q25.3) Neuronal differentiation, axon outgrowth/guidance, and synaptic plasticity1,3 Proprioception NT-3

Neurotrophin Signaling1,3

AKT, protein kinase B; ERK, extracellular signal-regulated kinase; Tyr, tyrosine.1. Nakagawara A. Cancer Letters. 2001;169:107-114.2. Vaishnavi A, et al. Cancer Discov. 2015;5:25-34.3. Blake J, et al. EORTC-NCI-AACR Conf. 2016;69:ENA-0491/

Poster No. 442.

4. https://www.ncbi.nlm.nih.gov/gene/4914, accessed April 10, 2018. 5. https://www.ncbi.nlm.nih.gov/gene/4915, accessed April 10, 2018. 6. https://www.ncbi.nlm.nih.gov/gene/4916, accessed April 10, 2018.

https://www.ncbi.nlm.nih.gov/gene/4914



Increased activation

Substitution

ERK

AKT

NTRK1/2/3

Constitutive kinase activity (autophosphorylation) Ligand-independent

receptor activation

DNA

ProteinPP

PPChimeric TRK receptor expressed

NTRK gene fusion

mRNA 5′ partner NTRK kinase domainIn-frame fusion transcribed Large intronic regions excised

5′ partner NTRK kinase domain5′ partner (with promoter) LBD Kinase domain

Intron Intron Intron

NTRK Gene Fusions May Lead to TRK Fusion Proteins That Are Oncogenic DriversNRTK gene fusions – NOT SNVs, CNVs, or other alterations – are oncogenic

AKT, protein kinase B; CNV, copy number variant; ERK, extracellular signal-regulated kinase; LBD, ligand-binding domain; SNV, single nucleotide variant.1. Amatu A, et al. ESMO Open. 2016;1:e000023; 2. Vaishnavi A, et al. Cancer Discov. 2015;5:25-34; 3. Hyman DM, et al. J Clin Oncol. 2017;35:LBA2501.

Timeline of key advances relating to the biology and therapeutic targeting of TRK signaling

Cocco E. et al. NaTureReviews. 2018

• The discovery of gene fusions dates back to the 1980s

Distribution and frequency of NTRK fusions in adult and paediatric tumours

Cocco E. et al. NaTureReviews. 2018

NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfallsSolomon et al . Modern Pathology 2019

Prevalence of NTRK fusions in various tumor types

NTRK: n=87

• In carcinomas of the lung, pancreas, biliary tract, and appendix, NTRK fusions are seen in our cohort at a prevalence ranging from 0.3% to 0.5%

• In this study, NTRK fusions were mutually exclusive with strong activating MAPK pathway alterations

• No KRAS, BRAF, NRAS, EGFR hotspotmutations nor kinase fusions were detected in the NTRK fusion cohort in Trk-inhibitor naive cancers

Relation between NTRK gene fusions and the other oncogenic drivers

Cocco et al. Cancer Research 2019

• 2,314 colorectal carcinomas

• NTRK gene fusions are associated to MSI-high tumors

• NTRK gene fusions are mutually exclusive of other genomic alterations

Spectrum and molecular characteristics of kinase fusions in colorectal carcinoma


NTRK have been reported as more frequently expressed in MSI-high tumors in colorectal carcinoma patients

Pietrantonio, F et al. JNCI 2017

Relationship between MLH1 hypermethylation status and the presence of NTRK

Wang et al. Modern Pathology (2019)

• Survival outcomes in patients with Stage III/IV dMMR colorectal cancer. - Cancer-specific survival in patients with oncogenic fusions (red line) is compared with those without

oncogenic fusions (blue line) using the Kaplan–Meier method.

dMMR: DNA mismatch repair deficient

NTRK rearranged tumors had short OS independent from MSI status

Pietrantonio, F et al. JNCI 2017

• Survival in metastatic colorectal cancer patients carrying ALK, ROS1, and NTRKrearranged tumors

