LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers Alexander Drilon, 1 Vivek Subbiah, 2 Geoffrey R. Oxnard, 3 Todd M. Bauer, 4 Vamsidhar Velcheti, 5 Nehal J. Lakhani, 6 Benjamin Besse, 7 Keunchil Park, 8 Jyoti D. Patel, 9 Maria E. Cabanillas, 2 Melissa L. Johnson, 4 Karen L. Reckamp, 10 Valentina Boni, 11 Herbert H. F. Loong, 12 Martin Schlumberger, 7 Ben Solomon, 13 Scott Cruickshank, 14 S. Michael Rothenberg, 14 Manisha H. Shah, 15 and Lori J. Wirth 16 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 MD Anderson Cancer Center, Houston, TX; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 5 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 6 START Midwest, Grand Rapids, MI; 7 Institut Gustave Roussy, Villejuif, France; 8 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 9 University of Chicago, Chicago, IL; 10 City of Hope Comprehensive Cancer Center, Duarte, CA; 11 START Madrid CIOCC Hospital Universitario Sanchinarro, Madrid, Spain; 12 The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong; 13 Peter MacCallum Cancer Centre, East Melbourne, Australia; 14 Loxo Oncology, Stamford, CT; 15 The Ohio State University Comprehensive Cancer Center, Columbus, OH; 16 Massachusetts General Hospital Cancer Center, Boston, MA Dr. Alexander Drilon
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LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers
Alexander Drilon,1 Vivek Subbiah,2 Geoffrey R. Oxnard,3 Todd M. Bauer,4 Vamsidhar Velcheti,5 Nehal J. Lakhani,6
Benjamin Besse,7 Keunchil Park,8 Jyoti D. Patel,9 Maria E. Cabanillas,2 Melissa L. Johnson,4 Karen L. Reckamp,10
Valentina Boni,11 Herbert H. F. Loong,12 Martin Schlumberger,7 Ben Solomon,13 Scott Cruickshank,14
S. Michael Rothenberg,14 Manisha H. Shah,15 and Lori J. Wirth16
1Memorial Sloan Kettering Cancer Center, New York, NY; 2MD Anderson Cancer Center, Houston, TX; 3Dana-Farber Cancer Institute, Boston, MA; 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 5Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 6START Midwest, Grand Rapids, MI; 7Institut Gustave Roussy, Villejuif, France; 8Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 9University of Chicago, Chicago, IL; 10City of Hope Comprehensive Cancer Center, Duarte, CA; 11START Madrid CIOCC Hospital Universitario Sanchinarro, Madrid, Spain; 12The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong; 13Peter MacCallum Cancer Centre, East Melbourne, Australia; 14Loxo Oncology, Stamford, CT; 15The Ohio State University Comprehensive Cancer Center, Columbus, OH; 16Massachusetts General Hospital Cancer Center, Boston, MA
Dr. Alexander Drilon
2
RET is activated by two major mechanisms in cancer
KIF5B (most common in lung cancer)
CCDC6 or NCOA4 (most common in thyroid cancer)
Dr. Alexander DrilonDrilon et al. Nat Rev Clin Oncol 2018;15:151–67; Kato et al. Clin Cancer Res 2017;
23:1988–97; Pietrantonio et al. Ann Oncol 2018;Mar 10; Su et al. PLoS One 2016;11(11)
RET fusions Non-small cell lung cancer (2%)
Papillary and other
thyroid cancers (10–20%)
Pancreatic cancer (<1%)
Salivary gland cancer (<1%)
Spitz tumors (<1%)
Colorectal cancer (<1%)
Ovarian cancer (<1%)
Myeloproliferative disorders (<1%)
Many others (<1%)
KinaseDimerization
P P P P
P P P P
Medullary thyroid cancer
sporadic (>60%)
hereditary (>90%)
RET mutations
Common mutation: RET M918T
P
P
P
P
P
P
P
P
P
P
P
P
Activation by ligand-
independent dimerization
Direct kinase
activation
Covalent disulfide
bonds in cysteine-rich
region
Kinase domain
mutation
LOXO-292 is a potent and selective RET inhibitor
Subbiah et al. Ann Oncol 2018 (accepted manuscript/available online); Cabo = cabozantinib;
1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2). 2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-
baseline response assessment. 3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive
(30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18). 4. Excludes patients with unconfirmed CR/PR pending confirmation
at time of data cut-off. 5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment. 6. Patients that discontinued treatment prior to a first post-
Efficacy of LOXO-292 in RET fusion-positive cancers
Dr. Alexander Drilon
–100
NSCLC = non-small cell lung cancer
Note: Three patients not displayed due to treatment discontinuation prior to first post-
baseline response assessment; *Denotes patient with 0% maximum change in tumor size
April 2, 2018 data cut-off date
40
20
NSCLC
Thyroid
Pancreatic
Tumor type0
–20
–40
–60
–80
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
*
11
Efficacy of LOXO-292 regardless of RET fusion partner
