targeting kras and down streaming pathways federico cappuzzo istituto toscano tumori ospedale civile...
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Targeting KRAS and down streaming pathways
Federico CappuzzoIstituto Toscano Tumori
Ospedale CivileLivorno-Italy
Istituto Toscano Tumori – Livorno, Italy
Molecular events in lung cancer
Adenocarcinoma
Unknown53.8%
KRAS27%
EGFR9.5%
EGFR resistance mutations0.8%
HER20.9%
BRAF1.7%
PI3K2.6%ALK
3.7%
Squamous-cell carcinoma
KRAS mutations in NSCLC
• KRAS is the most frequently mutated oncogene in NSCLC outside Asia. Mutations in ~20% of tumors
• KRAS mutations occur in lung adenocarcinoma and less frequently in the squamous cell carcinoma subtype
• KRAS mutations are usually associated with a history of tobacco use (transversion mutations), even if have been detected in 10% of never smoker (transition mutations)
• The vast majority of KRAS mutations involves codons 12 or 13
Istituto Toscano Tumori – Livorno, Italy
Questions on KRAS mutations in lung cancer
• Are KRAS mutations prognostic?• Are KRAS mutations predictive for chemotherapy
sensitivity?• Are KRAS mutations predictive for targeted therapy
sensitivity?• Has KRAS any influence on sensitivity to checkpoint
inhibitors?• Any drug really working?
Istituto Toscano Tumori – Livorno, Italy
KRAS mutations and NSCLC prognosis
Istituto Toscano Tumori – Livorno, Italy
KRAS mutations and prognosis• Over 50 studies published• Different methods for detection (IHC versus PCR)• Conflicting results
Reference N Mutated (%) p value for OS
Cappelletti 258 27 0.7
Grossi 249 19 0.07
Kern 44 36 0.16
Ma 718 14 0.31
Tsao 450 26 0.4
Mascaux* 3779 18 0.01
*2005 meta-analysis
Istituto Toscano Tumori – Livorno, Italy
No prognostic effect of KRAS mutations in the LACE-Bio pooled analysis
Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, JCO 2013
All Patients Adenocarcinoma Patients
Pooled analysis of prognostic and predictive effect of KRAS mut in patients treated with
EGFR-TKIs
Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
Prognostic effect of KRAS mutationin placebo arm only
9
All patients
Median OS 4.7 v 5.0 m HR 1.095, p=0.48
Resected Adenocarcinoma
Advanced adenocarcinoma
Median OS 4.7 v 4.4 m HR 0.91, p=0.63
Median OS 5.2 v 5.1 m HR 1.0, p=0.98
Time in months
Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
Prognostic Effect of KRAS Codon 12 Mutation Subtype
10
mOS 6.3 mo(n=75)
mOS 3.9 mo(n=12)
mOS 1.8 mo(n=21)
p=0.01
Pe
rce
nta
ge
0
20
40
60
80
100
Time (Months) # At Risk(G12C or G12V) # At Risk(G12D or G12S) # At Risk(G12A or G12R)
0 752112
2 5788
4 4564
6 2130
8 1710
101310
SUMMARY STATISTICS:Stratified Log Rank test: p=0.0105Median for G12C or G12V: 6.28 -95% C.I. (4.08 ,9.80 )Median for G12D or G12S: 1.77 -95% C.I. (1.28 ,6.31 )Median for G12A or G12R: 3.88 -95% C.I. (1.05 ,4.54 )Stratified Hazard Ratio of G12D or G12S/G12C or G12V: 2.734 - 95 % C.I. (1.498, 4.993)Stratified Hazard Ratio of G12A or G12R/G12C or G12V: 1.818 - 95 % C.I. (0.846, 3.909)
