Nuovi inibitori irreversibili di EGFRNuovi inibitori irreversibili di EGFR

Cesare GridelliDivision of Medical Oncology

“S.G. Moscati” Hospital – Avellino (Italy)cgridelli@libero.it

1

N= 440 patientsStratification-Race-Exon 19 v 21

NEGATIVE TRIAL

Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/21

Ramalingam SS et al. WCLC 2015

121 EGFR Mutant Patients Retrospectively analysed from ARCHER 1028 (Ramalingam S JCO 2012) and ARCHER 1009 (Ramalingam S Lancet Oncol 2014)

PFS OS

Dacomitinib (N=66)

Erlotinib (N=55) 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 (7.4-17.4) 9.6 (7.4-11.3) 26.6 (20.1-29.0) 24.1 (17.9-39.4)

Un-stratified HR (95% CI) 0.815 (0.542-1.224) 0.958 (0.596-1.538)

P-value (1-sided) 0.160 0.431

PFS OS

ARCHER 1050: Randomized Phase III Study ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Dacomitinib vs Gefitinib

Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21

mut+• First-line treatment• PS 0-1

RANDOMIZE

Dacomitinib 45mg qd

Gefitinib 250mg qd

1

1

N= 440 patients

Primary endpoint in

PFS14.8 vs 9.5

months

Primary endpoint in

PFS14.8 vs 9.5

months

Stratification-Race-Exon 19 v 21

Acquired resistance in Acquired resistance in EGFREGFR Mut+ NSCLC Mut+ NSCLC

Mechanisms of acquired resistance to EGFR TKIs

Ohashi et al, J Clin Oncol 2013

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/NFB activation?

Epithelial-mesenchymal transition?(AXL, Slug activation?)

Loss or spliced variant of BIM?

Other? (eg. CRKL or ERK amplification)

~1% BRAF mutations

~5% small-cell cancer transformations

~5% PIK3CA mutations

-5–10% MET amplification

~60% second-site EGFR mutations (mostly T790M)

~30–40%

Yoon HJ et al, Radiology 2012

Adequacy and Complications of re-biopsy

• 126 patients referred for repeat biopsywith 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

33rdrd Generation Irreversible EGFR TKIs Under Generation Irreversible EGFR TKIs Under Development: AZD9291Development: AZD9291

Janne et al. N Engl J Med 2015; 372: 1689–1699

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: 80 mg daily

ZD9291: clinical developmentZD9291: clinical development

FLAURA• Phase III – efficacy and safety of AZD9291 vs

gefitinib or erlotinib in first-line patients with EGFR M+, advanced/metastatic NSCLC

AURA2: Phase II, open-label, single-arm studyAURA2: Phase II, open-label, single-arm study

*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 regimenBICR, 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

Primary objectiveTo 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

Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved

EGFR-TKI

Central T790M mutation testing* of biopsy sample

collected following confirmed disease progression

Central T790M mutation testing* of biopsy sample

collected following confirmed disease progression

T790M positive(n=210)

T790M negative

AZD9291 80 mg once daily

Not eligible for enrollment

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

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

Tumor response (independent central review)Tumor response (independent central review)

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)

DCR92%

(95% CI 87, 95)

Best percentage change from baseline in target lesion – all patients

Complete responsePartial responseStable diseaseProgressive diseaseNot evaluable

100

80

60

20

-20

-40

-60

-80

-100

40

0

Mitsudomi T et al. WCLC 2015

Duration of response and progression-free survivalDuration of response and progression-free survival

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

Progression-free survival

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

Duration of response

Number of patients at risk:

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

bab

ility

of

pro

gre

ssio

n-fr

ee s

urvi

val

129630Month

0.6

0.1 AZD9291 80 mg

210 172 115 15

Censored observations

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

bab

ility

of

resp

onse

129630Month

0.6

0.1

Number of patients at month:

