Targeted therapy beyond EGFR/ALK: BRAF and ROS1

ESMO PRECEPTORSHIP ON

Targeted therapy beyond

EGFR/ALK: BRAF and ROS1

David Planchard, MD, PhD

Head 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

ALK (7%)

EGFR other (4%)

MET (3%)

>1 mutation (3%)

HER2 (2%)

ROS1 (2%)

BRAF (2%)

RET (2%)

NTRK1 (1%)

PIK3CA (1%)

MEK1 (<1%)

Unknown oncogenic driver detected (31%)

KRAS (25%)

EGFR sensitizing (17%)

ROS1

Crizotinib; Cabozantinib; Ceritinib; Lorlatinib; Entrectinib; Ropotrectinib, DS-6051b

BRAF

Vemurafenib;Dabrafenib; Dabrafenib + Trametinib

RET

Cabozantinib; Alectinib; Apatinib; Vandetanib; sunitinib; Ponatinib; Lenvatinib; BLU-667;

LOXO-292

NTRK1

Entrectinib; LOXO-101 (larotrectinib); loxo-195; DS-6051b; ropotrectinib

PIK3CA

LY3023414; PQR 309

ALK

Crizotinib; Alectinib; Ceritinib; Lorlatinib; Brigatinib

MET

Crizotinib; Cabozantinib; Capmatinib; Savolitinib; Tepotinib; Merestinib; Glesatinib

HER2

Trastuzumab emtansine; Afatinib; Neratinib-temsirolimus; Dacomitinib; Poziotinib;

XMT-1522; TAK-788; DS-8201a,

MEK1

Trametinib; Selumetinib;Cobimetinib

EGFR sensitizing

Gefitinib; Erlotinib; Afatinib; Osimertinib; Dacomitinib

Great advances have been made in lung cancer therapy:

targeting of oncogenic drivers

PI3K/AKT/mTORpathway

RT

Ks SOS

Grb2SHC

PPPP

Proliferation, Growth, Survival

MEK

p90RSK MSK1

PP

BRAF CRAFBRAF

V600

ERK1/2

RAS

Dabrafenib

Vemurafenib

Inhibition of BRAF V600 Kinase

Vemurafenib in BRAF mutant NSCLC

VE-Basket trial

20 BRAFV600 NSCLCORR: 42%

PFS: 7.3 mo

AcSé trial

Mazières – WCLC 2018

VemurafenibVemurafenib

Hyman – NEJM 2015

79 BRAFV600 NSCLCORR: 43%

PFS : 5.2 mo

84 BRAFV600E NSCLCORR: 33%

D. Planchard et al – lancet Oncol 2016

PFS: 5.5 months (2.8 - 6.9)

Dabrafenib in BRAF NSCLC in 2nd line (BRF113928 Study)

Kristina M. Ilieva et al, mol cancer therapeutics

MECHANISM OF ACTION FOR DUAL MAPK PATHWAY INHIBITION WITH

DABRAFENIB + TRAMETINIB TO OVERCOME ERK ESCAPE MECHANISM

BRF113928 STUDY : MAXIMUM CHANGE IN TARGET LESION BY BEST

CONFIRMED RESPONSE WITH DABRAFENIB + TRAMETINIB IN 2ND LINE

Planchard D et al. Lancet Oncol 2016;17:984–993;Planchard D et al. J Clin Oncol 2017;35(Suppl):Abst 9075

Min

imum

per

cent

red

uctio

n fr

om

base

line

mea

sure

men

t

40

0

−20

−80

−60

20

−40

−100

−120

*

CR

PR

SD

PD

NE

ORR: 66.7% (95% CI 52.9, 78.6)

Best confirmed response†

Cohort B (N=57 NSCLC BRAF V600E)

mPFS: 10.9m (7.0-16.6)

BRF113928 STUDY : MAXIMUM CHANGE IN TARGET LESION BY BEST

CONFIRMED RESPONSE WITH DABRAFENIB + TRAMETINIB IN 1ST LINE

Planchard D et al. Lancet Oncol 2017;18:1307–1316

Max

imum

red

uctio

n fr

om b

asel

ine

mea

sure

men

t, %

Best confirmed response CR

PR

SD

PD

NE

10

0

−10

−20

−30

−40

−50

−60

−100

−70

−80

−90

ORR: 64% (95% CI 46, 79)

Cohort C (N=36 NSCLC BRAFV600E)

mPFS: 10.2m (6.9-16.7)

+ 4 years

Lady, 58-year, BRAFV600E:

Dabrafenib (150mg twice a day) + Trametinib (2mg/day)

D.Planchard et al, Gustave Roussy

July 2014 February 2018

2 mo

3 years

• Mean Bayesian Estimated Success rate : 5.9% ; credibility 95%CI : [0.2%; 20.6%]

• Prob ORR < futility bound (10%): 81.5% - study stopped

PFS: 1.8 m. [1.4;2.1] Response rate: 0%

Non V600 mutations

n = 17G466A : n=1

G466V : n=3

G469A : n=3

G469V : n=1

N581S : n=3

G596R : n=1

K601E : n=3

K601N : n=2

BRAF non V600 cohort (AcSé Vemu)

J.Mazieres et al, WCLC 2018

Immunotarget- Low benefit of immunotherapy in case of molecular alteration...need for specific studies

