1. No category

Efficacy of Rociletinib (CO-1686) in
Plasma-genotyped T790M-positive
NSCLC Patients
Lecia V. Sequist, Jonathan Wade Goldman, Heather A. Wakelee, D. Ross
Camidge, Helena Alexandra Yu, Andrea Varga, Ben Solomon, Geoffrey R. Oxnard,
Sai-Hong Ignatius Ou, Vassiliki Papadimitrakopoulou, Bo H. Chao, Stephen V. Liu,
Karen L. Reckamp, Alexander I. Spira, Zofia Piotrowska, Darrin Despain,
Chris Alan Karlovich, Sergey Yurasov, Jean-Charles Soria
Disclosures
Research support for conduct of the CO-1686 Phase 1/2
clinical trial was provided by Clovis Oncology.
Dr. Sequist has provided noncompensated consulting services
for Clovis Oncology, Boehringer Ingelheim, Merrimack,
Novartis, AstraZeneca, Taiho, and Genentech.
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Rociletinib is a Mutant-selective EGFR TKI
•
EGFR TKI therapies have 2 important limitations
–
Wild-type EGFR inhibition leads to cutaneous toxicity and diarrhea
–
Efficacy is limited by emergence of the T790M resistance mutation in ≈60% of patients
•
Rociletinib (CO-1686) was designed as an oral, irreversible, potent inhibitor of activating
EGFR mutations as well as the T790M mutation, with sparing of wild-type EGFR
•
Breakthrough therapy designation was granted by FDA in May 2014
•
Rociletinib was studied initially in single-arm studies in mutant EGFR NSCLC patients with
acquired resistance to TKI therapies
–
TIGER-X: the initial phase 1/2 trial which will be discussed today
–
TIGER-2: a phase 2 trial in 2nd-line patients, which will be presented in the fall of 2015
EGFR=epidermal growth factor receptor; TKI=tyrosine kinase inhibitor; NSCLC=non-small cell lung cancer.
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TIGER-X: Phase 1/2 Trial of Rociletinib
Key eligibility criteria
•
•
•
•
Advanced or recurrent NSCLC with a documented activating EGFR mutation
Prior treatment with EGFR-directed therapy
Recent biopsy available or willing to undergo a new on-study biopsy; plasma samples collected
Phase 2 only
–
–
–
Disease progression while on treatment with EGFR-directed therapy
T790M-positive biopsy at the time of entering study
Treated stable CNS metastases are allowed
Phase 1 (Dose Escalation)
CO-1686 Treatment
21-day cycles; escalate to MTD
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Phase 2 Expansion Cohorts
2nd-line patients
PD upon 1 immediate prior TKI
500mg BID
625mg BID
>2nd-line patients
PD upon ≥2 TKI or chemotherapy
750mg BID
Key outcome measures
• Safety
• Tolerability
• PK profile
• ORR
TIGER-X: Patient Analysis Groups
Analysis group
Rociletinib dose
Subjects
Analysis
500mg BID**
625mg BID
750mg BID
1000mg BID
Total N
All patients who
received HBr
rociletinib#
Safety analysis
119
236
95
6
456
Centrally-confirmed
tissue T790M+*
Efficacy analysis
(ORR)
48
114
77
4
243
Paired plasma &
tissue T790M result
available*
Comparative
efficacy in patients
by T790M status in
plasma and tissue
42
59
83
4
188
Plasma T790M+*
Efficacy analysis
(ORR)
30
49
65
3
147
#Received
at least one dose of Rociletinib HBr;
*Received HBr formulation in 2014 or earlier & evaluable for ORR;
**Includes patients switched from 900mg BID free base formulation.
HBr=hydrobromide.
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TIGER-X: Patient Baseline Characteristics
All patients who received rociletinib HBr tablet formulation
500mg BID
625mg BID
750mg BID
1000mg BID
TOTAL
N
119
236
95
6
456
Median age, years
63
64
62
65
63
Female, %
71
64
66
83
66
Enrolled in US, %
81
84
86
100
84
Asian ethnicity, %
16
20
25
17
20
ECOG PS grade 0, %
25
28
33
50
28
Median no. of prior Rx
3
2
2
4
2
56/44
55/45
59/41
33/67
56/44
Immediate prior TKI, %
74
84
91
67
82
History of CNS disease, %
40
42
43
50
41
History of diabetes, %
8
13
6
0
10
History of cardiovascular disease, %
13
15
13
0
14
Number of prior TKIs, 1/>1 (%)
6
Best Response to Rociletinib (All Doses) in 243
Centrally Confirmed Tissue T790M+ Patients
100
SLD Change from Baseline (%)
80
60
40
625mg
750mg
1000mg
Total
N
48
114
77
4
243
ORR (%)
60
54
46
75
53
DCR (%)
90
84
82
100
85
ORR, objective response rate; DCR, disease control rate
20
0
−20
−40
−60
−80
−100
SLD, sum of longest diameters
7
500mg
500mg BID HBr
625mg BID HBr
750mg BID HBr
1000mg BID HBr
+ Ongoing
Maturing PFS in 270 Centrally Confirmed T790M+
Patients at 500mg or 625mg BID
1.0
+ Censored (35% maturity)
All Patients
No Baseline CNS Disease
Probability of PFS
0.9
0.8
Median PFS
Months
All Patients
8.0
No Baseline CNS Disease 10.3
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
Time (months)
187 (39)
118 (16)
104 (71)
68 (32)
57 (80)
37 (38)
29 (89)
20 (44)
At Risk (Events)
All patients
No baseline CNS disease
8
270 (0)
163 (0)
9 (90)
8 (45)
8 (92)
7 (47)
5 (94)
5 (48)
*Data analyzed 27 Apr 2015.