KM Curve for Overall SurvivalKRAS mutation genotype - Placebo and stratified by trials
G12C or G12VG12D or G12SG12A or G12R
Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
KRAS mutations as predictive factors for survival with adjuvant chemotherapy
Istituto Toscano Tumori – Livorno, Italy
KRAS mutations are not predictive for adjuvant CT in the LACE-Bio pooled analysis
Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, JCO 2013
Patients with KRAS mut Patients with KRAS wild-type
Interaction p value=0.37
Adjuvant CT potentially detrimental in codon 13 KRAS mutations: LACE-Bio pooled analysis
Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, JCO 2013
Patients withcodon 12 KRAS mut Patients with codon 13 KRAS mut
KRAS mutations as predictive factors for survival to EGFR-TKIs
Istituto Toscano Tumori – Livorno, Italy
Predictive Effect of KRAS Mutation in patients treated with EGFR-TKIs
15Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
KRAS Mutant KRAS WT
Predictive effect of KRAS mutations All Patients
HR=1.13, p=0.395
HR=0.91, p=0.18
Interaction p=0.17
16Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
Predictive effect of KRAS mutation Adenocarcinoma EGFRWT
KRAS Mutant KRAS WT
Perc
enta
ge
0
20
40
60
80
100
Time (Months) # At Risk(Placebo)
# At Risk(EGFR_TKI)
0 106198
2 80
155
4 54
125
6 3992
8 2974
102157
SUMMARY STATISTICS:Stratified Log Rank test: p=0.1904Median for Placebo: 4.30 -95% C.I. (3.02 ,5.91 )Median for EGFR_TKI: 5.36 -95% C.I. (4.60 ,7.52 )Stratified Hazard Ratio of EGFR_TKI/Placebo: 0.838 - 95 % C.I. (0.643, 1.092)
KM Curve for Overall Survival (Adenocarcinoma, EGFR WT) - excluding BR19KRAS mutation status - Wild type
Placebo EGFR_TKI
Perc
enta
ge
0
20
40
60
80
100
Time (Months) # At Risk(Placebo)
# At Risk(EGFR_TKI)
0 3986
2 2869
4 2249
6 1437
8 1225
109
18
SUMMARY STATISTICS:Stratified Log Rank test: p=0.8462Median for Placebo: 4.24 -95% C.I. (2.33 ,7.11 )Median for EGFR_TKI: 4.96 -95% C.I. (3.62 ,6.64 )Stratified Hazard Ratio of EGFR_TKI/Placebo: 1.042 - 95 % C.I. (0.687, 1.581)
KM Curve for Overall Survival (Adenocarcinoma, EGFR WT) - excluding BR19KRAS mutation status - Mutated
Placebo EGFR_TKI
HR=1.04, p=0.84
HR=0.83, p=0.19
Interaction p=0.31
17Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
Predictive effect of KRAS mutation, Codon 12 subtype in advanced adenocarcinoma
G12D, G12S, G12A, G12R
Median OS 3.3 v 6.4m HR 0.43, p=0.08
Interaction p=0.003
Perc
entag
e
0
20
40
60
80
100
Time (Months) # At Risk(Placebo)
# At Risk(EGFR_TKI)
0 3058
2 2445
4 2230
6 1621
8 1513
101110
SUMMARY STATISTICS:Stratified Log Rank test: p=0.0438Median for Placebo: 8.28 -95% C.I. (4.08 ,13.14 )Median for EGFR_TKI: 4.32 -95% C.I. (3.32 ,6.08 )Stratified Hazard Ratio of EGFR_TKI/Placebo: 1.644 - 95 % C.I. ( 1.01, 2.677)