AZD9291 80 mg

141 123 43

Censored observations

Mitsudomi T et al. WCLC 2015

AURA 3 TRIAL: AZD9291 vs Chemotherapy in II line AURA 3 TRIAL: AZD9291 vs Chemotherapy in II line in patients with EGFR in patients with EGFR

activating mutation and T790M+activating mutation and T790M+

Advanced NSCLC• Adenocarcinoma• EGFR mut+• EGFR T790M+• Second-line

treatment• PS 0-1

RANDOMIZE

AZD9291(80 mg daily)

ChemotherapyCDDP+Alimta

1

1

Primary EndpointEstimated Enrollment:

PFS410

Study Start Date: August 2014Accrual CompletedEstimated Primary Completion Date: April 2016 (Final data collection date for

primary outcome measure)

ASTRIS TRIAL

ZD9291 in 1-line EGFR M+ (19/21): ZD9291 in 1-line EGFR M+ (19/21): Response in first-line cohorts by doseResponse in first-line cohorts by dose

80 mgN=30

160 mgN=30

TotalN=60

Confirmed objective response rate67%

(95% CI 47, 83)83%

(95% CI 65, 94)75%

(95% CI 62, 85)

Disease control rate93%

(95% CI, 78, 99)100%

(95% CI 88, 100)97%

(95% CI 89, 100)

Best objective responseComplete responsePartial responseStable diseaseProgressive disease

02082

2*2350

2*43132

D

DD

D DDDDD

D

D

80 mg

160 mg

D

D

D

100

807060

40

2010

0-10-20

-40

-60

-80

-100

50

30

-30

DD

Best percentage change in target lesion size – all patients

-90

-70

-50

90

Ramalingam S et al. WCLC 2015

DoR and PFS in AZD9291 first-line cohorts (investigator assessed)DoR and PFS in AZD9291 first-line cohorts (investigator assessed)

80 mg N=30

160 mg N=30

Total N=60

Median PFS,‡ months (95% CI)

NC (12.3, NC) Maturity: 40%

NC (11.1, NC)

Maturity: 30%

NC (13.7, NC) Maturity: 35%

Maximum PFS, months 19.2+ 13.8+ 19.2+

Remaining alive and progression-free,† % (95% CI)9 months12 months

83 (64, 93)75 (55, 87)

80 (60, 90)69 (48, 82)

81 (69, 89)72 (58, 82)

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+ 18.0+

Remaining in response,† % (95% CI)9 months12 months

89 (64, 97)76 (46, 90)

78 (56, 90)69 (45, 84)

83 (68, 92)71 (53, 83)

Progression-free survivalDuration of response1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

bab

ility

of

resp

onse

15

12630Month

0.6

0.1

Number of patients at risk:

AZD9291 80 mg

30 26 23

9 18

AZD9291 160 mg

80 mg 22 19 12 3

30 29 27160 mg 23 17 0 0

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

bab

ility

of

resp

onse

15

12

630Month

0.6

0.1AZD9291 80 mg

20 20 17

9 18

AZD9291 160 mg

14 10 5 0

25 25 21 18 8 0 0

Number of patients at month:

80 mg

160 mg

Censored observation

Censored observation

Censored observation

Censored observation

Ramalingam S et al. WCLC 2015

FLAURA Phase III trial: AZD9291 vs Gefitnib or FLAURA Phase III trial: AZD9291 vs Gefitnib or Erlotinib in I line in patients with EGFR mutationErlotinib in I line in patients with EGFR mutation

Advanced NSCLC• Adenocarcinoma• EGFR mut+• First-line treatment• PS 0-1

RANDOMIZE

AZD9291(80 mg daily)

Gefitinib or Erlotinib

1

1

Primary EndpointEstimated Enrollment:

PFS650

Study Start Date: December 2014Accrual OngoingEstimated Primary Completion Date: May 2017 (Final data collection date for

primary outcome measure)

3 3 rdrd generation EGFR TKIs under generation EGFR TKIs under development: Rociletinib (CO-1686)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: 1000 mg (500 mg BID )

