ESMO ADVANCED COURSEON NTRK GENE FUSION:Tolerance profile and recommendation for use

Lyon, 13-14 September 2019

David Planchard, MD, PhDHead of thoracic groupDepartment of Cancer MedicineInstitut Gustave Roussy Villejuif, France

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 paediatricand 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- cognitivedisturbance- dizziness

NTRK1

NTRK2

NTRK3

E. Cocco et al, nature reviews 2018

Profiles of TRK inhibitor activity

E. Cocco et al, nature reviews 2018

TRK Inhibitors in Development and Trials that Contributed Data to Regulatory Cohorts

Demetri et al ESMO 2018, Drilon et al NEJM 2017

Larotrectinib EntrectinibTKI Generation

First ✓ ✓Drug Inhibits

TRKA/B/C ✓ ✓ROS1 ✓ALK ✓

Contributory TrialsAdult/Adolescent Trials

NAVIGATEPhase I Trial

STARTRK-2STARTRK-1

ALKA-372001Pediatric Trials Phase I/II STARTRK-NG

Entrectinib

54 patients on ALKA-372-001:-19 on Schedule A : fasted, 4 days on entrectinib and 3 days off entrectinib for 21 of 28 days)- 29 on Schedule B (fed, continuous daily dosing for 28 days)- and 6 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 the study and fully recovered from the event

• No Grade 5 treatment-related adverse events reported

Recommended dose (entrectinib)• Continuous dose of 600 mg daily then tested and identified as the fixed-dose

MTD and RP2D in adults• The plasma half-life of entrectinib estimated to be between 20 and 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 steadystate (continuous daily dosing)

In the STARTRK-1 study, entrectinib administeredwith food and exposure increased in a linear manner from 100to 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 (~76%)• 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 approvals

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%)– and 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, visualimpairment, 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 InducersBoceprevir, clarithromycin, conivaptan, grapefruitjuice, 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 SubstratesCYP450 Enzyme Sensitive Substrates Substrates with Narrow

Therapeutic RangeCYP2C9 Celecoxib Warfarin, phenytoinCYP2D6 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

six cohorts according to a standard 3+3 dose escalation schemeQD or twice daily (b.i.d.) dose for continuous 28-day cycles

Treatment AEs (n=70pts) 60% grade 3 or worse treatment AEs, with the most common being:

– anaemia– fatigue – aspartate aminotransferase

increasedAEs leading to dose interruption or modification recorded 43% of ptsMost common:

– dizziness (7%) – aspartate aminotransferase

increased – and pyrexia (4%)

DLT (Larotrectinib)• One of the first six pts at 100mg two times a day and none seen at 200 mg QD

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

– alanine aminotransferase and aspartate aminotransferase increased • One of six pts treated at 200 mg two times a day

– dizziness

• MTD consequently not reached, and the 100 mg two times a day dosing schedule chosen as the recommended phase II dose

• Short half-life: 2.9 hours

Larotrectinib, patients with TRK fusion cancer

Dose Reduction: 9% (n=11/122 pts with TRK fusion cancer) – all maintained tumour regression on reduced doseDiscontinue due to AE: <1% (n=1/122 pts with TRK fusion cancer)

Treatment-emergent AEs (%) Treatment-related AEs (%)Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total

Fatigue 18 15 3 – 36 <1 – 18Dizziness 25 3 1 – 29 <1 – 21Nausea 24 3 1 – 29 1 – 15Constipation 22 5 <1 – 27 – – 12Anaemia 10 7 10 – 27 2 – 11ALT increased 17 5 3 <1 26 2 <1 21AST increased 18 5 3 – 26 1 – 19Cough 23 3 <1 – 26 – – 1Diarrhoea 16 6 1 – 23 – – 5Vomiting 17 6 <1 – 23 – – 10Pyrexia 12 5 <1 <1 18 – – 1Dyspnoea 10 6 2 – 18 – – 1Headache 13 4 – – 16 – – 4Myalgia 12 3 1 – 16 <1 – 7Peripheral oedema 12 4 – – 15 – – 7

LAROTRECTINIB SAFETY PROFILE

AEs in ≥15% of patients (n=207, safety data set)AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Data cut-off 30 July 2018