KM Curve for Overall Survival (Adenocarcinoma) - excluding BR19KRAS codon 12 - G12C/G12V Mutated
Placebo EGFR_TKI
G12C or G12V
Median OS 8.2 v 4.3 m HR 1.64, p=0.04
Perc
enta
ge
0
20
40
60
80
100
Time (Months) # At Risk(Placebo)
# At Risk(EGFR_TKI)
0 1222
2 7
20
4 3
17
6 2
12
8 19
1016
SUMMARY STATISTICS:Stratified Log Rank test: p=0.0826Median for Placebo: 3.32 -95% C.I. (1.28 ,4.54 )Median for EGFR_TKI: 6.44 -95% C.I. (4.24 ,13.77 )Stratified Hazard Ratio of EGFR_TKI/Placebo: 0.437 - 95 % C.I. (0.171, 1.116)
KM Curve for Overall Survival (Adenocarcinoma) - excluding BR19KRAS codon 12 - G12D/G12S/G12A/G12R Mutated
Placebo EGFR_TKI
18Istituto Toscano Tumori – Livorno, Italy
Zer et al, ESMO 2014
(n=350)Placebo
(N=973) Randomizationstratified by:
histology, stage, prior adjuvant chemo, EGFR FISH status, smoking
status, country
(n=623)Erlotinib
150mg/day
Up to 4 cycles ofplatinum-based
doublet
Tumor samplesEGFR IHC+ and/or EGFR FISH+
90 d
180 d
RADIANT trial design
• Radiology assessment: every 3 months on treatment and yearly during long-term follow up
• Primary endpoint: DFS• Secondary endpoints: Overall survival (OS); DFS and OS in patients with del19/L858R (EGFR M+)
No adjuvant chemotherapy
2:1
StageIB–IIIA NSCLC
Complete surgical
resection
2-yr treatment period
Istituto Toscano Tumori – Livorno, Italy
Kelly K, ASCO 2014
RADIANT: DFS and OS in the whole study population
Istituto Toscano Tumori – Livorno, Italy
DFS OS
ErlotinibErlotinib
Placebo
Placebo
Kelly K, ASCO 2014
RADIANT Trial: Prognostic Effect of KRAS:Placebo Arm, All patients
DFS OS
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease
-fre
e S
urv
ival
Pro
bab
ility
KRAS M+ WT
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease
-fre
e S
urv
ival
Pro
bab
ility
KRAS M+ WT
HR=1.14 (95% CI: 0.72, 1.81) HR=1.19 (95% CI: 0.67, 2.12)
21Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, ESMO 2014
Predictive Value of KRASon DFS: All Randomized
22
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease-f
ree S
urv
ival P
rob
ab
ilit
y
Erlotinib Placebo
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease-f
ree S
urv
ival P
robabili
ty
Erlotinib Placebo
Interaction HR: 0.87; P=0.64
KRAS M+ KRAS WT
HR: 0.81 (95% CI: 0.48, 1.38) HR: 0.93 (95% CI: 0.73, 1.19)
22Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, ESMO 2014
23
Predictive Value of KRASon OS: All Randomized
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease
-fre
e S
urv
ival
Pro
bab
ility
PlaceboErlotinib
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dis
ease
-fre
e S
urv
ival
Pro
bab
ility
Erlotinib Placebo
Interaction HR: 0.90; P=0.78
KRAS M+ KRAS WT
HR: 1.05 (95% CI: 0.56, 1.99) HR: 1.15 (95% CI: 0.85, 1.55)
23Istituto Toscano Tumori – Livorno, Italy
Shepherd et al, ESMO 2014
Can we use KRAS testing for precluding an EGFR-TKI to pretreated NSCLC?
