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ESMO ADVANCED COURSE ON NTRK GENE FUSION: Tolerance profile and recommendation for use David Planchard, MD, PhD Head of thoracic group Department of Cancer Medicine Institut Gustave Roussy Villejuif, France Barcelona, 21-22 October 2019

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Page 1: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

ESMO ADVANCED COURSEON NTRK GENE FUSION:

Tolerance profile and recommendation for

use

David Planchard, MD, PhD

Head of thoracic groupDepartment of Cancer Medicine

Institut Gustave Roussy

Villejuif, France

Barcelona, 21-22 October 2019

Page 2: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

DISCLOSURE OF INTEREST

Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim,

Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche

Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck,

Novartis, Pfizer, prIME Oncology, Peer CME, Roche

Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck,

Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo

Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer

Page 3: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

NTRK fusions are identified across multiple paediat ricand adult cancer histologies

E. Cocco et al, nature reviews 2018

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TRK inactivation can result in unique consequences

reported in patients

treated with TRK

inhibitors

- paresthesias

- weight gain

- cognitive

disturbance

- dizziness NTRK1

NTRK2

NTRK3

E. Cocco et al, nature reviews 2018

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Profiles of TRK inhibitor activity

E. Cocco et al, nature reviews 2018

Larotrectinib

(Vitrakvi)

Entrectinib

(Rozlytrek)

Regulatory Approval

United States

Canada

Brazil

Europe (24 sept 2019)

United States

Japan

Page 6: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

TRK Inhibitors in Development and Trials that

Contributed Data to Regulatory Cohorts

Demetri et al ESMO 2018, Drilon et al NEJM 2017

Larotrectinib (Vitrakvi) Entrectinib (Rozlytrek)

TKI Generation

First ✓ ✓

Drug Inhibits

TRKA/B/C ✓ ✓

ROS1 ✓

ALK ✓

Contributory Trials

Adult/Adolescent TrialsNAVIGATE

Phase I Trial

STARTRK-2

STARTRK-1

ALKA-372001

Pediatric Trials Phase I/II STARTRK-NG

Page 7: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

54 patients on ALKA-372-001:

-19pts on Schedule A (fasted, 4 days on entrectinib and 3 days off entrectinib for 21 of 28 days)

- 29pts on Schedule B (fed, continuous daily dosing for 28 days)

- 6pts on Schedule C (fed, 4 days on entrectinib and 3 days off entrectinib for 28 days)

All 65 patients on STARTRK-1 received continuous daily dosing with entrectinib (daily for 28 days)

Page 8: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Patient characteristics at baseline

once-daily (fed) in

4-week cycles A.Drilon et al, cancer discovery 2017

Page 9: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Adverse events (reported in ar least 10% of pts (n=119) (phase I ALKA-372 or STARTRK-1)

A.Drilon et al, cancer discovery 2017

• All related AEs reversible with dose modifications• Dose reduction occurred in 15% (n=18/119) of pts

Page 10: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

DLT (entrectinib ALKA-372- 001 and STARTRK-1)

• No DLT observed on ALKA-372- 001

• 2 DLTs occurred on STARTRK-1 at a daily dose of 800 mg:

– Cognitive disturbance (grade 3)

– Fatigue (grade 3)

� both resolved with dose interruption

• At the 800 mg dose level, one additional patient experienced Grade 4

eosinophilic myocarditis (the only Grade 4 treatment-related adverse event)

– This event occurred after two doses of entrectinib

– pt subsequently discontinued from study and fully recovered from the event

• No Grade 5 treatment-related adverse events reported

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Recommended dose (entrectinib )• Continuous dose of 600 mg daily identified as the fixed-dose MTD and RP2D in

adults

• Plasma half-life of entrectinib: 20 to 22 hours and compatible with a once-daily,

continuous dosing regimen

• A high-fat (approximately 50% of total caloric content), high-calorie

(approximately 800 to 1000 calories) meal did not have a significant effect on

entrectinib exposure

PK of entrectinib at steady

state (continuous daily dosing)

In the STARTRK-1 study, entrectinib administered

with food and exposure increased in a linear manner from 100

to 400 mg/m2, and from 600 to 800 mg flat dosing.

