noemi reguart, md, phd hospital clínic barcelona idipaps · 2015. 5. 26. · fgfr1 amp 20% pik3ca...
TRANSCRIPT
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Inhibidores de EGFR Noemi Reguart, MD, PhD
Hospital Clínic Barcelona
IDIPAPS
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Mountain, Chest 1997 Lung Cancer Consortium ASCO 2011; Perez-Moreno et al. CCR 2012
Unknown 36% KRAS 25% EGFR 15% ALK 4% HER2 2% Double Mut 2% BRAF 2% PIK3CA
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Selecting Targeted Drugs in Lung Adenocarcinoma
Mark G. Kris,et al, JAMA 2014
0.69 [95%CI, 0.53-0.9], P = .006
Over 64% of lung ADK have an actionable driver oncogene
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EGFR mutations in lung cancer
Sharma SV, et al. Nat Rev Cancer 2007;7;169–81 Sharma SV, et al. Nat Rev Cancer 2007;7:169–81
ACTIVATING MUTATIONS
10-14% white 30-40% asian
* Most frequent
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EGFR mutations are oncogenic in vitro & in vivo
Sharma SV, et al. Nat Rev Cancer 2007;7;169–81 Greulich H, et al. PLoS 2005 ; Hongbin Ji, et al. Cancer Cell 2006
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Paez Science 2004; Lynch NEJM 2004; Pao PNAS 2004
EGFR mutations are sensitive to TKIs
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STUDY EGFR TKI N RR (%) PFS (mo) OS (mo) Ref
IPASS Gefitinib 261 71 vs 47 9.5 vs 6.3* 21.6 vs 21.9 Fukuoka, 2011
First-Signal Gefitinib 42 84 vs 37 8.0 vs 6.3 27.2 vs 25.6 Han, 2012
WJTOG3405 Gefitinib 177 62 vs32 9.2 vs 6.3* 36 vs 39 Yoshioka, 2014
NEJ002 Gefitinib 228 73 vs 30 10.8 vs 5.4* 27.7 vs 26.6 Inoue, 2013
OPTIMAL Erlotinib 154 83 vs 36 13.7 vs 4.6* 22.6 vs 28.8 Zhou, 2011
EURTACC Erlotinib 173 58 vs 15 9.7 vs 5.2* 19.3 vs 19.5 Rosell, 2012
ENSURE Erlotinib 148 68 vs 39 11 vs 5.5* NR Wu, 2013
LUX-LUNG 3 Afatinib 345 56 vs 23 13.6 vs 6.9* 31.6 vs 28.2 Sequist, 2013
LUX-LUNG 6 Afatinib 364 67 vs 23 11 vs 5.6* 23.6 vs 23.5 Wu, 2014
Efficacy of 1st & 2nd Generation TKIs in First Line
Erlotinib, Gefitinib, Afatinib, approved Phase III ‘TKI vs TKI’:
ARCHER 1050 (NCT01774721): phase III
dacomitinib vs gefitinib, final accrual Febr 2015
LUX-Lung 7 (NCT01466660): phase IIb
afatinib vs gefitinib, final accrual Sept 2013
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Yang et al. Lancet Oncol 2015
L858R
Del 19
Common mutations
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FIRST LINE
TKI
12 mo
SECOND LINE
QTP
6 mo
THIRD LINE
QTP
3-5 mo
BSC
2 mo
OS 22-24 mo
Current treatment beyond TKI progression
EGFRMUT
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Pooled data from the 2 largest re-biopsy series after TKI-progression.
Arcila, CCR 2011; Sequist et al. Sci Transl Med 2011
Resistance Mechanisms for TKIs
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Strategies to overcome AR to TKIs
Chong et al, Nature Medicine 2013
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Generation TKI EGFRwt H2073
EGFRm ELREA (Exon 19)
EGFRm L858R (Exon 21)
T790M- PC-9
T790M+ PC-9 VanR
T790M- H3255
T790M+ H1975
FIRST Gefitinib 61 7 741 11 3102
Erlotinib 108 6 1262 9 6073
SECOND Afatinib 25 0.6 3 0.9 36
Dacomitinib 26 0.7 6 1 40
THIRD AZD9291 1865 17 6 60 15
CO1686 3900 - - - 9
HM61713 2725 9 - - 10
Data form Cross et al, Cancer Discov 2014; Walter et al, Cancer Discov 2013
3rd Generation T790M inhibitors TKIs spare EGFRWT
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Activity of AZD9291 in vitro & in vivo
• In vitro resistance to AZD9291 took significantly longer to emerge
Eberlein et al. Proceedings of the 105th AACR 2014; abstract 1722.