Istituto Toscano Tumori – Livorno, Italy
KRAS mutations are predictive for lack of response to EGFR-TKIs
Reference N % Mutated RR (%)
Massarelli 70 22.8 0
Miller 80 22.5 0
BR21 118 16.9 5.0
Eberhadt 264 21.0 8.0
Zer• Codon 12• Codon 13
79685
19.3 1.31.50
25Istituto Toscano Tumori – Livorno, Italy
Gefitinib versus docetaxelOverall survival by biomarkers
0.5 1.0 1.5 2.0HR (gefitinib vs docetaxel) and 95% CI
Overall
EGFR FISH +
EGFR FISH -
EGFR expression +
EGFR expression -
EGFR mutation +
EGFR mutation -
K-RAS mutation +
K-RAS mutation -
0
Favors gefitinib Favors docetaxel
Istituto Toscano Tumori – Livorno, Italy
TAILOR Study Design
ERLOTINIB 150 mg po, daily
DOCETAXEL75 mg/m2 iv day 1,22 OR 35 mg/m2 iv day 1,8,15,29
R 1:1
CRO
SS O
VER
N
OT
ALLO
WED
Garassino MC, et al Lancet Oncol 2013
N 222
EGFR wild-type
Istituto Toscano Tumori – Livorno, Italy
Prognostic impact of KRASUnivariate analysis
PFS OS
Garassino MC, et al ESMO 2013
Istituto Toscano Tumori – Livorno, Italy
HR 1.02, p=0.93 HR 1.28, p=0.14
Predictive impact of KRAS on OS
KRAS mutants KRAS wild-type
Test for interaction Univariate p=0.82; Multivariate =0.97
HR 0.81 (95%CI 0.45-1.47) p=0.492 HR 0.79 (95%CI 0.57-1.10) p=0.167
Garassino MC, et al ESMO 2013
Istituto Toscano Tumori – Livorno, Italy
HR 0.81, p=0.492 HR 0.79, p=0.167
Can we use KRAS testing for selecting patients candidate for checkpoint inhibitors?
Istituto Toscano Tumori – Livorno, Italy
Clinical Development of Inhibitors of PD-1 Immune Checkpoint
Target Agent Molecule Company Development
PD-1 Nivolumab-BMS-936558
Fully human IgG4 mAb Bristol-Myers Squibb Phase II, III multiple tumors
PidilizumabCT-011
Humanized IgG1 mAb CureTech Phase II multiple tumors
LambrolizumabMK-3475
Humanized IgG4 mAb Merck Phase I-II
AMP-224 Recombinant PD-L2-Fc fusion protein
GlaxoSmithKline Phase I
PD-L1 BMS-936559 Fully human IgG4 mAb Bristol-Myers Squibb Phase I
MedI-4736 Engineered human IgG1 mAb
MedImmune Phase I
MPDL-3280A Engineered human IgG1 mAb
Genentech Phase I-II
Istituto Toscano Tumori – Livorno, Italy
a ORR includes investigator-assessed unconfirmed and confirmed PR. Patients first dosed at 1-20 mg/kg by Oct 1, 2012. Data cutoff: Apr 30, 2013.
Patie
nts
With
PR,
%
Response by Smoking Status (ORRa)
n = 43n = 10
MPDL3280A Phase Ia: Response by Smoking Status - NSCLC
Former/current smokers
Never smokers
Patient Smoking Status (n = 53)
Soria et al et al. ESMO 2013
Istituto Toscano Tumori – Livorno, Italy
Activity of pembrolizumab according to clinical characteristics
N ORR (%)
Total 236 21
Previous treatment 236
• Treatment naive 42 26
• Previuos treated 194 20
Histology 230
• Non-squamous 191 23
• Squamous 39 18
Smoking history 230
• Current/Former 165 27
• Never 65 9
Garon et al et al. ESMO 2014
Istituto Toscano Tumori – Livorno, Italy
Nivolumab more effective in smokers
Variable ORR, % (n/N) [95% CI] P-value
Smoking exposure 0.018
≤5 pack-yrs 0 (0/14) [0, 23]
>5 pack-yrs 30 (20/66) [20, 43]