Steady state was reached within 2 weeks of continuous dosing

Page 12: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Recommended Dose Reductions

Page 13: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment
Page 14: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Analysis design (ROS1+ NSCLC)

Page 15: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment
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≥20%

Page 18: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment
Page 19: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Analysis design (NTRK NSCLC)

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The overall safety profile of first-generation TRK inhibition (entrectinib ) is favorable

Demetri et al, ESMO 2018

≥20%

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The overall safety profile of first-generation TRK inhibition (entrectinib ) is favorable

Demetri et al, ESMO 2018

≥20%

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ROZLYTREK (entrectinib)• Adult patients with metastatic NSCLC whose tumors are ROS1-positive

• Adult and pediatric patients 12 years of age and older with solid tumors that: have a NTRK

gene fusion without a known acquired resistance mutation

• Entrectinib is metabolized primarily by CYP3A4 (~75%)

• 600 mg orally once daily with or without food

– Moderate CYP3A Inhibitors: 200 mg orally once daily

– Strong CYP3A Inhibitors: 100 mg orally once daily

• No dose adjustment recommended for pts with mild or moderate renal impairment

• No dose adjustment recommended for pts with mild (total bilirubin ≤ 1.5 times ULN)

hepatic impairment

FDA and Japan approvals

FDA

Page 23: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Clinical Trial Experience• Most frequent adverse reactions resulting dose reductions (≥ 1%):

– Dizziness (3.9%)

– Increased blood creatinine (3.1%)

– Fatigue (2.3%)

– Anemia (1.7%)

– Increased weight (1.4%)

• Most frequent adverse reactions (≥ 2%) resulted in interruption:

– Increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea

(2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%),

pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%)

Page 24: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

• CNS Effects:

– Cognitive impairment, mood disorders, dizziness, and sleep disturbances

• QTc interval prolongation can occur (0.6% QTc interval > 500 ms)

• Vision disorders (21% all grades, 0.8% grade 3):

– blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder,

photophobia, photopsia, retinal hemorrhage, vision blurred, visual

impairment, vitreous adhesions, vitreous detachment

Clinical Trial Experience

Page 25: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Toxicity Grade 1 Grade 2 Grade3 Grade 4

Non-hematologic Continue at same dose level Continue at same dose level

For prolonged or intolerable CNS

toxicity, withhold dose until toxicity

is ≤ G1 or has returned to baseline,

then reduce by 1 dose level and

resume treatment

Withhold dose until toxicity is ≤ G1

or has returned to baseline, then

reduce by 1 dose level and resume

treatment

Withhold dose until toxicity is ≤ G1 or

has returned to baseline, then reduce

by 1 dose level and resume

treatment; or discontinue treatment

Hematologic Continue at same dose level Continue at same dose level Withhold dose until toxicity is ≤ G2,

or has returned to baseline, then

resume treatment at the same dose

level or reduce by 1 dose level as per

the Investigator’s discretion

Grade 3 lymphopenia without other

dose-limiting events (e.g.,

opportunistic infection) may

continue study treatment without

interruption

Withhold dose until toxicity is ≤ G2,

or has returned to baseline, then

reduce the dose by 1 dose level and

resume treatment

Grade 4 lymphopenia without other

dose-limiting events (e.g.,

opportunistic infection) may continue

study treatment without interruption

Prolonged QTc Continue at same dose level Interrupt entrectinib until recovery

to baseline

Assess and correct electrolytes and

concomitant medications

Continue at same dose level

Interrupt entrectinib until recovery

to baseline

Assess and correct electrolytes and

concomitant medications.