Driver n RR PFS OS Impact (+/X) on PFS of Comments

PDL1 Smoking Nb line Subtype

Total 19% 2.8 13.3 Outcome consistent with

registration trials for ICI

KRAS 271 26% 3.2 13.5 + X X X Clear benefit across all

subgroups

EGFR 125 12% 2.1 10 + X X X Could be considered in PDL1 +

after TKIs exhaustion

BRAF 43 24% 3.1 13.6 X + X NA Could be considered in smokers

MET 36 16% 3.4 18.4 NA X NA XCould be considered after

conventionnal treatmentHER2 29 7% 2.5 20.3 NA + X NA

ALK 23 0 2.5 17

X X X NAPoor outcome. New biomarker

needed.RET 16 6% 2.1 21.3

ROS1 7 17% - -

Julien MAZIERES et al, ASCO 18

Italien Expanded Access Program of 2nd

line Nivolumab

Best response to Nivolumab

BRAF-mutatedN=11 (%)

BRAF Wild TypeN=199 (%)

BRAF Not evaluatedN=1378 (%)

CR 0 1 (0.5%) 9 (0.6%)

PR 1 (9.1%) 38 (19.1%) 241 (17.5%)

SD 0 45 (22.6%) 369 (26.8%)

PD 8 (72.7%) 92 (46.2%) 588 (42.7%)

Death 1 (9.1%) 16 (8.1%) 113 (8.2%)

NE 1 (9.1%) 7 (3.5%) 58 (4.2%)

Retrospective trial

Rihawi K et al, JTO 2019

Multi-institutional retrospective39 pts BRAF mutant NSCLC-54%: V600E (group A, n = 21) -non-V600E (group B, n = 18)-38% never-smokers

PD-L1 high (≥50%):-in 42% -V600E pts-50% non –V600E pts

PFS:-3.7 mo V600E pts-4.1 mo non-V600E pts

Dudnik E et al, JTO 2018

BRAF and immunotherapyORR:-25% V600E pts-33% non-V600E pts

Early clearance and dynamics of BRAF mutations in ctDNA as a predictor of response to BRAF targeted therapies

Complete clearance of BRAF V600E at the first CT-scan evaluation* in 12/20 (60%)

Serial longitudinal follow-up of BRAF V600E in plasma under BRAF-TT is associated with response to trtt

Ortiz-Cuaran*, Mezquita* et al. submitted

BRAF-TT: BRAF-targeted therapy

* Within 100 days after treatment initiation

Sandra Ortiz-Cuaran, Centre Léon Bérard - Cancer Research Center of Lyon, France

Genomic ctDNA profiling of disease progression on BRAF-targeted therapies

Consistent rebound in BRAF V600E at PD in 17/27 (63%) patients

Ortiz-Cuaran*, Mezquita* et al. submitted

BRAF mutation in 56.5% (16/46) of samplesMolecular progression observed in 3 patients with a

median of 57 days before confirmation of radiographic progression

35 patients (46 samples)

Sandra Ortiz-Cuaran, Centre Léon Bérard - Cancer Research Center of Lyon, France

Previously Treated Treatment

Naive

VE-Basket trial

vemurafenib

(n=20)

AcSé trial

vemurafenib

(n=100)

BRF113928

dabrafenib

(n = 78)

BRF113928

Dabrafenib Plus

Trametinib

(n = 57)

BRF113928

Dabrafenib Plus

Trametinib

(n = 36)

Male 14 (70%) - 39 (50%) 29 (51%) 14 (39%)

Never smoker 7 (35%) - 29 (37%) 16 (28%) 10 (28%)

ORR % (95% CI) 42 (20-67) 44.9 33 (23–45) 67 (53–79) 64 (46-79)

PFS, median (95% CI) 7.3 (3.5-10.8) 5.2 5.5 (3.4–7.3) 10.2 (6.9–16.7) 10.9 (7.0-16.6)

OS, median (95% CI) NA 9.3 12.7 (7.3–16.3) 18.2 (14.3–NE) 24.6 (12.3-NE)

So where we are in 2019…BRAFV600-mutant

Dabrafenib+trametinib

mPFS (10.9 months)Platinum-

based CT+/-IOImmunotherapy…

Dabrafenib+trametinib

mPFS (10.2 months)Immunotherapy…

Platinum-

based CT+/-IO

D.Planchard et al, ASCO 18

EMA and FDA approvals 2017

D.Planchard et al, annals onco 2018

ESMO and NCCN Guidelines

EMA and FDA approvals 2017

• Present in 1-2% of NSCLC cases

• Enriched in younger, never or light smokers with adenocarcinoma histology

• No overlap with other oncogenic drivers

ROS1 rearrangements in NSCLC

Jessica J. Lin et al, JTO2017

Different partners

Patient history (started 2017)

50-year-old lady

History of adenocarcinoma NSCLC (CK7+, TTF1+), T2N2M1a

(lung, and pleural metastasis with pleural effusion, cytology+)

No smoking history

Molecular testing (tissue): EGFR, KRAS, BRAF, MET, HER2 and

ALK WT but ROS1+ (IHC and confirmed by FISH)

PD-L1 70%+ IHC

ECOG PS of 1

D.Planchard , Gustave Roussy 2017

Baseline CT-Scan

D.Planchard, Gustave Roussy

What would be your treatment recommendation for this patient?

