tommaso de pas european institute of oncology · pts without progression received maintenance...

Target therapy: first line?

Tommaso De Pas

European Institute of Oncology

EGFRTKI monotherapy

Rosell et al

NEJM

2009

Giaccone, JCO 2004

INTACT-1

1093 pts, 66-72% IV stadio

9.9 vs 9.9 vs 10.9 ms

CDDP + GCB +

P: .4

INTACT-1

INTACT-2

… IDEAL 1- IDEAL 2

On average

Estimating the magnitude of the treatment effect

First line treatment in selected patients: evidence from randomized trial

Mok et al NEJM 2009

Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

patients in East Asia who had advanced pulmonary

adenocarcinoma and who were nonsmokers or former light

smokers

IPASS: PFS

Fukuoka et al JCO 2011

Exon 19

deletion L858R

Mok et al NEJM 2009

First line treatment in selected patients: evidence from randomized trial

Han et al, JCO 2012

First SIGNAL

159 pts: gefitinib

150 pts: GP

EGFRTKI combined with

chemotherapy

Mok T, ESMO 2012 FASTACT2

Randomized, placebo-controlled, phase 3 study

Patients with untreated stage IIIB/IV NSCLC and ECOG

PS 0/1 received up to 6 cycles of gemcitabine (1,250 mg/m2

on d1 & 8) plus platinum (carboplatin AUC = 5 or cisplatin

75 mg/m2 on d1) q4w, with either intercalated erlotinib (150

mg/day on d15-28; GC-E; n = 226) or placebo (GC-P; n =

225).

Pts without progression received maintenance erlotinib or

placebo until progression, unacceptable toxicity

or death.

Mok T, ESMO 2012 FASTACT2

mPFS 6.0 vs 7.6 HR 0.5

mOS 15.2 vs 18.3 HR 0.7

Overall results, updated

ESMO 2012

… INTACT 1 – INTACT-2

IDEAL 1- IDEAL 2 …

Mok T, ESMO 2012

FASTACT2

EGFR: 241 tested

97 EGFR M+ 49 erlotinib, 46 placebo

136 EGFR WT 69 erlotinib, 67 placebo

EGFR M+

PFS 6.9 vs 16.8 HR 0.2

OS 20.6 vs 31.4 HR 0,4 (p= .009)

EGFR WT

PFS 5.9 vs 6.7

OS 12.2 vs 14.9 (not sgn)

Mok T, ESMO 2012 FASTACT2

Conclusion

EGFR M+ pts benefit with intercalated erlotinib

EGFRWT pts: not detrimental -> to be considered for EGFR

unknown pts

Results not due to unbalance in post randomization treatment:

85% of EGFR M+ in the placebo arm received erlotinib after

progression

91% Overall population: 40% EGFR M+ and 60% EGFRWT

Erlotinib

Erlotinib

+ CT

Conclusion:

EGFR M+ -> EGFRTKI

EGFR M+ receiving CT -> + EGFRTKI

(FASTACT2)

EGFR ? -> adding EGFRTKI is not

detrimental in M- and it is better in M+

(FASTACT2)

EGFRTKI: only EGFR

mutation?

Molecular Predictors of Outcome With Gefitinib and Docetaxel in Previously Treated Non–Small-Cell Lung Cancer: Data From the Randomized Phase III INTEREST

Trial

Douillard JCO 2010

Progression free survival

(A) high EGFR copy number

(B) low EGFR copy number

(C) EGFR protein expression positive

(D) EGFR protein expression negative

(E) mutant EGFR

(F) wild-type EGFR

(G) mutant KRAS

(H) wild-type KRAS.

Molecular Predictors of Outcome With Gefitinib and Docetaxel in Previously Treated Non–Small-Cell Lung Cancer: Data From the Randomized Phase III INTEREST

Trial

Douillard JCO 2010

Biomarker Analyses and Final Overall Survival

Results

IPASS

Fukuoka et al JCO 2011

Biomarker Analyses and Final Overall Survival

Results

IPASS

Fukuoka et al JCO 2011

In all, 1,217 patients were randomly assigned.

Biomarkers analyzed were:

EGFR mutation (437 patients evaluable)

EGFR gene copy number (406 patients evaluable)

EGFR protein expression (365 patients evaluable)

Fukuoka et al JCO 2011

PFS EGFR M+

Copy n° H

EGFR M+

Copy n° L

EGFR M-

Copy n° H

EGFR M-

Copy n° L

Fukuoka et al JCO 2011

PFS

EGFR mutations are the strongest predictive biomarker for

PFS and tumor response to first-line gefitinib versus

carboplatin/paclitaxel.

The predictive value of EGFR gene copy number was driven

by coexisting EGFR mutation (post hoc analysis).

EGFRTKI: OS

IPASS: Fukuoka et al JCO2011

Overall population

EGFR M unknown EGFR M-

EGFR M+

OS

OS

Treatment-related differences observed for PFS in the EGFR

mutation–positive subgroup were not apparent for OS.

OS results were likely confounded by the high proportion of

patients crossing over to the alternative treatment.

