1. Nuovi inibitori irreversibili di EGFR
Cesare Gridelli
Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy)

2. NEGATIVE TRIAL 1
N= 440 patients
Stratification
-Race
-Exon 19 v 21

3. Ramalingam SS et al. WCLC 2015
Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/21
121 EGFR Mutant Patients Retrospectively analysed from ARCHER 1028 (Ramalingam S JCO 2012) and ARCHER 1009 (Ramalingam S Lancet Oncol 2014) OS
PFS
PFS OS
Dacomitinib (N=66)
Erlotinib (N=55)
Events(%)
51 (77.3%)
44 (80.0%)
39 (59.1%)
32 (58.2%)
Median (95% CI) in Mons
10.9 ( )
9.6 ( )
26.6 ( )
24.1 ( )
Un-stratified HR (95% CI)
0.815 ( )
0.958 ( )
P-value (1-sided)
0.160
0.431
Ramalingam SS et al. WCLC 2015

4. ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib
Dacomitinib 45mg qd
Advanced NSCLC
Adenocarcinoma
EGFR exon 19/21 mut+
First-line treatment
PS 0-1
Primary endpoint in PFS
14.8 vs 9.5 months 1
Gefitinib 250mg qd 1
N= 440 patients
Stratification
-Race
-Exon 19 v 21

5. Acquired resistance in EGFR Mut+ NSCLC
Mechanisms of acquired resistance to EGFR TKIs
Acquired resistance to EGFR TKIs in metastatic setting is inevitable
The average PFS is 8–13 months
Activation of other receptor tyrosine kinases? (eg. ERBB2 amplification)
FAS/NFB activation?
Epithelial-mesenchymal transition? (AXL, Slug activation?)
Loss or spliced variant of BIM?
Other? (eg. CRKL or ERK amplification)
~30–40%
~60% second-site EGFR mutations (mostly T790M)
Can we add this slide instead of the previous one (more clear than previous one concerning the figure ?). Perhaps you can redraw the figure ?
~1% BRAF mutations
~5% small-cell cancer transformations
~5% PIK3CA mutations
-5–10% MET amplification
Ohashi et al, J Clin Oncol 2013

7. Adequacy and Complications of re-biopsy
126 patients referred for repeat biopsy
with NSCLC resistant to conventional chemotherapy or EGFR Tki
94 patients (31 men, 63 women) selected for rebiopsy (75%)
(25% of case it was not possible)
Technical success rate for biopsy was 100% (80% suitable for mutational analyses).
Postprocedural complications occurred in 13 (14%) patients
Of 126 patients evaluated for re-biopsy, 94 were eligible for this
procedure: specimens resulted adequate for mutational analysis in
75 cases (80%), while post-procedural complications occurred in 13
(14%) of patients, thus proving that lung re-biopsies may be a feasible
and adequate procedure in approximately 4/5 of patients, when
performed by employing rigorous computed tomography (CT)
criteria.
Yoon HJ et al, Radiology 2012

9. 3rd Generation Irreversible EGFR TKIs Under Development: AZD9291
Selectively targets mutated EGFR, including T790M
Phase I dose escalation study in patients with EGFR Mut+ disease and PD on EGFR TKI
Encouraging activity :
61 % response rate months in 127 pts T790M+
21 % response rate in 61 pts T790M-
No DLTs
Recommended dose: mg daily
In the Ref N°3: « ECCCO »
Is it possible to put on one slide CO-1686 as you done and on the right of the slide the waterfall plot of the study (see, next slide N°15) and same thing for AZD9291 (waterfall plot slide N°16) (it might be more visuel) ?
Janne et al. N Engl J Med 2015; 372: 1689–1699

10. ZD9291: clinical development
Phase II extension – further assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC
AURA
Confirmatory global Phase II – assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC
AURA 2
Phase III – efficacy and safety of AZD9291 vs platinum-based doublet chemotherapy in second-line patients with T790M+, advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI
AURA 3
FLAURA
Phase III – efficacy and safety of AZD9291 vs gefitinib or erlotinib in first-line patients with EGFR M+, advanced/metastatic NSCLC