Larotrectinib Overview

Larotrectinib Is a Highly Selective TRK Inhibitor

First and only selective TRK inhibitor1

High potency against TRKA, TRKB, and TRKC1

IC50 = 5–11 nM in cellular assays

Slow dissociation; inhibitor stays bound to target2

T1/2: 160 min

High selectivity1,2

Limited inhibition of other kinases≥100-fold selectivity versus 229 other kinases

1. Hyman DM, et al. J Clin Oncol. 2017;35:LBA2501.

2. Drilon A, et al. N Engl J Med. 2018;378:731-739.

50403020100

–10–20–30–40–50–60–70–80–90

–100

Soft-tissue sarcoma93.2

Lung tumor

Gastrointestinal stromal tumor

Thyroid tumor

Colon tumor

Melanoma

Salivary-gland tumor

Cholangiocarcinoma

Pancreatic tumor

Appendix tumor

Infantile fibrosarcoma

Breast tumor

Response by Tumor Type Response by Adult vs. Pediatric

Efficacy Across Tumor Type, Age, NTRK Gene, or Fusion Partner

50403020100

-10-20-30-40-50-60-70-80-90

-100

93.2Adult patients

Pediatric patients

Response by Fusion Partner50403020100

-10-20-30-40-50-60-70-80-90

-100

TPM393.2

TPM4

LMNA

STRN

ETV6

TRIM63TPRNTRK1

NTRK2

NTRK3

PDE4DIPCTRC IRF2BP2 SQSTM1 PPL

Response by NTRK Gene50403020100

-10-20-30-40-50-60-70-80-90

-100

93.2NTRK1

NTRK2

NTRK3

Drilon A, et al. N Engl J Med. 2018;378:731-739.

Safety

Hyman, David M., van Tilburg, Cornelis M., Albert, Catherine M., et al. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. European Society of Clinical Oncology 2019; September 28, 2019. Barcelona, Spain. Abstract 445PD.

Efficacy and Safety of Larotrectinib in Patients with TRK Fusion Gastrointestinal Cancer Data cut-off was February 19, 2019 ASCO GI 2020 - Abstract Number: 824

Jordan Berlin et al. ASCO GI 2020 – Abstract N° 824

Patient characteristics• From March 2015 through February 2019, 159 patients with TRK fusion cancer were enrolled

- 14/159 (8.8%) had TRK fusion GI cancer

• A variety of NTRK fusion partner genes were present across the different GI tumor types

• Among patients with colon cancer, seven were MSI-high and one was microsatellite-stable



Efficacy of Larotrectinib in Patients with TRK Fusion Gastrointestinal Cancer


Efficacy of Larotrectinib in Patients with TRK Fusion Gastrointestinal Cancer Best change in tumor size by tumor type

• Median time to response: 1.8 months (range 1.7–2.1)

• Duration of response ranged from 3.5 to 14.7+ months

• Time on treatment ranged from 0.9 to 19.0+ months

• At the data cut-off, 4 patients with colon cancer and 1 patient with pancreatic cancer were alive without disease progression



• median PFS: 5.3 months (95% CI, 2.2–9.0)(for the patients with colon cancer, the PFS ranged from 1.5 to 16.7+ months)

• Median OS: 33.4 months (95% CI, 2.8–36.5)(3 patients continued treatment post-progression at the investigator’s discretion)



Patients with multiple severity ratings for a given AE are counted once under the maximum severity.Reported AE terms were coded using MedDRA dictionary (version 21.1). Severity grade assignment based on CTCAE (v4.03)

Safety of Larotrectinib in Patients with TRK Fusion Gastrointestinal Cancer Grade 3–5 treatment-emergent AEs in patients with TRK fusion GI tumors

• Grade 3 or 4 treatment-emergent AEs occurred in 9 patients

• Grade 3 or 4 treatment-related AEs occurred in 1 patient (Grade 3 nausea)

• 1 patient discontinued due to a treatment-emergent AE of Grade 4 jaundice (this was deemed not related to treatment)

• Grade 5 treatment-emergent AEs occurred in 2 patients. - The deaths were deemed not related to treatment- There were no discontinuations or deaths due to treatment-

related AEs

• Dose modifications (missed, skipped, or delayed doses) due to AEs occurred in 7 patients.

