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)
Sebastian Michels et al, JTO 2019
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
Sebastian Michels et al, JTO 2019
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)
Shaw.A et al, ELCC 2019 and annals onco 2019
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
Shaw.A et al, ELCC 2019 and annals onco 2019
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
Shaw.A et al, ELCC 2019 and annals onco 2019
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
Shaw.A et al, ELCC 2019 and annals onco 2019
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)
Sun Min Lim et al, JCO 2017
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
Sun Min Lim et al, JCO 2017
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.
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 (
%)
Off treatment or PD occurred
Complete response (CR)
Partial response (PR)
Stable disease (SD)
ORR: 61.5%
mPFS : 21 months
N=13 pts
Sai-Hong Ignatius Ou et al, IASLC 2018
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.
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 (
%)
Off treatment or PD occurred
Complete response (CR)
Partial response (PR)
Stable disease (SD)
IC-ORR 66.7%
Sai-Hong Ignatius Ou et al, IASLC 2018
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)
Sai-Hong Ignatius Ou et al, IASLC 2018
*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
Jessica J. Lin et al, IASLC 2018
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
D.Planchard, Gustave Roussy
+ 6 mo
+ 16 mo
Crizotinib 250 mg twice daily, no side effect
2 months
D.Planchard, Gustave Roussy
Increased dyspnea and radiological progression on the right side (pleural and pulmonary lymphangitic carcinomatosis)
+ 20 mo
Molecular testingon pleural effusion:ALK G2032R mut
D.Planchard, Gustave Roussy
Patients ROS1+ NSCLC
Crizotinib
Ceritinib
Entrectinib
3nd generationALK TKI
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
What would be your treatment recommendation for this patient?
1. Carboplatin + pemetrexed
2. Platinum + pemetrexed + Pembrolizumab
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)
Complete response (CR)
Partial response (PR)
Stable disease (SD)
Progressive disease (PD)
Off treatment or PD occurred ORR: 26.5%
N=34 pts
mPFS : 8.5 months
Sai-Hong Ignatius Ou et al, IASLC 2018
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 (
%)
Off treatment or PD occurred
Complete response (CR)
Partial response (PR)
Stable disease (SD)
IC-ORR: 52.6%
Sai-Hong Ignatius Ou et al, IASLC 2018
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
Jessica J. Lin et al, IASLC 2018
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
Jessica J. Lin et al, IASLC 2018
Lorlatinib …major clinical benefit and radiological response
+2mo
+8mo
D.Planchard, Gustave Roussy
Evolution
+10mo
+12mo
D.Planchard, Gustave Roussy
What would be your treatment recommendation for this patient?
1. Carboplatin + pemetrexed
2. Platinum + pemetrexed + Pembrolizumab
3. Pembrolizumab or Nivolumab
4. Ceritinib
5. Crizotinib
We decided to start carbo+Pemetrexed
+ 6 weeks
D.Planchard, Gustave Roussy
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)
Julien MAZIERES et al, ASCO 18
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)
Julien MAZIERES et al, ASCO 18
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%
Julien MAZIERES et al, ASCO 18
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
Patients ROS1+ NSCLC
2nd lineROS1
TKI therapy
Brigatinib
Foretinib
Cabozantinib
3nd generationALK TKI
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
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