11. AURA2: Phase II, open-label, single-arm study
Primary objective
To investigate the efficacy of AZD9291 by assessment of ORR (RECIST 1.1 BICR)
Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI
Key inclusion criteria
Aged ≥18 (≥20 in Japan)
Confirmation of tumor EGFR mutation associated with EGFR-TKI
At least one lesion suitable for accurate repeated measurements
WHO performance status 0 or 1
Acceptable organ function
Stable brain metastases allowed
Central T790M mutation testing* of biopsy sample collected following confirmed disease progression
T790M positive
(n=210)
AZD mg once daily
T790M negative
Not eligible for enrollment
*The EGFR T790M mutation status of the patient’s tumor was prospectively determined by the designated central laboratory using the cobas™ EGFR Mutation Test (Roche Molecular Systems) by biopsy taken after confirmation of disease progression on the most recent treatment regimen
BICR, blinded independent central review; EGFR, epidermal growth factor receptor; EGFRm, EGFR-TKI-sensitizing mutation; NSCLC, non-small cell lung cancer; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor; WHO, World Health Organization

12. Tumor response (independent central review)
100 80
Best percentage change from baseline in target lesion – all patients 60 40 20
-20
-40
-60
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable
-80
-100
Confirmed objective response
Total
ORR†
71% (95% CI 64, 77)
Complete response,‡ n (%)
Partial response,‡ n (%)
Stable disease ≥6 weeks,§ n (%)
Progressive disease, n (%)
2 (1)
139 (70)
41 (21)
15 (8)
DCR
92% (95% CI 87, 95)
Tables , ,
Figure
Mitsudomi T et al. WCLC 2015

13. Duration of response and progression-free survival
1.0
0.9
0.8
0.7
0.5
0.4
0.3
0.2
0.0
Probability of response 12 9 6 3
Month
0.6
0.1
Number of patients at month:
AZD mg
141
123 43
Censored observations
Number of patients at risk:
1.0
0.9
0.8
0.7
0.5
0.4
0.3
0.2
0.0
Probability of progression-free survival 12 9 6 3
Month
0.6
0.1
AZD mg
210
172
115 15
Censored observations
KM-based estimated†
Total‡
Median DoR,¶ months (95% CI)
7.8 (7.1, NC)
Maturity: 27%
Remaining in response, % (95% CI)
6 months
9 months
75 (65, 82)
NC (NC, NC)
Range of DoR, months
1.3–8.4
KM-based estimated†
Total§
Median PFS,** months (95% CI)††
8.6 (8.3, 9.7)
Maturity: 38%
Remaining alive and progression free, % (95% CI)
6 months
9 months
70 (63, 76)
48 (36, 58)
Median follow-up for PFS
6.7 months
Tables , , ,
Figure
Mitsudomi T et al. WCLC 2015

14. AURA 3 TRIAL: AZD9291 vs Chemotherapy in II line in patients with EGFR activating mutation and T790M+
R A N D O M I Z E
AZD9291
(80 mg daily)
Advanced NSCLC
Adenocarcinoma
EGFR mut+
EGFR T790M+
Second-line treatment
PS 0-1 1
Chemotherapy
CDDP+Alimta 1
Primary Endpoint
Estimated Enrollment:
PFS
410
Study Start Date:
August 2014
Accrual
Completed
Estimated Primary Completion Date:
April 2016 (Final data collection date for primary outcome measure)

15. ASTRIS TRIAL

16. Best percentage change in target lesion size – all patients
ZD9291 in 1-line EGFR M+ (19/21): Response in first-line cohorts by dose
100 90 80
Best percentage change in target lesion size – all patients 70 60 50 40 D 30 20 10
-10
-20
-30 D
-40
-50 D
-60 D
-70
-80
80 mg D D
-90
-100
160 mg
80 mg
N=30
160 mg
Total
N=60
Confirmed objective response rate
67%
(95% CI 47, 83)
83%
(95% CI 65, 94)
75%
(95% CI 62, 85)
Disease control rate
93%
(95% CI, 78, 99)
100%
(95% CI 88, 100)
97%
(95% CI 89, 100)
Best objective response
Complete response
Partial response
Stable disease
Progressive disease 20 8 2 2* 23 5 43 13
Ramalingam S et al. WCLC 2015

