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

Lyon, 13-14 September 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 paediatric and adult cancer histologies

E. Cocco et al, nature reviews 2018 TRK inactivation can result in unique consequences

NTRK2

NTRK3 reported in patients treated with TRK inhibitors - paresthesias - weight gain - cognitive disturbance NTRK1 - dizziness

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

Larotrectinib Entrectinib TKI Generation First ✓ ✓ Drug Inhibits TRKA/B/C ✓ ✓ ROS1 ✓ ALK ✓ Contributory Trials Adult/Adolescent Trials STARTRK-2 NAVIGATE STARTRK-1 Phase I Trial ALKA-372001 Pediatric Trials Phase I/II STARTRK-NG

Demetri et al ESMO 2018, Drilon et al NEJM 2017 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)

• All related AEs reversible with dose modifications

• Dose reduction occurred in 15% (n=18/119) of pts A.Drilon et al, cancer discovery 2017 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 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

≥20%

Demetri et al, ESMO 2018 The overall safety profile of first-generation TRK inhibition (entrectinib) is favorable

≥20%

Demetri et al, ESMO 2018 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 FDA approvals

• 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 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%) Clinical Trial Experience

• 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 Toxicity Grade 1 Grade 2 Grade3 Grade 4

Non-hematologic Continue at same dose level Continue at same dose level Withhold dose until toxicity is ≤ G1 Withhold dose until toxicity is ≤ G1 or For prolonged or intolerable CNS or has returned to baseline, then has returned to baseline, then reduce toxicity, withhold dose until toxicity reduce by 1 dose level and resume by 1 dose level and resume is ≤ G1 or has returned to baseline, treatment treatment; or discontinue treatment then reduce by 1 dose level and resume treatment Hematologic Continue at same dose level Continue at same dose level Withhold dose until toxicity is ≤ G2, Withhold dose until toxicity is ≤ G2, or has returned to baseline, then or has returned to baseline, then resume treatment at the same dose reduce the dose by 1 dose level and level or reduce by 1 dose level as per resume treatment the Investigator’s discretion Grade 4 lymphopenia without other Grade 3 lymphopenia without other dose-limiting events (e.g., dose-limiting events (e.g., opportunistic infection) may continue opportunistic infection) may study treatment without interruption continue study treatment without interruption Prolonged QTc Continue at same dose level Interrupt entrectinib until recovery Interrupt entrectinib until recovery Discontinue treatment permanently to baseline to baseline Assess and correct electrolytes and Assess and correct electrolytes and concomitant medications concomitant medications. Continue at same dose level 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 Pneumonitis (in absence of disease Withhold dose until toxicity is Grade Withhold dose until toxicity is Grade Discontinue treatment permanently Discontinue treatment permanently progression, pulmonary embolism, 0, then resume treatment at same 0, then resume treatment at same positive cultures or radiation effect) dose dose Discontinue treatment permanently Discontinue treatment permanently if pneumonitis recurs if pneumonitis recurs 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

Cytochrome P450 CYP3A Inhibitors and Inducers

Strong Inhibitors Strong Inducers Boceprevir, clarithromycin, Alfentanil, cyclosporine, conivaptan, grapefruit dihydroergotamine, juice, indinavir, itraconazole, ergotamine, fentanyl, pimozide, ketoconazole, quinidine, sirolimus, lopinavir/ritonavir, mibefradil, tacrolimus nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole Cytochrome P450 Enzyme-Specific Substrates

CYP450 Enzyme Sensitive Substrates Substrates with Narrow Therapeutic Range CYP2C9 Celecoxib Warfarin, phenytoin CYP2D6 Atomoxetine, desipramine, Thioridazine, pimozide dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine

CYP3A4 Alfentanil, aprepitant, budesonide, Alfentanil, cyclosporine, buspirone, conivaptan, darifenacin, dihydroergotamine, darunavir, dasatinib, dronedarone, eletriptan, ergotamine, fentanyl, pimozide, eplerenone, everolimus, felodipine, indinavir, quinidine, fluticasone, lopinavir, lovastatin, lurasidone, sirolimus, tacrolimus maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil six 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) 60% 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: – 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 LAROTRECTINIB SAFETY PROFILE