Dr. Alexander DrilonNote: Three patients not displayed due to treatment discontinuation prior to first post-
baseline response assessment; *Denotes patient with 0% maximum change in tumor size†Fusion partner unknown due to FISH+ detection; April 2, 2018 data cut-off date
NSCLC
KIF5B Non-KIF5B
Response rate 13/16 (81%) 9/11 (82%)
–100
40
20
0
–20
–40
–60
–80
RET fusion partner
KIF5B
C CCDC6 CLIP1 NCOA4 ERC1 RUFY3 TFG PRKAR1A
Unknown†
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
*
12
Efficacy of LOXO-292 regardless of starting dose
Dr. Alexander Drilon
QD = once-daily; BID = twice-daily;
Note: Three patients not displayed due to treatment discontinuation prior to first post-baseline
response assessment; *Denotes patient with 0% maximum change in tumor size
April 2, 2018 data cut-off date
–100
80 mg BID
120 mg BID
Starting dose
20 mg QD
20 mg BID
160 mg BID
240 mg BID
40 mg BID
60 mg BID
40
20
0
–20
–40
–60
–80
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
*
13
Efficacy of LOXO-292 regardless of prior therapy
–100
40
20
0
–20
–40
–60
–80
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
*
● ●● ● ● ● ● ● ● ● ●
● ●● ●
●● ●
●●
●● ● ●
●● ●
●● ● ● ● Prior chemotherapy
Prior immunotherapy
● ● ● ● ● ● Prior radioactive iodine●
● ●● ● ●
Prior multikinase
inhibitor†
Yes
No
Note: Three patients not displayed due to treatment discontinuation prior to first post-baseline response
assessment; *Denotes patient with 0% maximum change in tumor size; †Includes alectinib, cabozantinib,
lenvatinib, pazopanib, ponatinib, RXDX-105, sitravatinib, sorafenib, and vandetanib; April 2, 2018 cut-off dateDr. Alexander Drilon
14
RET-mutant medullary thyroid cancer
Dr. Alexander Drilon
15
Efficacy of LOXO-292 in RET-mutant medullary thyroid cancer
Note: Two patients not displayed (one due to treatment discontinuation prior to first post-baseline response
assessment; one due to non-measurable disease at baseline (uCR)); †Includes cabozantinib, lenvatinib,
pazopanib, RXDX-105, sorafenib, sunitinib, and vandetanib; *CR; April 2, 2018 data cut-off date
–100
●● ●
●●● ●●
●●
● ●●●
Prior cabozantinib
Prior multikinase
inhibitor (MKI) †
Yes
No
● ●● ● ●
● ●●●●
●● Prior vandetanib
Prior other MKI
20
0
–20
–40
–60
–80
40
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
● ● ● ● ●
Dr. Alexander Drilon
*
●
16
Efficacy of LOXO-292 regardless of mutation and starting dose
–100
20
0
–20
–40
–60
–80
40
Ma
xim
um
ch
an
ge in
tu
mo
r s
ize
(%
)
Dr. Alexander Drilon
BID = twice-daily; QD = once-daily
Note: Two patients not displayed (one due to LOXO-292 discontinuation prior to first post-
baseline response assessment; one due to non-measurable disease at baseline (uCR)); *CR
April 2, 2018 data cut-off date
160
mg
BID
20 m
g Q
D
80 m
g B
ID
40 m
g B
ID
20 m
g B
ID
60 m
g B
ID
40 m
g B
ID
40 m
g B
ID
80 m
g B
ID
20 m
g B
ID
40 m
g B
ID
60 m
g B
ID
80 m
g B
ID
80 m
g B
ID
40 m
g B
ID
80 m
g B
ID
60 m
g B
ID
20 m
g B
ID
80m
g B
ID
80 m
g B
ID
Starting dose
E632_L633 del
D631_L633 del
RET mutation
M918T
V804M D378_G385>E
A883F
C618Y
*
17
Substantial decline in MTC tumor markers
Dr. Alexander Drilon
Carcinoembryonic antigen (CEA) Calcitonin
MTC = medullary thyroid cancer
April 2, 2018 data cut-off date
Bes
t C
EA
re
sp
on
se
(%
)
–100
100
0
–20
–40
–60
–80
Bes
t c
alc
ito
nin
re
sp
on
se
(%)
–100
–20
–40
–60
–80
100
0
18
Duration of LOXO-292 therapy
Dr. Alexander Drilon
Time on treatment (months)
0 1 2 3 4 5 6 7 8 9 10 11
NSCLC
Thyroid
Pancreatic
MTC
First response
Treatment after progression
Still on treatment
44/49 (90%) of patients with RET fusion-positive
cancers remain on therapy
27/29 (93%) of patients with RET-mutant
medullary thyroid cancer remain on therapy
RE
Tfu
sio
n-p
osit
ive
ca
nc
ers
RE
T-m
uta
nt
MT
C
NSCLC = non-small cell lung cancer;
MTC = medullary thyroid cancer
April 2, 2018 data cut-off date
19
Duration of LOXO-292 therapy in patients with brain metastases
NSCLC = non-small cell lung cancer
1. Initiated treatment at 120 mg BID; dose escalated at C5D1 to 160 mg BID; on study in month 4
2. Derived based on investigator assessments of brain metastases per RECIST 1.1
Brain metastases only observed in RET fusion-positive cancers; April 2, 2018 data cut-off date
Dr. Alexander Drilon
Yes
No
Time on treatment (months)
First response
Still on treatment
0 1 2 3 4 5 6 7 8 9 10 11
Baseline Week 4
CLIP1-RET fusion-positive NSCLC1
previously received two multikinase inhibitors and chemotherapy
3/3 intracranial responses in patients
with intracranial target lesions2
Presence of brain metastases2R
ET
fus
ion
-po
sit
ive
ca
nc
ers
KIF5B-RET fusion-positive NSCLC response to LOXO-292