17. DoR and PFS in AZD9291 first-line cohorts (investigator assessed)
Duration of response
Progression-free survival
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Probability of response
0.5
Probability of response
0.5
0.4
0.4
0.3
0.3
0.2
0.2
AZD mg
Censored observation
AZD mg
Censored observation
0.1
0.1
AZD mg
Censored observation
AZD mg
Censored observation
0.0
0.0
Number of patients at month: 3 6 9 12 15
Number of patients at risk: 18 3 6 9 12 15 18
Month
Month
80 mg 20 20 17 14 10 5
80 mg 30 26 23 22 19 12 3
160 mg 25 25 21 18 8
160 mg 30 29 27 23 17
80 mg
N=20
160 mg
N=25
Total
N=45
Median DoR,* months (95% CI)
13.6 (11.1, NC) Maturity: 35%
NC (9.7, NC) Maturity: 28%
NC (12.3, NC) Maturity: 31%
Maximum DoR, months
18.0+
12.6+
Remaining in response,† % (95% CI)
9 months
12 months
89 (64, 97)
76 (46, 90)
78 (56, 90)
69 (45, 84)
83 (68, 92)
71 (53, 83)
80 mg
N=30
160 mg
Total
N=60
Median PFS,‡ months (95% CI)
NC (12.3, NC) Maturity: 40%
NC (1
1.1, NC) Maturity: 30%
NC (13.7, NC) Maturity: 35%
Maximum PFS, months
19.2+
13.8+
Remaining alive and progression-free,† % (95% CI)
9 months
12 months
83 (64, 93)
75 (55, 87)
80 (60, 90)
69 (48, 82)
81 (69, 89)
72 (58, 82)
Ramalingam S et al. WCLC 2015

18. Gefitinib or Erlotinib
FLAURA Phase III trial: AZD9291 vs Gefitnib or Erlotinib in I line in patients with EGFR mutation
R A N D O M I Z E
AZD9291
(80 mg daily)
Advanced NSCLC
Adenocarcinoma
EGFR mut+
First-line treatment
PS 0-1 1 1
Gefitinib or Erlotinib
Primary Endpoint
Estimated Enrollment:
PFS
650
Study Start Date:
December 2014
Accrual
Ongoing
Estimated Primary Completion Date:
May 2017 (Final data collection date for primary outcome measure)

19. 3 rd generation EGFR TKIs under development: Rociletinib (CO-1686)
Selectively targets mutated EGFR, including T790M
spares EGFR WT
Phase I dose escalation study in EGFR Mut+ T790M+(n=243/458)
encouraging activity:
53% response rate
Median PFS 8 months
AE profile consistent with lack of EGFR WT inhibition
T790M negative 37% OR
Positive agreement T790M
liquid (81%) vs tissue (87%) biopsy
Recommended dose: mg
(500 mg BID )
In the Ref N°3: « ECCCO »
Is it possible to put on one slide CO-1686 as you done and on the right of the slide the waterfall plot of the study (see, next slide N°15) and same thing for AZD9291 (waterfall plot slide N°16) (it might be more visuel) ?
Sequist L et al, ASCO 2015

20. Dose Optimization of Rociletinib for T790M Mutated NSCLC
100 80 60 40 20
−20
−40
−60
−80
−100
500mg
625mg
750mg
Total n 48
114 77
239
ORR (%) 60 54 46 52
DCR (%) 90 84 82 85
+ Ongoing
500mg BID HBr
625mg BID HBr
750mg BID HBr
SLD change from baseline (%)
Grade ≥3 treatment-related AEs observed in >10% of patients, n (%) AE
Rociletinib dose
500mg BID
(n=119)
625mg BID
(n=236)
750mg BID
(n=95)
Hyperglycemia
20 (17)
56 (24)
34 (36)
The risk-benefit profile of rociletinib is optimal at the recommended
dose (500 mg BID)
Goldman JW et al. WCLC 2015

21. TIGER-X: Phase 1/2 study of rociletinib in advanced NSCLC
625mg BID
500mg BID
Phase 1 (Dose Escalation)
Phase 2 Expansion Cohorts
(Required Central Tissue T790M Testing)
Rociletinib Treatment
(free base rociletinib,
followed by 500, 625, 750, and 1000mg BID HBr)
750mg BID
2nd-line patients
PD upon 1 immediate prior TKI
>2nd-line patients
PD upon ≥2 TKI or chemotherapy
21-day cycles; escalate to MTD
Key outcome measures
Safety
Tolerability
PK profile
ORR
ORR in centrally confirmed tissue T790M-positive pts (n=48) enrolled at the 500mg BID dosing level was 60%
ORR in centrally confirmed tissue T790M-negative pts (n=35) was 37%1
Updated results in centrally confirmed tissue T790M-negative pts are presented
As of August 11, 2015, 111 and 482 pts (T790M±) were enrolled on the phase 1 and 2 portions, respectively
Wakelee H et al, WCLC 2015