• Sustained tumour shrinkage in tumour xenografts
H3255 (EGFR L858R)
0 10 20 30 40 50 60 70 80 Day
s
Lo
g t
um
ou
r v
olu
me
(cm
3)
1
0.1
0.01
Vehicle only BID
Gefitinib 6.25 mg/kg QD
AZD9291 5 mg/kg QD
Afatinib 7.5 mg/kg QD
PC9 (EGFR exon 19 deletion)
Lo
g t
um
ou
r v
olu
me
(cm
3)
1
0.1
0.01
0.001
0 20 40 60 80 100 120 140 160 180 200 Da
ys
Vehicle only BID
Gefitinib 6.25 mg/kg QD
AZD9291 5 mg/kg QD
AZD9291 25 mg/kg QD
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Cohort 1 20 mg
T790M+
Cohort 2 40 mg
Cohort 3 80 mg
Cohort 4 160 mg
T790M+
T790M-
T790M+
T790M-
T790M+
T790M-
Escalation Not preselected by T790M status
Expansion Enrolment by local testing followed by central laboratory confirmation (cobas® EGFR Mutation Test) of T790M status or by central laboratory testing alone
Cohort 5 240 mg
T790M+
1st-line EGFRm+*
Biopsy#
Rolling six design
Tablet##
1st-line EGFRm+*
Biopsy#
Phase I dose escalation/expansion study design (AURA)
Total 253 patients included
Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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• Confirmed ORR in patients with T790M+ 61% (78/127; 95% CI 52, 70)
• DCR (CR+PR+SD) was 95% (121/127; 95% CI 90, 98)
20 mg 40 mg 80 mg 160 mg 240 mg
N (127) 10 32 43 28 14
ORR 50% 59% 70% 61% 50%
20 mg
40 mg
80 mg
160 mg
240 mg
40
20
0
-20
-40
-60
-80
-100
ORR in T790M+ patients (central test)
61% ORR (per RECIST)
Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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• Confirmed ORR in patients with T790M- 21% (13/61; 95% CI 12, 34)
• DCR (CR+PR+SD) was 61% (37/61; 95% CI 47, 73)
20 mg 40 mg 80 mg 160 mg 240 mg
N (127) 3 17 23 18 -
ORR 67% 6% 17% 33% -
20 mg
40 mg
80 mg
160 mg
40
20
0
-20
-40
-60
-80
-100
ORR in T790M- patients (central test)
21% ORR (per RECIST)
Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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Progression-free survival in T790M+ (central test)
138 Patients at risk:
T790M+ 100 70 14 1
Pro
bab
ility
of
pro
gres
sio
n-f
ree
surv
ival
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 12 3 6 9 Study month
T790M+ (95% CI)
Preliminary median PFS = 9.6 months
(95% CI 8.3, not reached)
(30% maturity, 41/138 events)
Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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62 Patients at risk:
T790M- 27 13 3 0
Pro
bab
ility
of
pro
gres
sio
n-f
ree
surv
ival
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 12 3 6 9 Study month
T790M- (95% CI)
Preliminary median PFS = 2.8 months
(95% CI 2.1, 4.3)
(71% maturity, 44/62 events)
Progression-free survival in T790M- (central test)
Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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All-causality AEs, all grades
Patients with an AE, n (%)
20 mg N=21
40 mg N=58
80 mg N=90
160 mg N=63
240 mg N=21
Total N=253
AE by preferred term occurring in at least 10% of patients overall
Diarrhoea 5 (24) 24 (41) 30 (33) 43 (68) 16 (76) 118 (47)
Rash 5 (24) 13 (22) 29 (32) 40 (63) 15 (71) 102 (40)
Fatigue 4 (19) 15 (26) 9 (10) 11 (17) 5 (24) 44 (17)
Paronychia 2 (10) 5 (9) 11 (12) 18 (29) 6 (29) 42 (17)
Hyperglycaemia 0 1 (2) 3 (3) 2 (3) 0 6 (2)
QT prolongation 0 2 (3) 4 (4) 4 (6) 1 (5) 11 (4)
Pneumonitis-like ev. 0 0 2 (2) 4 (6) 0 6 (2)
- No dose-limiting toxicities at any dose
- MTD not defined Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009
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Phase 1/2 of CO-1686 (Rociletinib)
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Phase 1 (Dose-escalation period) Phase 2 (RP2D evaluation) TIGER X Expansion Cohorts
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
• Phase 2 only
– Disease progression while on treatment with EGFR-directed therapy
– T790M-positive biopsy at the time of entering study
CO-1686 Treatment 625 mg BID
750 mg BID
2nd-line patients
PD upon 1 immediate prior TKI
>2nd-line patients
PD upon ≥2 TKI or chemotherapy
500 mg BID
21-day cycles; escalate to MTD
DoR, duration of response; ORR, objective response rate; FIH, first in human; MTD, maximum tolerated dose PK, pharmacokinetic;
RP2D, recommended Phase 2 dose L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014
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Best Response for Evaluable T790M+ Patients (N= 46)
59% ORR 93% DCR
Median PFS 13.1 months*
L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014