1. Carboplatin + pemetrexed

2. Platinum + pemetrexed + Pembrolizumab

3. Pembrolizumab

4. Crizotinib

5. Ceretinib

Crizotinib:

Inhibitor of c-MET, ALK and ROS1

Kinase

IC50 (nM)

mean*

Selectivity

ratio

c-MET 8 –

ALK 40-60 5-8X

ROS1 60 7X

RON 80 10X

Axl294 34X

322 37X

Tie-2 448 52X

Trk A 580 67X

Trk B 399 46X

Abl 1,159 166X

IRK 2,887 334X

Lck 2,741 283X

Sky >10,000 >1,000X

VEGFR2 >10,000 >1,000X

PDGFR >10,000 >1,000X

Co-crystal structure of crizotinib

(PF-02341066) bound to c-MET

Cui et al. J Med Chem 54: 6342-63, 2011 and Pfizer data on fileCamidge et al, ASCO 2014

Significant Responses to Crizotinib in Patients

with ROS1-Positive NSCLC

Baseline After 3 months of crizotinib

Bergethon et al., JCO 30(8): 863-70, 2012

Results From the EUROS1 Cohortretrospective cohort

Julien Mazières et al, JCO 2015

mPFS: 9.1 months

ORR: 80%

Julien Mazières et al, JCO 2015

Results From the EUROS1 Cohortretrospective cohort

N=31pts

Efficacy of crizotinib in pts with ROS1-rearranged lung cancer (EUCROSS): A European phase 2

Sebastian Michels et al, JTO 2019

N=30ptsORR: 70% (50.6-85.3)


Efficacy of crizotinib in pts with ROS1-rearranged lung cancer (EUCROSS): A European phase 2

Results

mPFS: 20.8 (10.1-NR)

mOS (95% CI, 17.1-NR) not met at data cut-off

CD74-ROS1-positive pts trend towards a longer mPFS


Single biomarker tests in

the 15 malignancies

AcSé Crizotinib :

objectives

To identify patients

with an advanced

malignancy presenting

a crizotinib-target

alteration and to

generate

epidemiological data

Gilles Vassal et al, ESMO-ECCO 2015

Results: ROS1+

NSCLC

Tumor shrinkage at best response

Best response

ORR = 26/36

72 % [55% ; 86%]

DCR = 32/36

89 % [74% ; 97%]

44% PFS at 12 months

Gilles Vassal et al, ESMO-ECCO 2015

*Additional 3 patients from a separate cohort were retrospectively determined to be ROS1-positive and

included in the updated analyses.aROS1 testing by central laboratory in 2 of the patients from a separate cohort.bECOG PS 2 could enroll upon investigator and sponsor agreement.c21-day cycles for the 3 patients from a separate cohort.dRECIST v1.1 for the 3 patients from a separate cohort.

BID, twice daily; CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology

Group; NSCLC, non-small cell lung cancer; PO, orally; RECIST, Response Evaluation Criteria in Solid Tumors.

PROFILE 1001: ROS1 EXPANSION COHORT (N=53)*

Key entry criteria

• Locally advanced or metastatic,

histologically confirmed NSCLC

• Positive for ROS1 rearrangements by

local molecular profilinga

• ECOG PS 0 or 1b

• Treated brain metastases allowed if

stable for ≥2 weeks

Crizotinib

250 mg BID PO,

continuous 28-dayc cycles

Treatment beyond PD

was allowed.

Enrollment period

Oct 2010–Aug 2013Endpoints

• Objective response rate derived

by investigator (ORR;

RECIST v1.0d)

• Duration of response (DOR)

• Time to tumor response (TTR)

• Progression-free survival (PFS)

• Overall survival (OS)

• Safety (CTCAE v3.0)

Data cutoff date:

June 30, 2018

Shaw.A et al, ELCC 2019 and annals onco 2019

EUROPEAN LUNG CANCER CONGRESS 2019

aSquamous cell carcinoma (n=1); poorly differentiated non-small cell carcinoma (n=1). bOne patient (1.9%) had an ECOG PS of 2 at baseline.c≥1 prior regimen; Median (range): 2 (1–6).

PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS

Characteristic ROS1-rearranged NSCLC (N=53)

Age, years Median (range) 55.0 (25–81)

Sex, n (%) Male 23 (43.4)

Female 30 (56.6)

Race, n (%) White 30 (56.6)

Asian 21 (39.6)

Black 2 (3.8)

Smoking status, n (%) Never smoked 40 (75.5)

Former smoker 13 (24.5)

Histological classification, n (%) Adenocarcinoma 51 (96.2)

Othera 2 (3.8)

ECOG PS, n (%)b 0 23 (43.4)

1 29 (54.7)

Number of prior advanced/metastatic

regimens, n (%)c

0 7 (13.2)

1 22 (41.5)

>1 24 (45.3)


UPDATED ANTITUMOR ACTIVITY

Best % change from baseline in target lesion size (N=51)a

Best overall response:

Complete response Partial response

Stable disease Progressive disease20

Cha

nge

Fro

m B

asel

ine

(%)

40

60

80

100

0

–20

–40

–60

–80

–100

*

*

*

*Indicates tumor assessment by RECIST v1.1.aExcludes 2 patients: one with early death and one with indeterminate response.

ROS1-rearranged

NSCLC (N=53)

Shaw et al.2014

(N=50)

BOR, n (%)CRPRSDPDNEa

6 (11.3)32 (60.4)10 (18.9)

3 (5.7)2 (3.8)

3 (6)33 (66)9 (18)3 (6)2 (4)

ORR, %95% CI

71.757.7–83.2

7258–84

Median TTR, wks Range

7.94.3–103.6

7.94.3–32.0

Median DORb, mos

95% CI

24.715.2–45.3

17.614.5–NR

aResponses could not be evaluated in 2 patients because of

early death or indeterminate response.bEstimated using the Kaplan-Meier method.BOR, best overall response; CI, confidence interval; CR, complete response; DOR, duration of response; mos, months; NE, not evaluable; NSCLC, non-small cell lung

cancer; ORR, objective response rate; PD, progressive disease; PR, partial response;

RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TTR, time to response; wks, weeks. Shaw.A et al, ELCC 2019 and annals onco 2019

ORR: 71.7% (57.7-83.2)

UPDATED PROGRESSION-FREE SURVIVAL

40

Pro

gres

sion

-fre

e S

urvi

val (

%)

Time (months)

60

80

100

20

00 4020 60 80

53No. at risk 41 35 31 19 17 16 11 10 9 4 2 2 01422 7 2

ROS1-rearranged NSCLC

(N=53)