Reduce dose by 1 dose level and

resume treatment. If an alternative

cause for QTc prolongation is found

and corrected, resume at same dose

level

Discontinue treatment permanently

Pneumonitis (in absence of disease

progression, pulmonary embolism,

positive cultures or radiation effect)

Withhold dose until toxicity is Grade

0, then resume treatment at same

dose

Discontinue treatment permanently

if pneumonitis recurs

Withhold dose until toxicity is Grade

0, then resume treatment at same

dose

Discontinue treatment permanently

if pneumonitis recurs

Discontinue treatment permanently Discontinue treatment permanently

Page 26: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Antiemetic and antidiarrheal Support

• For nausea and emesis, treat with standard antiemetics; using

institutional guidelines for treatment and/or published guidelines

• Treatment with antidiarrheal drugs may be warranted and should

follow institutional and/or published guidelines

– For Grade 1 diarrhea, treat with loperamide if needed; no dose modification is

necessary.

– For Grade 2 diarrhea, treat with loperamide (4 mg at first onset, then 2 mg every 2-4

hours or after each loose stool, until symptom free for 12 hours). No dose modification

necessary unless the patient is intolerant or symptom is recurrent

Page 27: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Antacids and entrectinib

• Absorption of entrectinib may be pH sensitive

• Coadministration of a proton pump inhibitor (PPI):

– lansoprazole with a single 600 mg ROZLYTREK dose reduced

entrectinib AUC by 25%

• Should preferentially take only H2 receptor antagonists or

antacids

Page 28: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Medications to use with caution

Strong Inhibitors Strong Inducers

Boceprevir, clarithromycin,

conivaptan, grapefruit

juice, indinavir, itraconazole,

ketoconazole,

lopinavir/ritonavir, mibefradil,

nefazodone,

nelfinavir, posaconazole,

ritonavir, saquinavir,

telaprevir, telithromycin,

voriconazole

Alfentanil, cyclosporine,

dihydroergotamine,

ergotamine, fentanyl, pimozide,

quinidine, sirolimus,

tacrolimus

Cytochrome P450 CYP3A Inhibitors and Inducers

Page 29: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Cytochrome P450 Enzyme-Specific Substrates

CYP450 Enzyme Sensitive Substrates Substrates with Narrow

Therapeutic Range

CYP2C9 Celecoxib Warfarin, phenytoin

CYP2D6 Atomoxetine, desipramine,

dextromethorphan, metoprolol, nebivolol,

perphenazine, tolterodine, venlafaxine

Thioridazine, pimozide

CYP3A4 Alfentanil, aprepitant, budesonide,

buspirone, conivaptan, darifenacin,

darunavir, dasatinib, dronedarone, eletriptan,

eplerenone, everolimus, felodipine, indinavir,

fluticasone, lopinavir, lovastatin, lurasidone,

maraviroc, midazolam, nisoldipine, quetiapine,

saquinavir, sildenafil, simvastatin, sirolimus,

tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil

Alfentanil, cyclosporine,

dihydroergotamine,

ergotamine, fentanyl, pimozide,

quinidine,

sirolimus, tacrolimus

Page 30: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

6 cohorts according to a

standard 3+3 dose escalation

scheme QD or twice daily

(b.i.d.) dose for continuous 28-

day cycles

Page 31: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Treatment AEs (n=70pts)

Grade 3 or worse treatment AEs, with

the most common being:

� anaemia

� fatigue

� aspartate aminotransferase

increased

AEs leading to dose interruption or

modification recorded 43% of pts

Most common:

o Dizziness (7%)

o Aspartate aminotransferase

increased

o Pyrexia (4%)

Page 32: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

DLT (Larotrectinib )

• One of the first six pts at 100mg two times a day

o Dizziness

• One of seven pts treated at 150 mg two times a day

o Alanine aminotransferase and aspartate aminotransferase increased

• One of six pts treated at 200 mg two times a day

o Dizziness

� MTD consequently not reached, and 100 mg two times a day dosing schedule

chosen as the recommended phase II dose

� Short half-life: 2.9 hours

Page 33: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Larotrectinib a selective TRK inhibitor(up-date ESMO 19)

D.M.Hyman et al, ESMO 2019

Page 34: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Dose Reduction due to AEs: 8% of both the overall patients (n=22/160 pts) and pts with TKK-fusion (13/159)