PFS=progression-free survival.
16
18
20
22
24
2 (94)
2 (48)
2 (94)
2 (48)
2 (94)
2 (48)
1 (94)
1 (48)
0 (94)
0 (48)
Common Treatment-related Adverse Events
Treatment-related adverse events
(all grades) seen in >10% of patients, N (%)
AE
Rociletinib dose
Grade 3/4 treatment-related adverse
events seen in >10% of patients, N (%)
AE
500mg
BID
(N=119)
625mg
BID
(N=236)
750mg
BID
(N=95)
1000mg
BID (N=6)
Hyperglycemia
42 (35)
107 (45)
56 (59)
4 (67)
Diarrhea
39 (33)
94 (40)
28 (30)
4 (67)
Nausea
23 (19)
79 (34)
35 (37)
3 (50)
Fatigue
15 (29)
37 (30)
21 (27)
1 (25)
QTc prolongation
16 (13)
53 (23)
25 (26)
3 (50)
Decreased
appetite
18 (15)
38 (16)
24 (25)
2 (33)
Muscle spasms
17 (14)
30 (13)
20 (21)
1 (17)
Vomiting
10 (8)
38 (16)
13 (14)
0 (0)
Weight loss
12 (10)
21 (9)
16 (17)
1 (17)
Hyperglycemia
Rociletinib dose
500mg
BID
(N=119)
625mg
BID
(N=236)
750mg
BID
(N=95)
1000mg
BID (N=6)
20 (17)
56 (24)
34 (36)
2 (33)
• No ILD observed in 500mg BID dose group
- 7/456 cases overall (1.5%)
- Rociletinib continuation possible with steroid cover
- No fatal ILD in program
• No paronychia or stomatitis observed; trivial rash
• Grade 3 QTc prolongation at 500mg BID = 2.5%
• Treatment-related AEs leading to drug discontinuation seen
in 2.5% of cases at 500mg BID (4% overall)
• Hyperglycemia readily managed with oral agents
- No contraindication for pre-existing diabetic patients
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ILD=interstitial lung disease.
Hyperglycemia Readily Managed with Oral Agents
•
•
•
•
Hyperglycemia is caused by iatrogenic insulin resistance, mediated by a
rociletinib metabolite (M502) that inhibits IGF1-R/IR
Hyperglycemia was not expected in humans since it was not observed in
preclinical testing
Once understood, a monitoring and treatment algorithm (monitor blood and/or
urine glucose; treat when necessary with oral insulin sensitizing agents or
SGLT2 inhibitors) was introduced into trial protocols
This approach has been successful in reducing grade ≥3 hyperglycemia
– Prior to September 2014, grade 3/4 hyperglycemia was observed in 22% of patients
on rociletinib 500mg BID
– After September 2014, grade 3/4 hyperglycemia was observed in 8% of such patients
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Quantitative and Sensitive BEAMing Test (Sysmex
Inostics) Used for Plasma EGFR Mutation Testing
Pre-amplification
Emulsion PCR & hybridization
Magnetic beads
coated with primer
DNA isolation
Amplified DNA
Water-in-oil
emulsion
Plasma
•
dNTPs
Polymerase
Primer
Oil-emulsifier mixture
Beaming is digital PCR followed by flow cytometry
–
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Tumor DNA
Wild-type DNA
EGFR test identifies L858R, del 19, and rare activating mutations plus T790M
Dressman D et al. Proc Natl Acad Sci U S A. 2003;100:8817-8822; Diehl F et al. Proc Natl Acad Sci U S A. 2005;102:16368-16373.