Shaw et al. 2014

(N=50)

Events, n (%) 36 (67.9) 23 (46)

Median PFS,

95% CI

19.3 months

15.2–39.1

19.2 months

14.4–NR


mPFS: 19.3mo (15.2-39.1)

EUROPEAN LUNG CANCER CONGRESS 2019

OVERALL SURVIVAL

40

Ove

rall

Sur

viva

l (%

)

Time (months)

60

80

100

20

00 4020 60 80

53No at risk. 48 42 37 31 27 23 20 18 17 9 5 4 02033 13 3

1-year OS rate

79%

4-year OS rate

51%

ROS1-rearranged NSCLC

(N=53)

Deaths, n (%) 26 (49.1)

Median OS (95% CI) 51.4 months (29.3–NR)

NR, not reached; NSCLC, non-small cell lung cancer; OS, overall survival.

Censored

Median follow-up for OS: 62.6 months

14 patients (26%) remain in follow-up


mOS: 51.4mo(29.3-NR)

aN is the number of patients who underwent ROS1 fusion partner testing. FISH, fluorescence in situ hybridization.

One patient had negative results per next-generation sequencing, with an EML4-ALK fusion detected.

One patient had an atypical FISH pattern and negative results per next-generation sequencing.

OVERALL SURVIVAL AND ROS1 FUSION PARTNERS (N=30)a

LIMA1MSNTPM3

Negative

Failed

SLC34A2

SDC4

EZR

CD74

EML4-ALK

Survival (months)0 10 20 30 40 50 60 70 80 90

* Censored


aThere were no Grade 4 or 5 TRAEs. bClustered term comprising AEs that represent similar clinical symptoms/syndromes.

TREATMENT-RELATED ADVERSE EVENTS IN ≥10% OF PATIENTS

TRAEs, n (%)

ROS1-rearranged NSCLC (N=53)

Any Grade Grade 3a

Vision disorderb 46 (86.8) 0 Nausea 27 (50.9) 1 (1.9)Edemab 25 (47.2) 0Diarrhea 24 (45.3) 0Vomiting 20 (37.7) 2 (3.8)Elevated transaminasesb 19 (35.8) 2 (3.8)Constipation 18 (34.0) 0Bradycardiab 11 (20.8) 0Fatigue 11 (20.8) 0Dizzinessb 10 (18.9) 0Dysgeusia 10 (18.9) 0Hypophosphatemia 9 (17.0) 8 (15.1)Decreased appetite 8 (15.1) 1 (1.9)Neutropeniab 8 (15.1) 5 (9.4)Rash 7 (13.2) 0

NSCLC, non-small cell lung cancer; TRAE, treatment-related adverse event. Shaw.A et al, ELCC 2019 and annals onco 2019

40

20

0

–20

Perc

ent chang

e in t

arg

et

lesio

ns f

rom

base

line

–40

–60

–80

–100

Goto J Clin Oncol. 2015. Abstract 9022, Wu YL et al, JCO 2018

N=127

Phase II study of crizotinib in East Asian

patients with ROS1+ advanced NSCLC

ORR (IRR): 71.7% (95% CI, 63.0-79.3)

mPFS (IRR): 15.9 months (95% CI, 12.9 -24.0 months)

PFS as assessed by independent radiology

review

Wu YL et al, JCO 2018

1. Mazières J, et al. J Clin Oncol. 2015 2. Vassal G, et al. ECCO 2015; abstract 12LBA 3. Shaw AT, et al. Annasl onco 2019. 4. Michels.S et al, JTO 2019 5. Wuu YL et al, JCO 2018

EUROS11

(N = 31)AcSé2

(N = 36)Profile 10013

(N = 51)EUCROSS4

(N=34)

East Asian patients5

(N=127)

Trial Retrospective Phase 2Phase 1

expansionPhase 2 Phase 2

Ethnicity Europe FranceGlobal (42%

Asian)Europe Asian

Diagnostic Local FISH FISH Local FISH Central FISH

Response rate 80% 72% 71.7% 70% 71.7%

Median PFS, months 9.1 9.1 19.3 20 15.9

Median follow-up, months

?? NA 16.4

Comparison of crizotinib efficacy

across studies on ROS1+ NSCLC

Stage IIIB−IV lung carcinoma1st line

ROS1+

Crizotinib(250 mg BID)

Crizotinib as a standard treatment

first line ROS1+ NSCLC

Best response*, n (%) All (N= 32) Crizotinib-naïve (N= 30)

CR 1 (3) 1 (3)

PR 19 (59) 19 (59)

SD 6 (19) 6 (19)

PD 2 (6) 2 (6)

Not evaluable** 4 (6) 2 (7)

Overall response rate, n (%)

20 (62%) 20 (67%)

Disease control rate (CR+PR+SD), n (%)

26 (81) 26 (87)

Duration of response, months

Median (95% CI)18.4 (8.0-18.4)

Sun Min Lim et al, JCO 2017

ORR: 62%

Ceritinib in ROS1-rearranged (Korean Nationwide Phase II Study)

PFS in all pts and crizotinib naıve pts

Crizotinib naive ptsmPFS: 19.3m (95%CI, 1-37)


Adverse Events That Occurred at Grades 1 to 2 in 10% or more Pts or at Grades 3 to 5750 mg/ day after 2-hour fasting

22 (68%) of 32 patients had at least one dosereduction


Lorlatinib: Phase 2 Study Design

Primary Endpoint

• Overall and intracranial (IC) antitumor activity measured

as confirmed overall and IC response by ICR

Secondary Endpoints

• Safety and tolerability

• Secondary measures of clinical efficacy

3nd generation ALK TKI QD PO,

continuous dosing, 21-day cyclea

EXP1

Tx naïve

EXP2

prior

crizotinib

only

EXP3A: prior crizotinib +

CT OR EXP3B:

1 non-crizotinib ALK TKI

± CT

EXP4

2 prior ALK

TKIs ± CT

EXP5

3 prior ALK

TKIs ± CT

EXP6

Treatment-naïve or any

line/type of prior treatment

(ie CT and/or ROS1

inhibitor therapies)

ROS1+bALK+

Patients with or without asymptomatic (untreated or treated) central nervous

system metastases were eligible.

aTreatment until PD or unacceptable toxicity; treatment beyond PD allowed if

deriving benefit.

bROS1 rearrangement status was determined locally via fluorescence in situ

hybridization, reverse transcriptase–polymerase chain reaction or next-

generation sequencing, and confirmed by central laboratory testing.