IPASS: Fukuoka et al JCO2011

Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of

patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a

randomised multicentre, open-label, phase 3 study

Ciuleanu et al Lancet Oncology 2012

Second-line in chemo-refractory patients

TITAN

Ciuleanu et al Lancet Oncology 2012

Second-line in chemo-refractory patients

Up to four cycles of first-line platinum doublet chemotherapy

PD during / immediately after CT

erlotinib 150 mg/day vs chemotherapy (1:1)

docetaxel or pemetrexed regimens, at the treating

investigators' discretion

TITAN

Ciuleanu et al Lancet Oncology 2012

TITAN

Ciuleanu et al Lancet Oncology 2012

(A) in the intention-to-treat population

(B) excluding patients with squamous-

cell carcinoma

(C) in patients with EGFR wild-type

tumour

(D) in patients with EGFR -activating

mutation-positive tumour

EGFRTKI: don’t forget tumor

response

WHIC MUTATION IS

BETTER?

Fukuoka et al JCO 2011

IPASS: PFS

PFS was significantly longer for gefitinib versus

carboplatin/paclitaxel in both the exon 19 deletions (HR, 0.38;

95% CI, 0.26 to 0.56) and the exon 21 L858R mutation (HR,

0.55; 95% CI, 0.35 to 0.87) subgroups.

Within-treatment analysis indicated no significant difference

in PFS with gefitinib in the exon 19 deletions versus exon 21

L858R mutation subgroup (HR, 0.78; 95% CI, 0.51 to 1.19).

IPASS: PFS

Fukuoka et al JCO 2011

Exon 19

deletion L858R

Fukuoka et al JCO 2011

IPASS: ORR

Exon 19 deletions: significantly higher with gefitinib

84.8% vs 43.2%; OR, 7.23; 95% CI, 3.19 to 16.37

L858R: higher but not statistically significant

60.9% v 53.2%; OR, 1.41; 95% CI, 0.65 to 3.05

EGFRTKI: only gefitinib /

erlotinib?

Afatinib(ErbB-family blocker) : LUX – lung 3

345 chemo-naive pts

Afatinib 40 mg (230pts)

Cisplatin + Pemetrexed (115 pts )

Del 19: 49%; L858R: 40%

other mutations, 11%.

ASCO 2012 Dr Yang

R (2:1)

EGFR M+

LUX-lung 3

mPFS: 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78] p=0.0004

308 pts with Del19/L858R: median PFS was 13.6 vs 6.9

mos (HR=0.47 [0.34–0.65]; p<0.0001).

ORR: 56% vs 23%; p<0.0001

Delay in time to deterioration of cancer-related symptoms

of cough (HR=0.60, p=0.0072) and dyspnea (HR=0.68,

p=0.0145)

DACOMITINIB

DACOMITINIB

DACOMITINIB

DACOMITINIB (PF-00299804), AN IRREVERSIBLE PAN-HER

TYROSINE KINASE INHIBITOR , FOR FIRST-LINE TREATMENT

OF EGFR-MUTANT OR HER2- MUTANT OR -AMPLIFIED LUNG

CANCERS

M. Kris et al, ESMO 2012

DACOMITINIB (PF-00299804), AN IRREVERSIBLE PAN-HER

TYROSINE KINASE INHIBITOR , FOR FIRST-LINE TREATMENT

OF EGFR-MUTANT OR HER2- MUTANT OR -AMPLIFIED LUNG

CANCERS

EGFR mutated 45 pts

CR 0

PR 76%

SD 22%

PD 1%

mPFS 18 mos

PFS 12 m 76%

Ex 19 = L858R

DACOMITINIB (PF-00299804), AN IRREVERSIBLE PAN-HER

TYROSINE KINASE INHIBITOR , FOR FIRST-LINE TREATMENT

OF EGFR-MUTANT OR HER2- MUTANT OR -AMPLIFIED LUNG

CANCERS

HER-2 mut /ampl 22 pts

CR 0

PR 14%

SD 27%

PD 45%

mPFS 1,9 mos

1 liver tox G5

FIRST-IN-HUMAN DOSE-FINDING STUDY OF THE ALK/EGFR

INHIBITOR AP26113 IN PATIENTS WITH ADVANCED

MALIGNANCIES S. Gettinger et al, ESMO 2012

ALK+

Crizotinib

naive

ALK+

Crizotinib

pretreated

EGFR+

EGFRTKI

pretreated

RR 2/2 6/9 1 RP > 120 mg

Too early

Duration of

response

9 mos 6 mos

Dose > 90 mg

EGFRTKI

only gefitinib / erlotinib?

AFATINIB + CETUXIMAB

EGFR mutation positive adenocarcinoma

Progressing after erlotinib / gefitinb

T790M + (53) T790M- (42) TOT

RR 32% 28% 30%

CB 81% 64% 75%

PD 13% 21% 16%

Duration of response 6.4m 9m 8m

mPFS 4,7 m

ALK?

ROS-1?

HER-2?

N pts DCR

Trastuzumab based CT

15 96%

Afatinib 4 100%

Lapatinib 2 pts 0

Masatinib 1 0

Mazeires et al ESMO 2012