Sequist L et al, ASCO 2015

100

80

60

40

20

0

−20

−40

−60

−80

−100

SL

D c

ha

ng

e f

rom

ba

se

lin

e (

%)

+ Ongoing

500mg BID HBr625mg BID HBr750mg BID HBr

500mg 625mg 750mg Total

n 48 114 77 239

ORR (%) 60 54 46 52

DCR (%) 90 84 82 85

Dose Optimization of Rociletinib for T790M Mutated NSCLC

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)

Goldman JW et al. WCLC 2015

The risk-benefit profile of rociletinib

is optimal at the recommended

dose (500 mg BID)

TIGER-X: Phase 1/2 study of rociletinib TIGER-X: Phase 1/2 study of rociletinib in advanced NSCLCin advanced NSCLC

•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

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 patientsPD upon 1 immediate prior TKI

>2nd-line patientsPD upon ≥2 TKI or chemotherapy

21-day cycles; escalate to MTD

Key outcome measures•Safety•Tolerability•PK profile•ORR

Wakelee H et al, WCLC 2015

Why do T790M-negative pts respond to rociletinib?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

1. Cortot A, et al. Cancer Res. 2013;73:834-43. Wakelee H et al, WCLC 2015

Trials enrolling in 2014Trials enrolling in 2014

TIGER4 (phase 2) (TIGER2 like ;pts T790M plasma)

TIGER 1 PHASE II TRIAL: 1-line Rociletinib vs TIGER 1 PHASE II TRIAL: 1-line Rociletinib vs Erlotinib in patients with EGFR mutation Erlotinib in patients with EGFR mutation

Advanced NSCLC• Adenocarcinoma• EGFR mut+• First-line treatment• PS 0-1

RANDOMIZE

Rociletinib

Erlotinib

1

1

1250 mg (625 mg BID)

Primary EndpointEstimated Enrollment:

PFS200

Study Start Date: November 2014Accrual OngoingEstimated Primary Completion Date: June 2016 (Final data collection date for

primary outcome measure)

TIGER 3 TRIAL: Rociletinib vs chemotherapy TIGER 3 TRIAL: Rociletinib vs chemotherapy in pretreated patients with in pretreated patients with

EGFR mutation and T790M+/-EGFR mutation and T790M+/-

Advanced NSCLC• Adenocarcinoma• EGFR mut+• EGFR T790M+ or -• Third or more line

treatment• PS 0-1

RANDOMIZE

Rocilietinib

Single agentChemotherapy

(Pem/Gem/Txt/Tax)

1

1

1250 mg (625 mg BID)

Primary EndpointEstimated Enrollment:

PFS600

Study Start Date: February 2015Accrual OngoingEstimated Primary Completion Date: March 2017 (Final data collection date

for primary outcome measure)

Study DesignStudy Design

Recommended dose: 800 mg (400 mg BID)

Best Overall Response: Expansion PartBest Overall Response: Expansion Part

HM61713

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

HM61713 PHASE II TRIAL in 2-line HM61713 PHASE II TRIAL in 2-line for patients with EGFR activating mutation for patients with EGFR activating mutation

and T790M+and T790M+

Advanced NSCLC• Adenocarcinoma• EGFR mut+• EGFR T790M+• Second-line

treatment (previous TKI)

• PS 0-1

HM61713800 mg (400 mg BID)

Primary EndpointEstimated Enrollment:

Response Rate150

Study Start Date: July 2015Accrual OngoingEstimated Primary Completion Date: December 2016 (Final data collection

date for primary outcome measure)

Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790MKenneth 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 OxnardNature Medicine 21, 560–562 (2015)

NATURE MEDICINE | BRIEF COMMUNICATION

T790M+AZD9291Resistance

15 pts

MOLECULAR SUBTYPES OF RESISTANCE T790M+ C797S+

T790M+ C797S-

T790M- C797S-Del19+ or Mut21+

4 pts

5 pts

6 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

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