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Best Response for Evaluable T790M- Patients (N=17)
29% ORR (per RECIST)
Median PFS 5.6 months
L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014
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• 3 previous treatment lines
• Erlotinib immediately before CO-1686
• 625 mg BID
• 82% target lesion reduction at C2
• CNS lesion response
Baseline C2
Signs of brain activity with CO-1686 (Rociletinib)
L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014
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TIGER-X clinical dose group: AEs
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*
24
*21% of patients had a grade 3/4 treatment-related adverse event and only hyperglycemia was observed in
≥5% of patients
• Rociletinib metabolite M502 is an inhibitor of IGF1R and accumulates in humans causing hyperglycemia
• Grade 3 QTc prolongation observed in 1 patient (625 mg BID)
• Pneumonitis observed in 4 patients (>200 patients, all doses, all genotypes) – all quickly reversible
L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014
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CO1686 -TIGER-
AZD9291 -AURA-
The U.S. FDA has granted Breakthrough Therapy designation for Rociletinib and AZD9291 as treatment for mutant NSCLC in patients with the T790M mutation after progression on EGFR-
directed therapy
Ongoing Trials with 3rd Generation TKI
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FIRST LINE
TKI
12 mo
T790M
INH
10-13 mo
SECOND LINE
QTP
6 mo
THIRD LINE
QTP
3-5 mo
BSC
2 mo
OS 35 mo
Current treatment beyond TKI progression
EGFRMUT/T790M+
EGFRMUT/T790M-
FIRST LINE
TKI
12 mo
????? SECOND LINE
QTP
6 mo
THIRD LINE
QTP
3-5 mo
BSC
2 mo
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• Search for alternative options for EGFRMUT/T790M- :
– Selective c-Met inhibitors (INC280, AZD6094) for c-
MetAMP
• Best sequence
– 1st/2nd then 3rd generation vs 3rd generation TKI upfront
• Rebiopsies, when, where, how?
• cfDNAT790M a good biomarker?
• Combos to delay resistance? TKIs plus c-Met inhibitors or
MEK inhibitors (selumetinib) or immune-checkpoint
inhibitors?
Final remarks
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Barlesi, et al ASCO 2013; Johnson, et al. ASCO 2013; Sun et al. JCO 2010
EGFR mutations among ethnicity (Asian vs Caucasian)
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• When ?
• Where ?
• How ?
Re-biopsies to asses for resistance mechanisms
Low-FDG uptake:T790M-?
High-FDG uptake: T790M+?
Gradual PD? Local PD ? Dramatic PD?
- Percentage of tumour cells ( >50-80%) ? - LCM or macrodisection ? - More sensitive technics ?
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Mark Kris, P03.07, WLCC Sidney 2013
Over 64% of lung ADK have an actionable driver oncogene
* ROS1 rearrangements in ~1%
Oncogenic Drivers in Lung Adenocarcinoma
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Third Generation T790M inhibitors
AZD9291
CO1686 (Rociletinib)
HM61713
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Advanced EGFR + NSCLC
CR/PR> 4 mo or SD> 6 mo
with fiirst line Gefitinib
No prior chemotherapy
RECIST progression to
Gefitinib
ECOG 0/1
• EU & Asia
• Primary endpoint: PFS
• Secondary endpoints: OS, RR, DCR
• Symptoms & QoL
Ran
do
m
Pemetrexed, IV, 500mg/m2
Cisplatin, IV, 75mg/m2
q 21 days x 6 cycles
plus placebo
Pemetrexed, IV, 500mg/m2
Cisplatin, IV, 75mg/m2
q 21 days x 6 cycles
plus Gefitinib 250 mg QD
N=265
IMPRESS Trial: Phase III continuation of Gefitinib beyond
progression
1:1
Mok et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA2_PR
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Mok et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA2_PR
Gefitinib (n=133)
Placebo (n=132)
Median OS, months
14.8 17.2
OS (33% of events)
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time of randomisation (months)
Pro
babili
ty o
f O
S
HRa (95% CI) 1.62 (1.05, 2.52)
p=0.029
Gefitinib (n=133)
Placebo (n=132)
PFS, mo 5.4 5.4
1.0
0.8
0.6
0.4
0.2
0
PFS
0 2 4 6 8 10 12 14
Time of randomisation (months)
Pro
babili
ty o
f P
FS
HRa (95% CI) 0.86 (0.65, 1.13);
p=0.273
IMPRESS: Phase III continuation of Gefitinib beyond
progression
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Phase Ib of combined afatinib and cetuximab in EGFRMUT
MTD: afatinib 40 mg daily and cetuximab 500 mg/m2 every 2
weeks
Janjigian, ESMO 2011; Cancer Discovery 2014
126 pts ORR: T790+ 32% and T790M- 25%
29% ORR (per RECIST)
Median PFS 4.7 months