Time since quitting 0.22
Current smoker 27 (6/22) [11, 50]
1–5 yrs prior 46 (6/13) [19, 75]
6–15 yrs prior 17 (2/12) [2, 48]
>15 yrs prior 18 (6/33) [7, 36]
0
20
80
60
40
Months Since Treatment Initiation
100
PFS
(%)
PFS by smoking exposure
Never/minimal smokers (mPFS 1.7 months)Former/current smokers (mPFS 2.2 months)HR (95% CI) = 0.41 (0.22, 0.74), P = 0.003
mPFS = median Progression-free survival
Istituto Toscano Tumori – Livorno, Italy
Hellmann et al et al. ASCO 2014
Istituto Toscano Tumori – Livorno, Italy
Altered protein contain new epitopes for immune recognition, providing a common denominator for immunotherapy
High mutational rates may contribute to increased immunogenicity
Response to anti-PD-1 is independent of EGFR or KRAS mutation status: nivolumab as an example
Subgroup ORR, % (n/N) [95% CI]
EGFR status
Mutant 17 (2/12) [2.1, 48.4]
Wild-type 20 (11/56) [10.2, 32.4]
Unknown 15 (9/61) [7.0, 26.2]
KRAS status
Mutant 14 (3/21) [3.0, 36.3]
Wild-type 25 (9/36) [12.1, 42.2]
Unknown 14 (10/72) [6.9, 24.1]
Ch
ang
e in
tu
mo
ur
size
, %
-100
-80-60
-40
120
-20
0
20
40
60
80
100
Patients
EGFR mutation statusMutantUnknownWild-type
-100
-80
-60
-40
120
-200
20
40
60
80
100
Patients
Ch
ang
e in
tu
mo
ur
size
, %
KRAS mutation statusMutantUnknownWild-type
CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy, NSCLC cohort
Brahmer J, et al. ASCO 2014 (Abstract 8112).
Istituto Toscano Tumori – Livorno, Italy
Response to anti-PD-1 is independent of EGFR or KRAS mutations: pembrolizumab and MPDL 3280A
Subgroup N ORR (%)
Total 53 23
EGFR status 46
• Mutant 6 17
• Wild type 40 23
KRAS status 37
• Mutant 10 10
• Wild type 27 30
MPDL 3280A PembroSubgroup N ORR (%)
Total 236 21
EGFR status
• Mutant 36 14
• Wild type 214 -
KRAS status
• Mutant 39 28
• Wild type 117 -
Istituto Toscano Tumori – Livorno, Italy
Garon et al et al. ESMO 2014Soria et al et al. ESMO 2013
There is any drug really working in KRAS mutated NSCLC?
Istituto Toscano Tumori – Livorno, Italy
Istituto Toscano Tumori – Livorno, Italy
Selumetinib
• Selumetinib (AZD6244, ARRY-142886) is a potent and selective allosteric inhibitor of MEK 1/21
• Tendency for greater sensitivity to selumetinib in BRAF/RAS-mutant cell lines2
1. Yeh et al. Clin Cancer Res 2007;13:1576–83; 2. Davies et al. Mol Cancer Ther 2007;6:2209–19
Ras
Raf
MEK 1/2
ERK 1/2
SelumetinibCe
ll vi
abili
ty in
hibi
tion
IC50
(µM
)
Cell line
RAS/BRAF mutation
0
5
10
15
20
25
30
NoneKRASBRAFNRAS
Selumetinib: preclinical/early phase clinical studies Preclinically, the combination of selumetinib and docetaxel demonstrated tumor regression in a KRAS-mutant cancer1
Phase I study showed that selumetinib plus docetaxel had a manageable tolerability profile2
1. Holt et al. Br J Cancer 2012; 2 Kim et al. Mol Can Ther 2011;
HCT-116 human tumor xenografts (KRAS-mutant)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
0 2 4 6 8 10 12 14
Mea
n tu
mou
r vol
ume
(cm
3) +
/-s.