22. Why do T790M-negative pts respond to rociletinib?
Qiagen therascreen and cobas central T790M tests are highly concordant
A sample that tests negative by one central test likely to be negative by other
Tumor heterogeneity
Not all cells express T790M; tissue biopsy samples one small area
Plasma test may be more representative, especially with extrathoracic spread
Other mechanisms of rociletinib action may be important
Rociletinib inhibits IGF-1R and IR kinases
IGF-1R/IR may drive resistance to initial EGFR inhibitor therapy
In a preclinical study, treatment with a T790M-potent EGFR TKI prevented emergence of the EGFR T790M mutation, resulting in sequential acquisition of non-T790M resistance mechanisms involving IGF-1R and MAPK pathways1
Wakelee H et al, WCLC 2015
1. Cortot A, et al. Cancer Res. 2013;73:

23. (TIGER2 like ;pts T790M plasma)
Trials enrolling in 2014
TIGER4 (phase 2)
(TIGER2 like ;pts T790M plasma)

24. TIGER 1 PHASE II TRIAL: 1-line Rociletinib vs Erlotinib in patients with EGFR mutation
R A N D O M I Z E
Rociletinib
Advanced NSCLC
Adenocarcinoma
EGFR mut+
First-line treatment
PS 0-1
1250 mg (625 mg BID) 1
Erlotinib 1
Primary Endpoint
Estimated Enrollment:
PFS
200
Study Start Date:
November 2014
Accrual
Ongoing
Estimated Primary Completion Date:
June 2016 (Final data collection date for primary outcome measure)

25. TIGER 3 TRIAL: Rociletinib vs chemotherapy in pretreated patients with EGFR mutation and T790M+/-
R A N D O M I Z E
Rocilietinib
Advanced NSCLC
Adenocarcinoma
EGFR mut+
EGFR T790M+ or -
Third or more line treatment
PS 0-1
1250 mg (625 mg BID) 1
Single agent
Chemotherapy
(Pem/Gem/Txt/Tax) 1
Primary Endpoint
Estimated Enrollment:
PFS
600
Study Start Date:
February 2015
Accrual
Ongoing
Estimated Primary Completion Date:
March 2017 (Final data collection date for primary outcome measure)

26. Recommended dose: 800 mg (400 mg BID)
Study Design
Recommended dose: 800 mg (400 mg BID)

27. Best Overall Response: Expansion Part
HM61713
Best Overall Response: Expansion Part

28. Progression-Free Survival<br />: Expansion part (T790M+ versus T790M-)

29. HM61713 PHASE II TRIAL in 2-line for patients with EGFR activating mutation and T790M+
Advanced NSCLC
Adenocarcinoma
EGFR mut+
EGFR T790M+
Second-line treatment (previous TKI)
PS 0-1
HM61713
800 mg (400 mg BID)
Primary Endpoint
Estimated Enrollment:
Response Rate
150
Study Start Date:
July 2015
Accrual
Ongoing
Estimated Primary Completion Date:
December 2016 (Final data collection date for primary outcome measure)

30. AZD9291 T790M+ T790M+ C797S+ T790M+ C797S- Resistance T790M- C797S-
NATURE MEDICINE | BRIEF COMMUNICATION
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M
Kenneth S Thress, Cloud P Paweletz, Enriqueta Felip, Byoung Chul Cho, Daniel Stetson, Brian Dougherty, Zhongwu Lai, Aleksandra Markovets, Ana Vivancos, Yanan Kuang, Dalia Ercan, Sarah E Matthews, Mireille Cantarini, J Carl Barrett, Pasi A Jänne & Geoffrey R Oxnard
Nature Medicine 21, 560–562 (2015)
T790M+ C797S+
6 pts
MOLECULAR SUBTYPES OF RESISTANCE
AZD9291
Resistance
T790M+ C797S-
T790M+
5 pts
15 pts
T790M- C797S-
Del19+ or Mut21+
4 pts
Cell-free plasma DNA (cfDNA)
Firstly next-generation sequencing of cfDNA from 7 patients detecting an acquired EGFR C797S mutation in 1 patient
Then droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated patients
All positive for the T790M mutation before treatment, but after AZD9291 resistance:
6 cases acquired the C797S mutation
5 cases maintained the T790M mutation but did not acquire the C797S mutation
4 cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation

31. Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer
15 (22%) out of 67 patients, had detectable C797S, all with detectable T790M (T790+/C797S+)
C797S was more common with EGFR exon 19 del (13/43, 30%) vs those with L858R (2/24, 8%, p=0.06)
32 of 67 (48%) had no detectable T790M in plasma despite presence of the EGFR-TKI-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism, such as MET or HER2 amplification or BRAF V600E
Oxnard G et al. WCLC 2015