Post on 03-Feb-2021
Inhibidores de EGFR Noemi Reguart, MD, PhD
Hospital Clínic Barcelona
IDIPAPS
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
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
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
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
Paez Science 2004; Lynch NEJM 2004; Pao PNAS 2004
EGFR mutations are sensitive to TKIs
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
Yang et al. Lancet Oncol 2015
L858R
Del 19
Common mutations
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
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
Strategies to overcome AR to TKIs
Chong et al, Nature Medicine 2013
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
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
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
• 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
• 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
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
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
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
Phase 1/2 of CO-1686 (Rociletinib)
20
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
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
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
• 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
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
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
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
• 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
Barlesi, et al ASCO 2013; Johnson, et al. ASCO 2013; Sun et al. JCO 2010
EGFR mutations among ethnicity (Asian vs Caucasian)
• 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 ?
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
Third Generation T790M inhibitors
AZD9291
CO1686 (Rociletinib)
HM61713
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
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
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