The data cut-off date was February 2, 2018.

Sai-Hong Ignatius Ou et al, IASLC 2018

Crizotinib-naïve (n=13)

BOR, n (%)CRPRSDPDIND

1 (7.7)7 (53.8)5 (38.5)

00

ORR, n (%) 95% CI

8 (61.5)31.6, 86.1

Median TTR, moRange

1.41.3–8.3

Median DOR, mo 95% CI

19.64.0, 25.3

DOR ≥12 mo, n⁰/n (%) 5/8 (62.5)

Median PFS, mo95% CI

21.04.2, 26.7

Patients with at least one on-study target lesion assessment as per independent central review were included. If any procedure was different

and not interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is not displayed.

BOR, best overall response; CI, confidence interval; DOR, duration of response; IND, indeterminate; mo, months; ORR, objective response rate; PD, progressive disease; PFS, progression-free

survival; TTR, time-to-first tumor response.

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50

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Best

Ch

an

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rom

Baselin

e (

%)

Off treatment or PD occurred

Complete response (CR)

Partial response (PR)

Stable disease (SD)

ORR: 61.5%

mPFS : 21 months

N=13 pts


Lorlatinib: Phase 2 Study Design

Intracranial Efficacy in Crizotinib-naïve ROS1+ Patients

Crizotinib-naïve (n=6)*

IC-BOR, n (%)CRPRSDPDIND

3 (50.0)1 (16.7)2 (33.3)

00

IC-ORR, n (%) 95% CI

4 (66.7)22.3, 95.7

IC-DOR ≥6 mo, n⁰/n (%) 2/4 (50.0)

BOR, best overall response; CI, confidence interval; DOR, duration of response; IC, intracranial; IND, indeterminate; mo, months; NR, not reached; ORR, objective response rate; PD, progressive

disease.

Patients with at least one on-study target lesion assessment as per independent central review were included. If any procedure

was different and not interchangeable from the procedure at screening, the percent change from baseline could not be

calculated and is not displayed.

*Based on all intracranial lesions.

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Stable disease (SD)

IC-ORR 66.7%


TRAEs in ≥10% of Patients, n (%)

Total

(N=47) Grade 3 Grade 4

Hypercholesterolemia* 39 (83.0) 4 (8.5) 0

Hypertriglyceridemia* 28 (59.6) 9 (19.1) 0

Edema* 21 (44.7) 1 (2.1) 0

Peripheral neuropathy* 16 (34.0) 1 (2.1) 0

Cognitive effects* 11 (23.4) 0 0

Weight increased 10 (21.3) 3 (6.4) 0

Dizziness 7 (14.9) 2 (4.3) 0

Mood effects* 6 (12.8) 0 0

Lipase increased 6 (12.8) 3 (6.4) 0

Fatigue* 5 (10.6) 1 (2.1) 0

ALT increased 5 (10.6) 0 0

Arthralgia 5 (10.6) 0 0

Thrombocytopenia 5 (10.6) 0 1 (2.1)

*Because the frequency of certain medical concepts or conditions may have been underestimated by reliance on a single

adverse event, selected adverse events were analyzed in aggregate using cluster terms.

Safety Summary, n (%)Total

(N=47)

TRAEs 45 (95.7)

Grade 3–4 TRAEs 23 (48.9)

TRAEs leading to dose delay 17 (36.2)

TRAEs leading to dose reduction 11 (23.4)

TRAEs leading to discontinuation 0

TRAEs leading to death 0

ALT, alanine aminotransferase; TRAEs, treatment-related adverse events.

Safety Summary (ROS1+ Patients)


*Patients with at least 12 months of follow-up; †All patients from STARTRK-1, STARTRK-2, ALKA-372-001 and STARTRK-NG (regardless of tumor type or gene rearrangement) who received ≥1 entrectinib dose; ‡Per blinded independent central review (RECIST

v1.1); §Patients with measurable and non-measurable CNS lesions at baseline

CNS: central nervous system; DoR: duration of response; ORR: objective response rate; OS: overall survival

NSCLC: non-small cell lung cancer; PFS: progression-free survival; RECIST: response evaluation criteria in solid tumorsBarlesi et al. ELCC 2019

ENTRECTINIB (ROS1/TRK/ALK TKI)

IN ROS1 FUSION-POSITIVE NSCLC

SYSTEMIC EFFICACY OF ENTRECTINIB

n (%)Total

(n=53)

CNS disease present at baseline†

(n=23)

CNS disease absent at baseline†

(n=30)

ORRb‡

(95% CI)41 (77.4)

(63.8, 87.7)17 (73.9)

(51.6, 89.8)24 (80.0)

(61.4, 92.3)

CR 3 (5.7) 0 3 (10.0)

Median DoR,‡ months (95% CI)

24.6 (11.4, 34.8)

12.6 (6.5, NE)

24.6 (11.4, 34.8)

