Rociletinib (CO-1686)
April, 2015
Lung adenocarcinoma is increasingly treated according to
driver mutation
• Lung cancer incidence
– Worldwide: 1.2M cases per year
– UK: 43K cases per year
• Activating mutations (e.g. del 19,
L858R) in EGFR found in ~15% of
all NSCLC
– Twice as common in East Asian
populations
• Standard of care in mutant EGFR
NSCLC is most often a reversible
EGFR inhibitor as first-line therapy
2
Globocan 2012; CRUK 2011; Blakely & Bivona, Cancer Discov. 2012
T790M is the most common reason for loss of initial benefit
with EGFR inhibitors in newly diagnosed NSCLC patients
• Tumor genetics in 155 mutant EGFR lung cancer patients
undergoing re-biopsy after development of acquired resistance to
erlotinib/gefitinib
3
Yu et al., Clinical Cancer Res. 2013
There are limited options for patients that progress on first
generation EGFR TKIs
• There are no therapies currently available to specifically target
T790M disease
• Current standard treatment is cytotoxic chemotherapy
– Platinum containing doublet chemotherapy (e.g. gemcitabine/cisplatin)
– Single agent chemotherapy (e.g. pemetrexed, docetaxel, gemcitabine)
• New treatment options with improved adverse event profiles and
reduced requirements for hospital care are needed.
4
Yu et al., Clinical Cancer Res. 2013
Rociletinib (CO-1686) nonclinical summary
• Rociletinib (CO-1686)
– Inhibits the T790M EGFR resistance mutation at clinically relevant
exposures
– Oral dosing
– Irreversible (covalent) inhibitor
– Inhibits EGFR activating mutations
– Spares wild-type (WT) EGFR signaling
– Highly selective across the entire kinome
• Rociletinib demonstrates potent activity and EGFR pathway blockade
in cell lines with activating and T790M EGFR mutations
• As a single agent rociletinib causes tumor regressions in front-line
and T790M xenograft models
– Includes subcutaneous, PDX, and transgenic models
5
CO-1686
Walter et al., Cancer Discov. 2013
Rociletinib (CO-1686) binds EGFR covalently
• Irreversible binding results in sustained EGFR pathway suppression
6
Acrylamide forms covalent
bond with C797
Interaction between trifluoromethyl
group and M790 increases potency
Walter et al., Cancer Discov. 2013
Rociletinib (CO-1686) inhibits mutant EGFR, including
T790M, but spares wild-type EGFR
• Growth inhibition of tumor cell lines with rociletinib (CO-1686)
7
GI 5
0 [
CO
-16
86
] n
M
NC
I-H
1975
HC
C827
PC
9
HC
C827-E
PR
A431
NC
I-H
1299
NC
I-H
358
1 0
1 0 0
1 0 0 0
1 0 0 0 0
G e n o ty p e
D e l1 9
L 8 5 8 R
T 7 9 0M
+ ++
+ +
+
-
- -
- --
-
-
-
-- -
-
-
-
Front line model
Second line model (T790M)
EGFR WT
Walter et al., Cancer Discov. 2013
Rociletinib (CO-1686) spares wild type EGFR
• Rociletinib (CO-1686) is uniquely WT EGFR sparing
8
Symbol Compound EC50 (nM)
afatinib 15
gefitinib 107
AZD9291 131
erlotinib 209
CO-1686 3930
0
2 5
5 0
7 5
1 0 0
1 2 5
1 5 0
A 4 3 1 (W T E G F R )
d o s e [n M ]
% v
iab
ilit
y (
me
an
S
EM
)
5 0001 2503137820510 .30 .080 .020 .004
rociletinib (CO-1686)
Clovis Oncology, data on file
Rociletinib (CO-1686) causes tumor regression in front-line
L858R transgenic model
• No cell line based models with EGFR L858R mutation available
• Performed “gold standard” transgenic model
• Conclusion: Xenograft and transgenic models show that rociletinib is
an effective inhibitor of initial activating EGFR mutations (Del19 and
L858R) and T790M
9
Erlotinib CO-1686 Vehicle
*
Me
an
tu
mo
r v
olu
me
(mm
3)
SE
M
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