Dose Discontinue due to trtt AE in 6 (2%) pts, 2 of the 6 pts had TRK fusion

LAROTRECTINIB SAFETY PROFILE (N=260)

D.M.Hyman et al, ESMO 2019

≥20%

Page 35: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

o Most common adverse (≥ 20%)

– Fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough,

increased ALT, constipation, and diarrhea

o Most common adverse (≥ 3%) resulting in dose modification

(interruption or reduction)

– Increased ALT (6%), increased AST (6%), and dizziness (3%)

o Nervous system problems

– Confusion, difficulty speaking, dizziness, coordination problems, tingling,

numbness, or burning sensation in hands and feet

Clinical Trial Experience

Page 36: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

VITRAKVI® (larotrectinib)

� 100 mg orally twice daily, with or without food

• Monitor liver tests including ALT and AST every 2 weeks during the first month of

treatment, then monthly

� Larotrectinib metabolized predominantly by CYP3A4

• Avoid coadministration of strong CYP3A4 inhibitors. If coadministration of a strong

CYP3A4 inhibitor, reduce the larotrectinib dose by 50%

• Avoid coadministration of strong CYP3A4 inducers. If coadministration of a strong

CYP3A4 inducer, double the Larotrectinbib dose

• No dose adjustment recommended for pts with mild hepatic impairment (Child-Pugh A)

• No dose adjustment recommended for pts with renal impairment of any severity

Page 37: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Recommended Dosage Modifications

Page 38: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Targeting ROS1 Fusion Positive NSCLCReprotectinib (ALK/ROS1/TRK inhibitor)• G2032R is the most common ROS1

resistance mutation after crizotinib

treatment1

• Repotrectinib is a next-generation

ROS1/TRKA-C/ALK inhibitor,

designed to overcome TKI

resistance mutations, especially

solvent front ROS1 G2032R2

Crizotinib Entrectinib Lorlatinib Repotrectinib

Repotrectinib is a Small, Rigid Macrocycle Designed to Overcome the ROS1 G2032R

Solvent Front Mutation

1Gainor JF et al., JCO Precis Oncol 20172Drilon A et al., Cancer Discov 2018

ROS1 Crizotinib Ceritinib Cabozantinib Entrectinib Lorlatinib Repotrectinib

WT 14.6 42.8 0.5 10.5 0.2 <0.2

G2032R 266.2 1391 11.3 1813 160.7 3.3

CD74-ROS1 Ba/F3 Cell Proliferation IC50 (nM)*

*Data based on evaluation of comparable proxy chemical reagents purchased from commercial sources except repotrectinib

ASCO 2019 B.C. Cho, M.D., PhD A.Drilon et al, cancer discovery 2018

Page 39: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

TRIDENT-1: A Phase 1/2 Study of Repotrectinib

Study Design/Eligibility (Phase 1)

• Advanced solid tumors harboring ROS1/NTRK1-

3/ALK fusions

• No limit on prior lines of therapy

• Asymptomatic CNS metastases allowed

Phase 1 Primary Objective

• Determine the MTD and RP2D

Phase 1 Secondary Objectives

• Safety and tolerability

• Preliminary objective response rate and clinical

benefit rate

ASCO 2019 B.C. Cho, M.D., PhD Drilon et al, ESMO 2019

Page 40: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Safety Summary: Treatment-Emergent and Treatment-Related AEs

*Add’l Grade 4 TEAEs: cerebrovascular accident, dyspnea, influenza, hyperkalemia, bacterial pneumonia (n=1 each), respiratory failure (n=2); None were determined to be related to treatment^ Grade 5 TEAEs: respiratory failure (n=2), sepsis, sudden death (n=1 each); Only the case of sudden death was determined to be possibly related to treatment

o Majority of treatment emergent adverse events

(TEAEs) were Grade 1 or Grade 2

• No Grade 3 or Grade 4 ALT or AST elevations

• No cases of dizziness have led to treatment discontinuation

o Four DLT events:

• Grade 2 or 3 dizziness (3 pts)

• 160 mg BID (n=2)

• 240 mg QD (n=1)

• Grade 3 dyspnea and hypoxia (1pt)

