Noemi Reguart, MD, PhD Hospital Clínic Barcelona IDIPAPS · 2015. 5. 26. · FGFR1 amp 20% PIK3CA...

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)


• 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)



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)


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)


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)


Median PFS 5.6 months


• 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)


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


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%


Median PFS 4.7 months

Noemi Reguart, MD, PhD Hospital Clínic Barcelona IDIPAPS · 2015. 5. 26. · FGFR1 amp 20% PIK3CA...

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Transcript of Noemi Reguart, MD, PhD Hospital Clínic Barcelona IDIPAPS · 2015. 5. 26. · FGFR1 amp 20% PIK3CA...