- There were no dose reductions due to AEs


Case study: TPM3-NTRK1 gene fusion-positive MSI-high colorectal cancer

Jordan Berlin et al. ASCO GI 2020 – Abstract N° 824 Images courtesy of Professor David Hong, MDACC

• 85-year-old female with colorectal cancer metastasized to the bowel and liver

• Testing of tumor sample detected deficient mismatch repair (MLH1/PMS2) and a TPM3-NTRK1 gene fusion; the tumor was identified as CpG island methylator phenotype (CIMP)-high

• Initially treated with pembrolizumab with progressive disease after 3 months

• The patient was enrolled in the phase II NAVIGATE trial and initiated treatment withlarotrectinib (100 mg twice daily orally).

• The patient developed Grade 3 elevation of liver function tests, was dose-reduced to 50 mgtwice daily, and re-escalated to full dose upon resolution of the elevated liver function tests.This AE occurred after the data cut-off of February 19, 2019.

• At 6 months, the patient achieved a confirmed partial response by investigator assessment(RECIST) with a maximum tumor shrinkage of –42%.

• The patient remains on larotrectinib with no foreseeable safety concerns and hasmaintained a partial response after 15 months on larotretinib.


Efficacy and Safety of Larotrectinib in Patients with TRK Fusion Gastrointestinal Cancer

Data cut-off was February 19, 2019

ESMO Scale of Clinical Actionability for Molecular TargetsESMO Scale of Clinical Actionability for Molecular Targets (ESCAT) has categorised Larotrectinib as Tier IC

As a Tier IC drug, access to Larotrectinib treatment should be considered standard of care for patients with NTRK gene fusions

Mateo J, et al. Ann Oncol. 2018 Sep 1;29(9):1895-190

Larotrectinib :

• 26 Novembre 2018 : La FDA a octroyé une AMM aux États-Unis pour le larotrectinib dans une indication indépendante de l’histologie (breakthrough therapy)• Libellé d’indication de l’AMM aux Etats-Unis:

• VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that : • have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and• have no satisfactory alternative treatments or that have progressed following treatment.

• 31 Janvier 2019 : La commission d’évaluation initiale de l’ANSM rend un avis favorable pour une première ATU de cohorte pour le larotrectinib dans une indication fondée sur un évènement moléculaire• Libellé d’indication dans le cadre de l’ATUc:

• LAROTRECTINIB est indiqué en monothérapie dans le traitement des patients adultes et pédiatriques à partir d’un mois, atteints de tumeurs solides localement avancées ou métastatiques présentant une fusion NTRK (Neurotrophic Tyrosine Receptor Kinase), réfractaires aux traitements standards ou en l’absence d’alternative thérapeutique appropriée.

• 19 septembre 2019 : EMA a octroyé une AMM européenne conditionnelle centralisée pour le larotrectinib

AMM conditionnelle Européenne

VITRAKVI est indiqué en monothérapie pour le traitement des patients adultes et pédiatriques atteints d’une tumeur solide présentant une fusion du gène NTRK (Neurotrophic Tyrosine Receptor Kinase), - ayant une maladie au stade localement avancé ou métastatique, ou pour laquelle une résection chirurgicale risquerait d’entraîner une morbidité sévère, et- lorsqu’il n’existe aucune option thérapeutique satisfaisante

Gene Fusion Diagnostic Testing

The Art of Identifying NTRK Gene FusionsMultiple Fusion Partners

• NTRK gene fusions occur in a tumor-agnostic manner , This highlights the need for comprehensive NTRK gene fusion testing