Median PFS,‡

months (95% CI)19.0

(12.2, 36.6)13.6

(4.5, NE)26.3

(15.7, 36.6)

Median OS, months(95% CI)

NE(NE, NE)

– –

Clinical benefit rate* (95% CI)

41 (77.4)(63.8, 87.7)

– –

Change in tumour size: ROS1+ NSCLC population

a. Best change at any single timepoint; b. Confirmed responses only

*Includes SD for at least 6 months. †CNS disease status determined by Investigator; ‡By blinded independent central review (RECIST v1.1)

Data cut-off date: 31 May 2018. ROS1 inhibitor-naïve patients with ROS1+ NSCLC (integrated analysis population)

CI, confidence interval; CNS, central nervous system; CR, complete response; DoR, duration of response; NE, not estimable;

ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SLD, sum of the longest diameter;

Best percent change from baseline in tumour sizea

CNS disease at baseline

Subjects with missing SLD percent change were excluded from plot

Bes

t% im

prov

emen

t fr

om b

asel

ine

in S

LD

-100

-75

-50

-25

0

25

Individual patients

CNS = Yes CNS = No

Barlesi et al. ELCC 2019

ORR: 77.4% (63.8-87.7)

PROGRESSION-FREE SURVIVAL (BICR ASSESSMENT)

Total n=53

CNS disease present at baseline (n=23) †

CNS disease absent at baseline (n=30) †

Patients with event, n (%)

25 (47.2) 11 (47.8) 14 (46.7)

PD, nDeath, n

205

83

122

Time to event (months)

Median(95% CI)

19.0(12.2, 36.6)

13.6(4.5, NE)

26.3(15.7, 36.6)

Median PFS 19.0 months

(95% CI 12.2, 36.6)

Median follow up: 15.5 months

PFS, ROS1+ NSCLC

100

0

80

60

40

20

0 6 12 18 24 30 36

Time (months)

Total

Censored

42

2837 8 6 353 1532 6 5 143 1Total

No. at risk

PF

S b

y B

ICR

(%

)

Median: 19.0 months

(95% CI: 12.2, 36.6)

Data cut-off date: 31 May 2018. ROS1 inhibitor-naïve patients with ROS1+ NSCLC (integrated analysis population). †CNS disease status determined by Investigator.

BICR: blinded independent central review; CI, confidence interval; CNS, central nervous system; NE, not estimable; PD, progressive disease; PFS, progression-free survival Barlesi et al. ELCC 2019

INTRACRANIAL ORR AND DoR (BICR ASSESSMENT)

Intracranial response – CNS metastases at baseline by BICR (n=20*)

Intracranial ORR, n (%) (95% CI)

11 (55) (31.5, 76.9)

CRPRSDPDNon CR/PD-Non evaluable

4 (20.0)7 (35.0)

03 (15.0)6 (30.0)

Intracranial median DoR, months (95% CI) 12.9 (5.6, NE)

Patients with event, n (%)Disease progression, n Death, n

5 (45.5)32

6 months Patients remaining at risk, nCNS event-free probability

70.71

*Patients with assessable CNS metastases at baseline per BICR.

Data cut-off date: 31 May 2018. ROS1 inhibitor-naïve patients with ROS1+ NSCLC (integrated analysis population)

BICR, blinded independent central review; CI, confidence interval; CNS, central nervous system; CR, complete response; DoR, duration of response; ORR, overall response

rate; PD, progressive disease; PR, partial response; SD, stable diseaseBarlesi et al. ELCC 2019

MOST COMMON (≥10%) TREATMENT-RELATED ADVERSE EVENTS, N (%)

ROS1+ NSCLC safety evaluable population* (n=134)

All grades Grade ≥3

Dysgeusia 57 (42.5) 1 (0.7)

Dizziness 44 (32.8) 1 (0.7)

Constipation 44 (32.8) 0

Diarrhoea 38 (28.4) 3 (2.2)

Weight increased 36 (26.9) 10 (7.5)

Fatigue 32 (23.9) 0

Nausea 23 (17.2) 0

Paraesthesia 23 (17.2) 0

Oedema peripheral 22 (16.4) 0

Myalgia 21 (15.7) 2 (1.5)

Vomiting 19 (14.2) 0

Blood creatinine increased 18 (13.4) 1 (0.7)

Aspartate aminotransferase increased 16 (11.9) 2 (1.5)

*All patients with ROS1+ NSCLC from the ALKA-372-001, STARTRK-1 and STARTRK-2 studies who received ≥1 dose of entrectinib

Data cut-off date: 31 May 2018 Barlesi et al. ELCC 2019

Characteristic N=30*Age, median (range) 52 (30, 75)

Sex, female n (%) 20 (67)

Race, Asian n (%) 17 (57)

CNS metastases at baseline, n/N (%)

TKI-naïve, n/N (%)

TKI-pretreated, n/N (%)

16/30 (53)

5/10 (50)

11/20 (55)

ROS1 fusion detection method, n (%)

FISH

NGS

22 (73)

8 (27)

Median lines of prior systemic therapy (range) 2 (1, 8)

Prior ROS1 TKI, n (%)

Crizotinib only, n (%)

20 (67)

11 (37)

Median # of prior TKIs (range)

No prior TKI(s), n (%)

1 prior TKI, n (%)

≥2 prior TKIs, n (%)

1 (0, 3)

10 (33)

14 (47)

6 (20)

Prior chemotherapy, n (%) 27 (90)

TRIDENT-1: ROS1+ NSCLC Patient Demographics

Jessica J. Lin et al, IASLC 2018

Repotrectinib, a Next-Generation ROS1/TRK/ALK TKI

Repotrectinib (ROS1/TRK/ALK Inhibitor) in

TKI-naïve ROS1+ NSCLC by BICR

ORR: 91%

IC-ORR: 100%

Drilon A et al, ESMO 2019

• Dose-limiting toxicities (n=4)