B a s e l in e
2 1 -d a y s p o s t -d o s in g
V e h ic le E r lo t in ib
5 0 m g /k g Q D
C O -1 6 8 6
5 0 m g /k g B ID
* * * *
L8
58
R
* Diffuse tumor cells in lung
Walter et al., Cancer Discov. 2013
• CO-1686 activity observed in L858R/T790M transgenic model
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
2 0 0
4 0 0
6 0 0
Ch
an
ge
fro
m B
as
eli
ne
(%
)
P D
S D
P R
C R
A fa tin ib
2 0 m g /k g
C O -1 6 8 6
5 0 m g /k g B ID
CO-1686 : Baseline CO-1686 : 3W
Afatinib: Baseline Afatinib : 3W
Rociletinib WT EGFR sparing profile allows for dosing to
efficacy - not MTD
10
Walter et al., Cancer Discov. 2013
Long-term Rociletinib activity superior to erlotinib in PC-9
(EGFRdel19) front line model
• Inhibition of T790M may improve durability of response
• rociletinib (CO-1686) administration better tolerated
– Impressive anti-tumor response in ~500 mm3 tumors
– No body-weight loss compared to vehicle treated animals
11
0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
1 4 0 0
D a y s o f d o s in g
Tu
mo
r v
olu
me
(Me
an
mm
3
SE
M)
V e h ic le
C O -1 6 8 6 (1 5 0 m g /k g B ID )
E rlo t in ib (5 0 m g /k g Q D )
C o n tin u e d o s in g n = 3 m ic e w ith e rlo tin ib
D o s e re m a in in g m ic e w ith C O -1 6 8 6
Clovis Oncology, data on file
TIGER-X Phase 1 identified 625 mg as Phase 2 dose
• TIGER-X, an international phase 1/2 study, examined 2 formulations
and multiple doses/schedules of rociletinib
– Therapeutic doses defined as 900 mg BID (original formulation) or ≥500
mg BID HBr salt tablet (PK optimized formulation)
• Two clinical doses under exploration – 500 mg BID and 625 mg BID
• 625 mg BID of optimized oral formulation (fed state) was identified as
the optimal dose and schedule
– 500 mg BID remains under investigation as step-down dose
– Clinical dose group: patients treated with 625/500 mg BID (n=56)
• Early evidence of activity was observed with durable RECIST
responses, particularly in T790M+ patients
• Wild-type EGFR sparing was confirmed by absence of cutaneous
toxicity (rash, paronychia, stomatitis, etc)
• Breakthrough status was granted by FDA in May 2014
FDA = US Food and Drug Administration; HBr = hydrobromide; RECIST = Response
Evaluation Criteria In Solid Tumors; RP2D = recommended phase 2 dose
12
Soria et al., ENA, 2014
TIGER-X expansion phase in T790M+
Key exclusion criteria:
– Symptomatic brain metastases
– Exon 20 insertion as activating EGFR mutation
• Patients with diabetes or cardiovascular disease were eligible
• Study sites in United States, Europe, and Australia
Key inclusion criteria:
– Advanced or metastatic EGFR mutation+ NSCLC
– At least 1 prior EGFR TKI therapy, with no upper limit or limit
on chemotherapy
– Biopsy within 60 days of study entry – molecular analysis T790M+
13
Soria et al., ENA, 2014
TIGER-X clinical dose group (T790M+):
baseline characteristics
625 mg BID 500 mg BID Total
N 30 26 56
Median age, years 59 59 59
Female, % 63 77 70
Asian, % 7 15 11
ECOG PS grade 0, % 13 27 20
Median no. of prior Rx 3 3 3
No. of prior TKIs, %
1 43 46 45
2 13 39 25
≥3 27 12 20
Immediate prior TKI, % 73 85 79
History of diabetes, % 3 12 7
History of cardiovascular disease, % 13 15 14
*7 patients started treatment with 900 mg BID free-base formulation and converted to 500 mg HBr salt tablet. The
majority of their treatment was with HBr tablet and they are aggregated with the 500 mg BID HBr tablet group.
ECOG PS = Eastern Cooperative Oncology Group Performance Status.