IFS, SBC, CMN, MASC, AML, PTC, pediatric gliomas

Pediatric gliomas

PTC

Colon, PTC, sarcoma, lung ADC

Spitz nevi

PTC

Cholangiocarcinoma

GlioblastomaLung ADC

Spitz nevi

Lung ADC

Glioblastoma

Pediatric gliomas

Lung ADC

Astrocytoma

SCCHN

AstrocytomaPediatric gliomas

NTRK3ETV6

BTBD1

TPR

TPM3

TP53

TFG

RABGAP1L

NTRK1NFASCMPRIP

CD74

VCL

BCAN

LMNA

TRIM24

QKI

PAN3NTRK2

NACC2 AGBL4

ADC, adenocarcinoma; AML, acute myeloid leukemia; CMN, congenital mesoblastic nephroma; IFS, infantile fibrosarcoma; PTC, papillary thyroid cancer; SBC, small bowel cancer; SCCHN, squamous cell carcinoma of the head and neck.Vaishnavi A, et al. Cancer Discov. 2015;5:25-34.Image adapted from: ArcherDx. Neurotrophic tyrosine kinase (NTRK) genes. http://archerdx.com/company/blog/applications/ntrk. Accessed August 14, 2018.

Diagnostic Testing Overview• NTRK gene fusions are oncogenic genomic alterations that are generally mutually exclusive with other

driver gene mutations such as ALK and BRAF1

• Testing for NTRK gene fusions is essential to identify patients who harbor these genomic alterations and may therefore benefit from larotrectinib1-3

NTRK gene fusions can be detected indirectly or directly by multiple methods, including:2-4

FISH RT-PCRIHC

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; FISH, fluorescence in situ hybridization; IHC = immunohistochemistry; NGS, next generation sequencing; RT-PCR, reverse transcriptase-polymerase chain reaction1. Stransky N, et al. Nat Commun. 2014;5:846.2. Prasad ML, et al. Cancer. 2016;122(7):1097-1107. 3. Brenca M, et al. J Pathol. 2016;238(4):543-549.4. Hechtman JF, et al. Am J Surg Pathol 2017;41:1547-1551.

NGS

ESMO-proposed NTRK Fusion Detection Algorithm

Histologic tumor type known to harbor highly recurrent NTRK

rearrangements

Is a sequencing platform available?

Consider FISH or RT-PCR assays with specific probes for the rearrangement involving the

known NTRK gene

Yes

No

YesNo

If cost-effective, use frontline MPS targeted gene panel

including NTRK genes (and possibility to investigate

rearrangements)

Use IHC as a screening tool

No TRK expression Detection of TRK expression

MPS, massive parallel sequencingMarchiò C on behalf of the ESMO Working Group, in preparationReis-Filho JS. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany

Workflow for molecular testing in colorectal carcinoma


should be performed universally in CRC

Proposed strategy for screening oncogenic fusions such as ALK, NTRK, and RET rearrangements in CRCs

Wang et al. Modern Pathology (2019)

CONCLUSION

• NTRK gene fusions are rare, but recurrent ongenic drivers identified across diverse pediatric and adult cancers.

• Larotrectinib, a highly selective and potent inhibitor of all TRKs, demonstrate robust tumor-agnostic and age-agnostic antitumor activity against NTRK fusion cancer, regardless of NTRK gene or gene fusion partner involved– ORR of 79% (n=153), per investigator assessment,– Confirmed responses and disease control were achieved with Larotrectinib in heavily pre-treated

TRK fusion GI cancer, 50% with colon cancer had a partial responses• Larotrectinib has a good safety profile. Larotrectinib was generally well tolerated in patient with TRK fusion

GI cancer; there were no discontinuations or death du to treatment-related AEs• Post ATUc is ongoing in France since 13/11/2019 after MAA was obtained• Larotrectinib obtained MAA in Europe since 19/09/2019• These results support routine testing for NTRK gene fusions

Documents

Cancers digestifs NTRK réarrangés –Larotrectinib