• 160 mg BID (n=1)

o Treatment related adverse events (TRAEs) leading

to dose modifications

• Dose reduction: n=8 (9.6%)

• Dose interruption: n=2 (2.4%)

• Drug discontinuation: n=2 (2.4%)

ASCO 2019 B.C. Cho, M.D., PhD Drilon et al, ESMO 2019

Page 41: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment
Page 42: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Disease and patients characteristics

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Phase I DLTs by dose level

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LOXO-195 safety profile

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In total: first-generation TRK inhibitors are

tolerable but occasional on-target AEs occur

Drilon Annals of Oncol 2019 (In Press)

0%

25%

50%

75%

100%

Neurologic/On-Target

Pare

sthesi

a

Dys

geusi

a

Diz

ziness

Weig

ht gain

Anem

ia

↑ C

reatinin

e

↑ A

lanin

e a

min

otr

ansf

era

se

Dia

rrhea

Const

ipation

Nause

a

Fatigue

Crizotinib

Entrectinib

Larotrectinib

Fre

quency

Treatment-Related Adverse Events

Page 46: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Drilon Annals of Oncol 2019 (In Press)

0%

25%

50%

75%

100%

Neurologic/On-Target

Pare

sthesi

a

Dys

geusi

a

Diz

ziness

Weig

ht gain

Anem

ia

↑ C

reatinin

e

↑ A

lanin

e a

min

otr

ansf

era

se

Dia

rrhea

Const

ipation

Nause

a

Fatigue

Crizotinib

Entrectinib

Larotrectinib

Fre

quency

Treatment-Related Adverse Events

In total : first-generation TRK inhibitors are

tolerable but occasional on-target AEs occur

Page 47: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

In total: in most patients on 1st-gen TRK inhibitors, dose

modification is not necessary due to well-tolerated AE profiles

Drilon Annals of Oncol (In Press) 2019, Lassen ESMO 2018, Demetri ESMO 2018

CrizotinibEntrectinib Larotrectinib

21%

13%

27%

4%

9%

<1%

Dose

Reduction

Treatment

Discontinuation

Page 48: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

In total: in most patients on 1st-gen TRK inhibitors, dose

modification is not necessary due to well-tolerated AE profiles

Drilon Annals of Oncol (In Press) 2019, Lassen ESMO 2018, Demetri ESMO 2018

CrizotinibEntrectinib Larotrectinib

21%

13%

27%

4%

9%

<1%

Dose

Reduction

Treatment

Discontinuation

Page 49: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

Champiat S et al., Annals of Oncology, 2015

ENDOCRINEHyper or

hypothyroidismHypophysitis

Adrenal insufficiencyDiabetes

EYEUveitis

ConjunctivitisScleritis, episcleritis

BlepharitisRetinitis

REPIRATORYPneumonitis

PleuritisSarcoid-like

granulomatosis

GASTRO INTESTINAL

ColitisIleitis

PancreatitisGastritis

NEUROLOGICNeuropathy

Guillain BarréMyelopathyMeningitis

EncephalitisMyasthenia

MUSCULO SKELETAL

ArthritisDermatomyositis

BLOODHemolytic anemiaThrombocytopenia

NeutropeniaHemophilia

SKINRash

PruritusPsoriasisVitiligoDRESS

Stevens Johnson

CARDIOVASCULAR

MyocarditisPericarditisVasculitis

RENALNephritis

LIVERHepatitis

More easy to manage than IO toxicities…

Page 50: Tolerance profile and recommendation for use€¦ · resume treatment. If an alternative cause for QTc prolongation is found and corrected, resume at same dose level Discontinue treatment

THANK YOU !Acknowledgments

[email protected]

Benjamin BESSE

Thierry LE CHEVALIER

Jean-Charles SORIA

Charles NALTET

Anas GAZZAH

Pernelle LAVAUD

Cécile LE PECHOUX

Angéla BOTTICELLA

Antonin LEVY

Laura MEZQUITA

@dplanchard

Alexander Drilon MD

Memorial Sloan Kettering Cancer Center