14
Soria et al., ENA, 2014
Rociletinib demonstrated linear pharmacokinetics across
efficacious dose range
• Rociletinib was absorbed rapidly with an elimination half-life of 2 – 4
hours, suitable for BID dosing regimen
• High fat breakfast slightly slowed the rate of absorption and
increased the amount absorbed with no change in the peak plasma
concentration of CO-1686
• No accumulation of CO-1686
15
5 0 0 7 5 0 1 0 0 0
0
1 2 5 0 0
2 5 0 0 0
3 7 5 0 0
5 0 0 0 0
6 2 5 0 0
7 5 0 0 0
1 0 0 0 0 0
1 2 5 0 0 0
H B r D o s e v s A U C
B ID D o s e (m g )
6 2 5
CO
-16
86
AU
C0
-24 (
ng
.h/m
L)
P h a s e 1
P h a s e 2
Wakelee et al., ELCC, 2014
TIGER-X clinical dose group responses
67% ORR 67% ORR (per RECIST 1.1)
89% DCR
Best Response for Evaluable T790M+ Patients
Ch
an
ge f
rom
Baselin
e (
%)
100
80
60
40
20
0
-20
-40
-60
-80
-
100
16
Soria et al., ENA, 2014
TIGER-X clinical dose group: PFS
*Data as of 25 September 2014 reflecting 31% data maturity
PFS = progression-free survival.
Kaplan-Meier Plot of PFS in T790M+ Patients
Su
rviv
al
Pro
bab
ilit
y
PFS (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
+ + + + + + + + +
+
+ + + + + +
+
+
+
+
+ +
56(0) 52(1) 27(4) 21(5) 18(7) 16(8) 14(10) 11(13) 11(13) 7(13) 6(13) 5(14) 5(15) 2(17) 1(17) 1(17) 1(17) 0(17)
At Risk (events)
Median PFS = 10.4 months*
17
Soria et al., ENA, 2014
TIGER-X clinical dose group: adverse events
Adverse event Frequency, %
Hyperglycemia 32
Diarrhea 25
Nausea 25
Reduced appetite 20
Fatigue 14
Muscle spasm 13
Vomiting 11
Treatment-related adverse events
(all grades) seen in >10% of patients
Adverse event Frequency, %
Hyperglycemia 14
Grade 3/4 treatment-related adverse events
seen in >5% of patients*
*21% of patients had a grade 3/4 treatment-related
adverse event and only hyperglycemia was
observed in ≥5% of patients
18
Soria et al., ENA, 2014
TIGER-X adverse events of interest
• No grade 3/4 adverse events observed in >1 patient except for
hyperglycemia
– Hyperglycemia readily managed with oral agent (typically metformin)
and, on occasion, dose reduction
• No cutaneous toxicity of note
– Grade 1 rash observed in 2 patients (transient, not acneiform/folliculitis)
– No paronychia or stomatitis
• Grade 3 QTc prolongation observed in 1 patient (625 mg BID)
• Across entire clinical program (>200 patients, all doses, all
genotypes):
– Pneumonitis observed in 4 patients – all quickly reversible; last 2 cases
resumed rociletinib therapy under steroid cover without recurrence of
pneumonitis
– No heart failure observed
19
Soria et al., ENA, 2014
Observed hyperglycemia relates to metabolite of rociletinib
• Rociletinib metabolite M502 is an inhibitor of IGF1R and accumulates
in humans causing hyperglycemia
– No hyperglycemia observed in toxicology studies of rociletinib
• Like rociletinib, M502 is wild-type EGFR sparing
Assay Rociletinib M502
A431 (IC50, nM) Cellular (wild-type EGFR)
903 907
NCI-H1975 (IC50, nM) Cellular (T790M EGFR)
36 961
IGF1R (IC50, nM) Kinase
477 57
IGF1R (IC50, nM) Cellular
458 58
IC50 = half maximal inhibitory concentration
IGF1R = insulin-like growth factor 1 receptor
20
Soria et al., ENA, 2014
IGF1R pathway activation may play a role in acquired
resistance to EGFR TKI
• Multiple publications have demonstrated a role for IGF1R signaling in
mediating resistance to EGFR inhibitors in NSCLC models
– Resistance to WZ4002 (a third-generation EGFR inhibitor structurally related to
CO-1686) is mediated by IGF1R signaling and can be reversed by the addition of
an IGF1R inhibitor (data from Janne lab)
100
80
60
40
20
0 0 0.01 0.1 1 10
WZ4002 (μmol/L)
+ DMSO
+ BMS536924
+ DMSO
+ BMS536924
WZR3
WZR4
WZ4002 + IGF1R inhibitor BMS536924 restores activity in resistant cell lines with IGF1R pathway activation
Pe
rce
nta
ge
of
Co
ntr
ol
Cortot et al., Cancer Res. 2013; Sharma et al., Cell 2010; Vazquez-Martin et al., Sci Rep. 2013
21
IGF1R inhibitor can overcome resistance in mutant EGFR
patient derived cell lines
• Cell line models derived from biopsy specimens collected after the
development of acquired resistance to EGFR inhibitors
• IGF1R inhibitor combination restores activity in 3/11 patient cell lines
Crystal et al., Science 2014
22
Cell line Patient
IGF1R
Combined responses from TIGER-X Phase 1/2 C
han
ge f
rom
Baselin
e (
%)
Best Response for All Patients (Any T790M
Status) on Therapeutic Doses (n=179)
ORR = 46% DCR = 84%
100
80
60
40
20
0
-20
-40
-60
-80
-
100
DCR = disease control rate; ORR = overall response rate.