e.m
ControlSelumetinib-25mg kg-1 per qdDocetaxel-15mg kg-1Combo
Istituto Toscano Tumori – Livorno, Italy
Istituto Toscano Tumori – Livorno, Italy
Phase II, double-blind, randomized, placebo-controlled, multi-center trial; NCT00890825
• Docetaxel was administered every 21 days; selumetinib/placebo administered daily• Following completion of patient enrollment, the primary endpoint was changed from PFS to OS, without
changing the sample size‡ – OS analysis was planned for after approximately 58 events; HR 0.57, 80% power assuming a 1-sided
10% significance level
Selumetinib 75 mg BID+ docetaxel 75 mg/m2
Placebo BID + docetaxel 75 mg/m2
EndpointsPrimary• OS
Secondary• PFS• ORR• Duration of response• Change in tumor size• Alive and progression-
free at 6 months• Safety and tolerability
Randomization(1:1 ratio)
Patients
• Locally advanced or metastatic NSCLC (stage IIIB-IV)
• Failed first-line therapy
• Confirmed KRAS mutant tumor*
• WHO PS 0-1
• Excluding symptomatic brain metastases
Janne PA et al, Lancet Oncol 2014
Overall survival
• There was a numerical increase in OS (median follow-up 7.2 mo); hazards non-proportional– 56/83 deaths (67% maturity): selumetinib + docetaxel 29/43, placebo + docetaxel 27/40
Median OSSelumetinib + docetaxel, n=43 9.4 moPlacebo + docetaxel, n=40 5.2 moHR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069*
Prop
ortio
n of
pati
ents
aliv
e
Days
0 50 100 150 200 250 300 350 400 450 500 550 600 650
Number at risk
1.0
0.8
0.6
0.4
0.2
0.0
4340
4135
3627
3520
2818
2515
1413
66
65
24
13 2 1
Istituto Toscano Tumori – Livorno, Italy
Janne PA et al, Lancet Oncol 2014
Trametinib and pemetrexed for KRAS mutated NSCLC
Istituto Toscano Tumori – Livorno, Italy
Mazieres J et al. WCLC 2013
Tivantinib: Study DesignRandomized, placebo-controlled, double-blind clinical trial
RANDOMIZE
Erlotinib 150 mg PO QD+ Placebo
28-day cycle
Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID
28-day cycle
Endpoints • 1° PFS• 2° ORR, OS• Subset analyses• Crossover: ORR
NSCLC• Inoperable locally adv/
metastatic dz.• ≥1 prior chemo
(no prior EGFR TKI)
• 33 sites in 6 countries
• Study accrual over 11 months (10/08-9/09)
• Randomization stratified by prognostic factors incl. sex, age, smoking, histology, performance status, prior therapy and best response, and geography (U.S. vs. ex-U.S.)
PD
Istituto Toscano Tumori – Livorno, Italy
5.02.0
Tivantinib: PFS in Histologic and Molecular Subgroups
ARQ197/erlotinib Placebo/erlotinib
Unadjusted HR (95% CI)N Median PFS (95% CI, weeks)
Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0)
Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0)
c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3)
c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4)
EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0)
EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9)
KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0)
KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0)
1.00Favors
ARQ 197/ErlotinibFavors
Erlotinib/placebo
HR=0.70
HR=0.18
0.5 1.5
HR=1.01
HR=1.23
HR=0.45
HR=0.71
HR=1.05
HR=0.71
Istituto Toscano Tumori – Livorno, Italy
MARQUEE phase III study design
Primary end-point: OSIstituto Toscano Tumori – Livorno, Italy
MARQUEE: Forest plot for OS in key subgroups
Istituto Toscano Tumori – Livorno, Italy
Conclusions• KRAS mutations are not prognostic in early nor advanced
NSCLC• KRAS mutations are not predictive for OS in:
– Early NSCLC exposed to adjuvant chemotherapy– Early NSCLC exposed to EGFR-TKIs– Advanced NSCLC exposed to EGFR-TKIs
• KRAS mutations predict no response to EGFR-TKIs• KRAS mutations cannot be used for precluding a treatment
with– Adjuvant Chemotherapy– EGFR-TKIs in second or subsequent lines– In patients candidate for checkpoint inhibitors
• No drugs are currently available in clinical practice• Several compounds are under investigation
Istituto Toscano Tumori – Livorno, Italy