Treatment-emergent AEs (%) Treatment-related AEs (%) ≥20% Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total Fatigue 18 15 3 – 36 <1 – 18 Dizziness 25 3 1 – 29 <1 – 21 Nausea 24 3 1 – 29 1 – 15 Constipation 22 5 <1 – 27 – – 12 Anaemia 10 7 10 – 27 2 – 11 ALT increased 17 5 3 <1 26 2 <1 21 AST increased 18 5 3 – 26 1 – 19 Cough 23 3 <1 – 26 – – 1 Diarrhoea 16 6 1 – 23 – – 5 Vomiting 17 6 <1 – 23 – – 10 Pyrexia 12 5 <1 <1 18 – – 1 Dyspnoea 10 6 2 – 18 – – 1 Headache 13 4 – – 16 – – 4 Myalgia 12 3 1 – 16 <1 – 7 Peripheral oedema 12 4 – – 15 – – 7 Dose Reduction: 9% (n=11/122 pts with TRK fusion cancer) – all maintained tumour regression on reduced dose Discontinue due to AE: <1% (n=1/122 pts with TRK fusion cancer) 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 Clinical Trial Experience • 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 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 NSCLC Reprotectinib (ALK/ROS1/TRK inhibitor) • G2032R is the most common ROS1 resistance mutation after crizotinib Repotrectinib is a Small, Rigid Macrocycle Designed to Overcome the ROS1 G2032R treatment1 Solvent Front Mutation

• Repotrectinib is a next-generation Crizotinib Entrectinib Lorlatinib Repotrectinib ROS1/TRKA-C/ALK inhibitor, designed to overcome TKI resistance mutations, especially solvent front ROS1 G2032R2

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

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

1Gainor JF et al., JCO Precis Oncol 2017 2Drilon A et al., Cancer Discov 2018 *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) Phase 1 Primary Objective • Advanced solid tumors harboring ROS1/NTRK1- • Determine the MTD and RP2D 3/ALK fusions Phase 1 Secondary Objectives • Safety and tolerability • No limit on prior lines of therapy • Preliminary objective response rate and clinical • Asymptomatic CNS metastases allowed benefit rate

Number of patients per dose cohort 120 mg 160 mg 160 mg 40 mg 80 mg 160 mg 240 mg 160 mg 200 mg QD w/ QD w/ QD/BID Total QD QD QD QD BID BID1 Food Food w/Food2 Safety population (ROS1+, NTRK1-3+, 13 12 23 10 12 2 3 5 3 83** ALK+ solid tumors) Efficacy population 5 5 10 2 6 0 2 3 0* 33 (ROS1+ NSCLC) 1 2 ALK patients enrolled 2160 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) BICR: Blinded Independent Central Review Data cut-off date of March 4, 2019 ASCO 2019 B.C. Cho, M.D., PhD Safety Summary: Treatment-Emergent and

Treatment-Related AEs • RMajority of treatment emergent adverse events All Treated Patients (N=83) (TEAEs) were Grade 1 or Grade 2 TEAEs (≥10% of patients) TRAEs Adverse Event • No Grade 3 or Grade 4 ALT or AST elevations All Grades Grade 3 Grade 4* Grade 3 Grade 4 ≥20% n(%) n(%) n(%) n(%) n(%) • No cases of dizziness have led to treatment discontinuation Dizziness 47(56.6) 2 (2.4) --- 2 (2.4) --- Dysgeusia 42 (50.6) ------• Four DLT events: Dyspnea 25 (30.1) 5 (6.0) 1 (1.3) 1 (1.2) --- • Grade 2 or 3 dizziness (3 pts) Fatigue 25 (30.1) 2 (2.4) ------• 160 mg BID (n=2) Constipation 24 (28.9) ------• 240 mg QD (n=1) Paresthesia 24 (28.9) ------Anemia 23 (27.7) 10 (12.0) --- 3 (3.6) --- • Grade 3 dyspnea and hypoxia (1pt) Nausea 19 (22.9) 2 (2.4) ------• 160 mg BID (n=1) Cough 17 (20.5) ------^ Pyrexia 16 (19.3) ------• Four TEAE Grade 5 events Headache 14 (16.9) 1 (1.2) ------Vomiting 13 (15.7) ------• Treatment related adverse events (TRAEs) leading Upper respiratory 11 (13.3) ------to dose modifications tract infection • Dose reduction: n=8 (9.6%) Ataxia 10 (12.0) ------Pain in extremity 10 (12.0) 1 (1.2) ------• Dose interruption: n=2 (2.4%) Abdominal pain 9 (10.8) ------• Drug discontinuation: n=2 (2.4%) 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 ASCO 2019 B.C. Cho, M.D., PhD Data cut-off date of March 4, 2019

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

Drilon Annals of Oncol 2019 (In Press) 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 More easy to manage than IO toxicities…

Champiat S et al., Annals of Oncology, 2015 THANK YOU ! Acknowledgments Benjamin BESSE Thierry LE CHEVALIER Jean-Charles SORIA Charles NALTET Alexander Drilon MD Anas GAZZAH Memorial Sloan Kettering Cancer Center Pernelle LAVAUD Cécile LE PECHOUX Angéla BOTTICELLA Antonin LEVY Laura MEZQUITA

@dplanchard [email protected]