• Grade 2 or 3 dizziness

- 160 mg BID (n=2)

- 240 mg QD (n=1)

• Grade 3 dyspnea/hypoxia

- 160 mg BID (n=1)

Most common (>10%)

treatment-related AEs

All Grades

(%)

Grade 3#

(%)

Any AE 60 (83.0)

Dizziness 36 (50.0) 2 (2.8)

Dysgeusia 33 (45.8)

Paresthesia 21 (29.2)

Constipation 14 (19.4)

Fatigue 13 (18.1)

Anemia 9 (12.5) 3 (4.2)

Nausea 8 (11.1)

Repotrectinib Treatment-Related Adverse Events

#Additional grade 3 treatment-related AEs: weight increased,

dyspnea/hypoxia, pleural effusion, hypophosphatemia (1 each)

No grade 4 treatment-related AEs observed

• Two deaths during study treatment

• 1 due to disease progression

• 1 due to sudden death possibly

related to study drug

• RP2D determination is ongoing


Patients ROS1+ NSCLC

Crizotinib

Ceritinib

Entrectinib

3nd generationALK TKI

Repotrectinib

Crizotinib 19.3

Ceritinib 19.3

Entrectinib 19.0

Lorlatinib 21.0

Repotrectinib ?

PROFILE 1001

Ceritinib Ph2

ALKA+STARTRK-1+STARTRK-2

Lorlatinib Ph2 (Cohort EXP-6)

TRIDENT-1 (ROS1 cohort)

0 10 20

After 2 months

What we done: Crizotinib


+ 6 mo

+ 16 mo

Crizotinib 250 mg twice daily, no side effect

2 months


Increased dyspnea and radiological progression on the right side (pleural and pulmonary lymphangitic carcinomatosis)

+ 20 mo

Molecular testingon pleural effusion:ALK G2032R mut



Crizotinib

Ceritinib

Entrectinib


Crizotinib 19.3

Ceritinib 19.3

Entrectinib 19.0

Lorlatinib 21.0

Repotrectinib ?

PROFILE 1001

Ceritinib Ph2

ALKA+STARTRK-1+STARTRK-2

Lorlatinib Ph2 (Cohort EXP-6)

TRIDENT-1 (ROS1 cohort)

0 10 20

?

Repotrectinib




3. Ceritinib

4. 3nd generation ALK TKI

5. Repotectinib

Acquired resistance to crizotinibfrom a mutation in CD74-ROS1.

N Engl J Med. 2013 Jun 20;368(25):2395-401.

Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

ROS1 - Acquired Resistance to Crizotinib

Biopsy

MTB

S1986

Ba/F3 EZR-ROS1S1986Y

0

50

100crizotinib

0 1000010001001010.1

ceritinib

lorlatinib

Drug Concentration (nM)%

Cell

Via

bili

ty

Francesco Facchinetti et al, CCR 2015

ROS1 resistance mutations in ROS1-positive

patients progressing on crizotinib

Justin F. Gainor et al, JCO precis oncol 2017

Massachusetts General Hospital, Boston

ROS1 Resistance mutations in Post-CrizotinibN=17

Lorlatinib: Overall Efficacy in Crizotinib-pretreated

ROS1+ Patients

Crizotinib-pretreated (n=34)

BOR, n (%)CRPRSDPDIND

2 (5.9)7 (20.6)

16 (47.1)3 (8.8)

6 (17.6)

ORR, n (%) 95% CI

9 (26.5)12.9, 44.4

Median TTR, moRange

2.51.4–4.2

Median DOR, mo 95% CI

NR7.1, NR

DOR ≥12 mo, n⁰/n (%) 5/9 (55.6)

Median PFS, mo95% CI

8.54.4, 18.0

BOR, best overall response; CI, confidence interval; DOR, duration of response; mo, months; NR, not reached; ORR, objective response rate; PFS, progression-free survival; TTR, Time-to-first tumor

response.

Patients with at least one on-study target lesion assessment as per independent central review were included. If any procedure was different and not

interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is not displayed.

70

60

10

0

30

20

50

40

‒10

‒20

‒30

‒40

‒50

‒60

‒70

‒80

‒90

‒100

Best

Ch

an

ge F

rom

Baselin

e (

%) Indeterminate (IND)



Stable disease (SD)

Progressive disease (PD)

Off treatment or PD occurred ORR: 26.5%

N=34 pts

mPFS : 8.5 months


Intracranial Efficacy in Crizotinib-pretreated ROS1+

Patients

Crizotinib-pretreated (n=19)*

IC-BOR, n (%)CRPRSDPDIND

8 (42.1)2 (10.5)5 (26.3)

04 (21.1)

IC-ORR, n (%) 95% CI

10 (52.6)28.9, 75.6

Median IC-DOR, mo 95% CI

NR5.0, NR

IC-DOR ≥6 mo, n⁰/n (%) 6/10 (60.0)

BOR, best overall response; CI, confidence interval; DOR, duration of response; IC, intracranial; IND, indeterminate; mo, months; NR, not reached; ORR, objective response rate; PD, progressive

disease.

*Based on all intracranial lesions

Patients with at least one on-study target lesion assessment as per independent central review were included. If

any procedure was different and not interchangeable from the procedure at screening, the percent change from

baseline could not be calculated and is not displayed.