≥20%

• Most common adverse (≥ 20%)– fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough,

increased ALT, constipation, and diarrhea

• Most common adverse (≥ 3%) resulting in dose modification (interruption or reduction) – increased ALT (6%), increased AST (6%), and dizziness (3%)

• Nervous system problems: – confusion, difficulty speaking, dizziness, coordination problems, tingling,

numbness, or burning sensation in your 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 is metabolized predominantly by CYP3A4• Avoid coadministration of strong CYP3A4 inhibitors. If coadministration of a strong

CYP3A4 inhibitor cannot be avoided, reduce the larotrectinib dose by 50%• Avoid coadministration of strong CYP3A4 inducers. If coadministration of a strong

CYP3A4 inducer cannot be avoided, 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 crizotinibtreatment1

• 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

Data cut-off date of March 4, 2019

Number of patients per dose cohort

40 mgQD

80 mg QD

160 mg QD

240 mg QD

160 mg BID

200 mg BID1

120 mg QD w/ Food

160 mg QD w/ Food

160 mg QD/BID w/Food2

Total

Safety population(ROS1+, NTRK1-3+, ALK+ solid tumors)

13 12 23 10 12 2 3 5 3 83**

Efficacy population (ROS1+ NSCLC) 5 5 10 2 6 0 2 3 0* 331 2 ALK patients enrolled2160 mg QD for one week followed by 160 mg BID* Not yet evaluable for efficacy by BICR** N=83 patients: 31 were ALK+, 9 were NTRK+, and 43 were ROS1+ (of which 33 ROS1+ NSCLC were evaluable for efficacy by BICR)

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 RP2DPhase 1 Secondary Objectives• Safety and tolerability• Preliminary objective response rate and clinical

benefit rate

BICR: Blinded Independent Central Review

ASCO 2019 B.C. Cho, M.D., PhD

Safety Summary: Treatment-Emergent and Treatment-Related AEs

Data cut-off date of March 4, 2019

Adverse Event

All Treated Patients (N=83) TEAEs (≥10% of patients) TRAEs

All Grades n(%)

Grade 3n(%)

Grade 4*n(%)

Grade 3n(%)

Grade 4n(%)

Dizziness 47(56.6) 2 (2.4) --- 2 (2.4) ---Dysgeusia 42 (50.6) --- --- --- ---Dyspnea 25 (30.1) 5 (6.0) 1 (1.3) 1 (1.2) ---Fatigue 25 (30.1) 2 (2.4) --- --- ---Constipation 24 (28.9) --- --- --- ---Paresthesia 24 (28.9) --- --- --- ---Anemia 23 (27.7) 10 (12.0) --- 3 (3.6) ---Nausea 19 (22.9) 2 (2.4) --- --- ---Cough 17 (20.5) --- --- --- ---Pyrexia 16 (19.3) --- --- --- ---Headache 14 (16.9) 1 (1.2) --- --- ---Vomiting 13 (15.7) --- --- --- ---Upper respiratory tract infection 11 (13.3) --- --- --- ---

Ataxia 10 (12.0) --- --- --- ---Pain in extremity 10 (12.0) 1 (1.2) --- --- ---Abdominal pain 9 (10.8) --- --- --- ---Muscular weakness 9 (10.8) 1 (1.2) --- --- ---

*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

• RMajority 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

• 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)

• Four TEAE Grade 5 events^

• 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

≥20%

Disease and patients characteristics

Phase I DLTs by dose level

LOXO-195 safety profile

≥20%

In total : first-generation TRK inhibitors are tolerable but occasional on-target AEs occur

Drilon Annals of Oncol 2019 (In Press)

Drilon Annals of Oncol 2019 (In Press)

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

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

Champiat S et al., Annals of Oncology, 2015

More easy to manage than IO toxicities…

THANK YOU !Acknowledgments

david.planchard@gustaveroussy.fr

Benjamin BESSEThierry LE CHEVALIERJean-Charles SORIA

Charles NALTETAnas GAZZAH

Pernelle LAVAUDCécile LE PECHOUXAngéla BOTTICELLA

Antonin LEVYLaura MEZQUITA

@dplanchard

Alexander Drilon MDMemorial Sloan Kettering Cancer Center