Flow cytometry
Plasma Testing for T790M has Good Sensitivity
and Likely Good Specificity
•
When inadequate tissue
specimens are factored in,
plasma testing identifies as
many patients as T790M+ as
tissue testing
•
T790M tissue-plasma+ are not
false positives – T790M
confirmed in plasma on
subsequent testing in 5/7
samples
Tissue*
Total
Positive
Negative
Inadequate
tissue
Positive
155
23
12
190
Negative
37
12
8
57
192
35
20
247
Plasma*
Total
* patients at all doses
Tissue as reference:
Positive percent agreement
12
T790M
81% (155/192)
Activating mutations
87% (193/221)
Best Response to Rociletinib (All Doses) in
Plasma T790M+ Patients
100
SLD Change from Baseline (%)
80
60
40
625mg
750mg
1000mg
Total
30
49
65
3
147
ORR (%)
57
55
49
67
53
DOR (%)
80
84
82
100
82
ORR, objective response rate; DCR, disease control rate
20
0
−20
−40
−60
−80
−100
SLD, sum of longest diameters
13
500mg
N
500 mg BID HBr
625 mg BID HBr
750 mg BID HBr
1000 mg BID HBr
+ Ongoing
T790M Plasma Testing is a Viable Alternative to
Tissue Testing
Objective response rate for 188 evaluable patients with both
central T790M tissue test result and plasma T790M result
Plasma T790M
+
Tissue
T790M
14
−
+
-
55%
(72/130)
43%
(13/30)
53%
(85/160)
35%
(6/17)
27%
(3/11)
32%
(9/28)
53%
(78/147)
39%
(16/41)
•
Similar ORR observed
when detecting T790M in
either tissue or plasma
•
Not all patients with
progression on first-line
TKI are candidates for
tissue re-biopsy
Rociletinib Activity Observed in Central T790M
Negative Patients
Best response for target lesions in
centrally confirmed T790M- patients
Change from Baseline (%)
100
ORR=37%
(13/35)
60
40
20
0
-20
-60
-100
Hypotheses to explain this activity
1. Tissue heterogeneity
2. Assay sensitivity
3. IGF1-R/IR activity
4. TKI retreatment effect
–
-40
-80
15
+ Ongoing
80
500 BID HBr
500 BID HBr
625 BID HBr
750 BID HBr
86% patients directly off TKI
Acquired Resistance to Rociletinib is
Heterogeneous
Longitudinal quantitative analyses of EGFR
T790M and activating mutations in plasma
MGH/Stanford analysis of primary/acquired*
rociletinib resistance (N=13)
T790-WT
SCLC
(n=2)
T790-WT
NSCLC
(n=4)
T790M-positive
NSCLC
(n=4)
T790M-positive
NSCLC
(EGFR-amplified)
(n=3)
*Acquired resistance = progression after initial tumor
shrinkage; primary resistance = PD at first assessment scan
Piotrowska et al. Cancer Discovery. 2015 [epub ahead of print].
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A Single Dominant Mechanism of Acquired
Resistance to Rociletinib is not Readily Identifiable
Current analysis of acquired rociletinib
resistance (N=20)* has not identified
consistent mechanism of resistance:
• 1 with MET focal amplification;
2 with MET copy gain
Chromosome 7 MET
rearrangement observed
• 1 case with FGFR3 mutation
• C797S has not been observed in
tissue or plasma
MET amplification Circos plot for patient with
acquired resistance to rociletinib
(copy number gain of 1.52x)
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*Analyses conducted by Foundation Medicine, Stanford (Diehn lab), MGH (Engelman lab), Personal Genome Diagnostics.
Conclusions
•
Rociletinib demonstrates compelling activity and is a well-tolerated agent at the recommended dose
(500mg BID) in US/EU mutant EGFR NSCLC patients with PD after immediate prior TKI
–
ORR of 60% and DCR of 90% in centrally confirmed tissue T790M+ patients at this dose
–
Grade 3 Hyperglycemia 17% and discontinuation rate due to adverse events = 2.5%,
demonstrating overall excellent tolerability
•
Current immature estimate of overall median PFS is 8.0 months among all centrally confirmed tissue
T790M+ patients, 10.3 months among those without a history of CNS metastasis
•
T790M plasma testing is a viable initial screen and an alternative to tissue testing with an ORR of 57%
in plasma T790M+ patients
•
ORR is 32-39% among T790-negative patients and ongoing trials continue to study this cohort
•
Acquired resistance to rociletinib appears to be distinct from other 3rd generation EGFR TKI*, with no
evidence to date of C797S in 20 acquired rociletinib resistance patients studied
*Nat Med, published online May 2015; JAMA Oncol, published online May, 2015
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Ongoing Development of Rociletinib
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TIGER-1 (Ph 2/3)
• Randomized rociletinib vs erlotinib
• 1st-line, treatment-naïve
TIGER-2 (Ph 2)
•
•
•
•
TIGER-3 (Ph 3)
• Randomized rociletinib vs chemotherapy
• >2nd-line mutant EGFR NSCLC, T790M+
and T790M– (sequential analysis)
Combination trials
•
•
•
•
Single-arm, 500mg BID going forward
2nd-line mutant EGFR NSCLC, T790M+
Patients progressing on 1st-line EGFR TKI
Both T790M + and – cohorts
Checkpoint inhibitors (anti-PD1/PDL1 mAb)
MEK inhibitor
VEGF inhibitor
C-MET inhibitor
Thank You
• My fellow investigators
• Our patients and their families
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