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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
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
NTRK fusions are identified across multiple paediat ricand adult cancer histologies
E. Cocco et al, nature reviews 2018
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
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
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
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)
Patient characteristics at baseline
once-daily (fed) in
4-week cycles A.Drilon et al, cancer discovery 2017
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
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
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
Recommended Dose Reductions
Analysis design (ROS1+ NSCLC)
≥20%
Analysis design (NTRK NSCLC)
The overall safety profile of first-generation TRK inhibition (entrectinib ) is favorable
Demetri et al, ESMO 2018
≥20%
The overall safety profile of first-generation TRK inhibition (entrectinib ) is favorable
Demetri et al, ESMO 2018
≥20%
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
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%)
• 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
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
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
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
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
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
6 cohorts according to a
standard 3+3 dose escalation
scheme QD or twice daily
(b.i.d.) dose for continuous 28-
day cycles
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%)
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
Larotrectinib a selective TRK inhibitor(up-date ESMO 19)
D.M.Hyman et al, ESMO 2019
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%
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
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
Recommended Dosage Modifications
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
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
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
Disease and patients characteristics
Phase I DLTs by dose level
LOXO-195 safety profile
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
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
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
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
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…
THANK YOU !Acknowledgments
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