tommaso de pas european institute of oncology · pts without progression received maintenance...
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Target therapy: first line?
Tommaso De Pas
European Institute of Oncology
EGFRTKI monotherapy
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