70

60

10

0

30

20

50

40

‒10

‒20

‒30

‒40

‒50

‒60

‒70

‒80

‒90

‒100

Best

Ch

an

ge F

rom

Baselin

e (

%)




Stable disease (SD)

IC-ORR: 52.6%


Repotrectinib, a Next-Generation

ROS1/TRK/ALK TKI

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

D2033N 200.9 535.4 0.2 169.2 3.3 1.3

L2026M 606.4 ND 29.1 2026 930.6 10

S1986F 63.7 68 5.5 3.4 0.4 <0.2

L1951R 157.6 785.5 91.8 35.4 2.8 <0.2

• ROS1 rearrangement is an

oncogenic driver in 1-2% of

NSCLC

• Crizotinib is the only approved

targeted therapy for patients with

advanced ROS1+ NSCLC

• 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

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

Crizotinib Entrectinib Lorlatinib Repotrectinib

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

Repotrectinib in

TKI-pretreated ROS1+ NSCLC by BICR

IC-ORR: 75%

ORR: 39%

Drilon A et al, ESMO 2019

Preliminary Clinical Activity of Repotrectinib Against

ROS1 G2032R

• 16 of 17 TKI-pretreated subjects had baseline

plasma cfDNA tested by NGS (Guardant360)

• ROS1 G2032R detected in 4 subjects (25%) who

had been crizotinib-pretreated

• All 4 subjects experienced tumor regressions on

Repotrectinib

• 1 cPR at 160 mg QD (DOR 7.4 mos and remains on

treatment at 11+ mos)

- 1 0 0 %

- 9 0 %

- 8 0 %

- 7 0 %

- 6 0 %

- 5 0 %

- 4 0 %

- 3 0 %

- 2 0 %

- 1 0 %

0 %

1 0 %

2 0 %

3 0 %

4 0 %

Ma

xim

um

ch

an

ge

in

tu

mo

r s

ize

(%

) fr

om

ba

se

lin

e

1 P rio r TK I

2 P rio r T K Is


0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4

1 6 0 B ID

1 6 0 B ID

2 4 0 Q D

4 0 Q D

4 0 Q D

8 0 Q D

1 6 0 Q D

1 6 0 B ID

1 6 0 B ID

1 6 0 B ID

1 6 0 B ID

1 6 0 Q D

1 6 0 Q D

2 4 0 Q D

8 0 Q D

8 0 Q D

1 6 0 Q D

1 6 0 Q D

1 6 0 Q D

8 0 Q D

1 6 0 Q D

1 6 0 Q D

1 6 0 Q D

8 0 Q D

4 0 Q D

4 0 Q D

4 0 Q D

T re a tm e n t D u ra t io n (m o n th )

Sta

rtin

g D

os

e (

mg

)

1 P rio r TK I

2 P rio r T K Is

0 P rio r TK I

3 P rio r T K Is

Treatment Ongoing

Time to Response

Radiographic PD

15 of 27 patients (56%) remain

on treatment 13 Jul 2018

Duration of Repotrectinib Treatment in N=27 ROS1+

NSCLC by BICR


Lorlatinib …major clinical benefit and radiological response

+2mo

+8mo


Evolution

+10mo

+12mo





3. Pembrolizumab or Nivolumab

4. Ceritinib

5. Crizotinib

We decided to start carbo+Pemetrexed

+ 6 weeks


Still on going

KRAS49%

EGFR23%

BRAF8%

MET7%

HER25%

ALK4%

RET3%

ROS11%

Oncogenic Driver

Driver Subgroup % Total

KRAS G12C

Other

42%

58%271

EGFR 18/19/21

20/other

48%

52%125

BRAF V600E

Other

48%

52%43

MET Exon 14

Other

56%

44%36

HER2 N/A 29

ALK N/A 23

RET KIF5B

Other

73%

27%16

ROS1 N/A 7

IMMUNOTARGET COHORT (n = 551)


020

40

60

80

10

0

% o

f tu

mo

r ce

lls P

DL1

EGFR KRAS ALK ROS1 BRAF HER2 RET MET

IMMUNOTARGET COHORT: PDL1 status

PDL1 expression

analyzed by IHC in

each center

Median of PDL1

expression for each

driver (median and

standard deviation)


IMMUNOTARGET COHORT: Response

Driver PD SD CR/PR

BRAF 46% 30% 24%

MET 50% 34% 16%

KRAS 51% 23% 26%

HER2 67% 26% 7%

EGFR 67% 21% 12%

ALK 68% 32% 0

RET 75% 19% 6%

ROS1 83% 0 17%

TOTAL 57% 24% 19%


IMMUNOTARGET: ALK/ROS1/RET subgroups

PFS by nb of line

(p = 0.47)0.0

00.2

50.5

00.7

51.0

0

Pro

gre

ssio

n F

ree

Su

rviv

al

0 6 12 18 24 30Months

1st-3rd line > 3rd line

Patients with ALK, ROS1 or RET mutation

PFS was not affected by number of previous lines before immunotherapy

Despite PDL1 positivity, no patients with gene rearrangements displayed tumor response.Julien MAZIERES et al, ASCO 18

In summary for ROS1+ NSCLC


2nd lineROS1

TKI therapy

Brigatinib

Foretinib

Cabozantinib


Resistance mutation

CNS disease

Repotrectinib

Ceritinib

Crizotinib

Ceritinib

Entrectinib

3nd generation ALK TKI

Repotrectinib

D.Planchard et al, annals of onco 2018

Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic NSCLC

Wu Y-L et al, annals of onco 2018

THANK YOU !Acknowledgments

[email protected]

Benjamin BESSEThierry LE CHEVALIERJean-Charles SORIA

Charles NALTETAnas GAZZAH

Pernelle LAVAUDCécile LE PECHOUXAngéla BOTTICELLA

Antonin LEVYLaura MEZQUITA

@dplanchard

Alexander Drilon MD

Memorial Sloan Kettering Cancer Center

Targeted therapy beyond EGFR/ALK: BRAF and ROS1

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