23
Soria et al., ENA, 2014
Striking Activity in T790M-negative Patients
24
*Database as of January 2nd 2015
• RECIST ORR = 42% overall
• RECIST ORR = 50% in patients treated
with 625mg BID immediately off prior TKI
• mPFS = 7.5mo
Best Response for Target Lesions Centrally Confirmed T790M Negative 1686-008 Pts at 500 or 625mg BID
(Clinical Dose Group)
Comprehensive Monotherapy Development Program
TIGER-X (Ph 2) TIGER-X (Ph 2) • Single arm – expansion cohorts
• ≥2nd-line mutant EGFR NSCLC, T790M+
TIGER-1 (Ph 2/3) TIGER-1 (Ph 2/3) • Randomized rociletinib vs erlotinib
• 1st-line, treatment-naïve
TIGER-2 (Ph 2) TIGER-2 (Ph 2)
• Single-arm
• 2nd-line mutant EGFR NSCLC, T790M+
• Patients progressing on 1st-line EGFR TKI
• Now adding T790M– cohort
TIGER-3 (Ph 3) TIGER-3 (Ph 3) • Randomized rociletinib vs chemotherapy
• >2nd-line mutant EGFR NSCLC, T790M+
and T790M– (sequential analysis)
25
Soria et al., ENA, 2014
Qiagen’s existing therascreen® EGFR test is being developed as a
tissue companion diagnostic (CDx) for rociletinib
• Qiagen therascreen EGFR test for FFPE specimens
– Detects 29 mutations in EGFR
– Uses allele-specific PCR
– FDA-approved (with Afatanib)
• Clinical validation required for approval with rociletinib
26
FFPE = formalin-fixed paraffin-embedded
Combination studies to begin
• Rociletinib to be combined with several targeted therapeutics and
checkpoint inhibitors
• Collaborations established with multiple partner
companies/physicians
• Initial combination with:
27
Target Drug
PDL1 mAb
PD1 Pembrolizumab (Merck)
MEK Trametinib (GSK)
Aurora kinase small molecule inhibitor
Soria et al., ENA, 2014
Conclusions
• Rociletinib (CO-1686) is an oral, potent, irreversible inhibitor of
activating EGFR mutations and T790M
• Compelling and durable activity was demonstrated with clinical
doses in T790M+ patients
– 67% objective response rate
– Median (immature) PFS estimated at 10.4 months
• Wild-type sparing was confirmed, with no cutaneous toxicity
• The only grade 3/4 adverse event observed in >5% of patients
was hyperglycemia, readily managed with oral Rx
• Encouraging activity was observed in T790M– patients
• Comprehensive pivotal trial program is advancing rapidly
• NDA and MAA filings planned for mid 2015
28
Differentiation and areas of interest
• Rociletinib (CO-1686) has a unique tolerability and efficacy profile
– No evidence of WT EGFR inhibition observed in patients
– Evidence of activity in T790M- patients
– Moderately short plasma half-life allows for flexibility in dosing regimens
and management of potential combination AEs
• Clovis is interested in performing combination studies beyond those
mentioned with rociletinib, for example:
29
Combination Rationale
Anti-angiogenesis PFS increase in mutant EGFR patients treated with EGFR TKI and bevacizumab
Anti-EGFR antibody Dual inhibition of EGFR; block dimerization; potential lack of overlapping toxicity
Met inhibitor Activating and T790M EGFR pathway blockade may drive bypass pathway
activation
PARP inhibitor Platinum sensitivity and HRD signature observed in NSCLC
Mathematical based
alternative dosing strategies Use mathematical evolutionary modeling to delay the onset of acquired resistance
Radiotherapy Radio-sensitizing potential; lack of overlapping toxicity