wilke h, et al. lancet oncol 2014

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wilke h, et al. lancet oncol 2014
Il trattamento sistemico del carcinoma gastrico avanzato
Giuseppe Aprile – AOU Udine
Gastric cancer: 2016 hot topics
Crash of biologics
Standard first-line
Second-line
options
Immunotherapy
Molecular biology
HER2 positive
disease
Continuum
of care
Surgery in
metastatic setting
Antiangiogenic
drugs
15%
CHEMO + trastuzumab
100%
DIAGNOSIS of
ADVANCED DIDEASE
10% never treated
75%
1st line
CHEMO
40%
20%
2nd line
3rd line
CHEMO
CHEMO
SUPPORTIVE CARE
MODIFIED FROM LINEE GUIDA AIOM, UPDATE OCTOBER 2015
2016: The data are the data
Median OS
Median OS 2L
~12 m
5m
Patients NO tx
Patients 2L
Patients 3L
10%
50%
25%
First-line chemotherapy: milestones
• Chemotherapy offers survival benefit over BSC
 HR 0.37 [0.24, 0.55]
• Chemotherapy improves symptoms control
• Combination chemotherapy better than single agent 5-FU
 Higher RR: OR 2.91 [2.15, 3.93]
 Prolonged TTP and OS: HR 0.82 [0.74, 0.90]
WAGNER AD, ET AL. COCHRANE DATABASE SYST REV 2010
First-line chemotherapy: which standard?
• Platinum + fluoropyrimidine accepted as standard
 OS benefit for platinum vs. non-platinum in meta-analysis
• Oxaliplatin equally effective than cisplatin
 Safety profile different
• Oral capecitabine and S-1 equally effective than 5-FU
 No need for CVC
WAGNER AD, ET AL. COCHRANE DATABASE SYST REV 2010
5-FU vs. capecitabine and cisplatin vs. oxaliplatin
Cunningham D et al. N Engl J Med 2008
Al-Batran SE et al. J Clin Oncol 2008
Kang YK et al. Ann Oncol 2009
First-line: the irinotecan effect
GUIMBAUD R, ET AL. J CLIN ONCOL 2014
First-line irinotecan + 5-FU: efficacy
Regimen
No.
RR
PFS
OS
TTF
CPT-11 + 5-FU
170
31.8%
5.0
9.0
4.0
CDDP + 5-FU
163
25.8%
4.2
8.7
3.4
0.23
0.088
HR=1.08
0.018
P-value1
FOLFIRI
207
37.8%
5.8
9.7
5.1
ECX
209
39.2%
5.3
9.5
4.2
NS
0.96
HR=1.01
0.008
P-value2
1
irinotecan 80 mg/m2, folinic acid 500 mg/m2, 5-FU 2000 mg/m2 22-h ci,
for 6 out of 7 weeks
2
irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU 400 mg/m2 bolus followed
by 5-FU 2000 mg/m2 46-h ci, every 2 weeks
DANK M, ET AL. ANN ONCOL 2008
GUIMBAUD R, ET AL. J CLIN ONCOL 2014
First-line irinotecan + 5-FU: safety (grade 3-4 toxicity)
Regimen
No.
Overall
Neutropenia (febrile
neutropenia)
Diarrhea
Tox death
CPT-11 + 5-FU
170
NR
24.8% (4.8%)
21.6%
1
CDDP + 5-FU
163
NR
51.6% (10.2%)
7.2%
5
-
<0.001
<0.001
NR
P-value1
Regimen
No.
Overall
Hematologic
Non-hematologic
Tox death
FOLFIRI
207
69%
38.4%
53.2%
7
ECX
209
83.5%
64.5%
53.5%
5
<0.001
<0.001
0.81
NR
P-value2
DANK M, ET AL. ANN ONCOL 2008
GUIMBAUD R, ET AL. J CLIN ONCOL 2014
First-line chemotherapy: FOLFIRI
• FOLFIRI can be considered a “standard” first-line option
 comparable activity and efficacy compared to platinum +
fluoropyrimidine
 lower hematologic toxicity compared to cisplatin-based
regimens
• FOLFIRI may be considered in patients progressing
 during or shortly after (within 6-12 months)
the end of peri-operative/adjuvant chemotherapy with
platinum-based regimens
First-line chemotherapy: is a third-drug needed?
• Anthracycline often used
 initial OS benefit for anthra vs. non-anthra not confirmed in
more recent meta-analysis
 no clear benefit in more recent randomized trials
• Docetaxel increases efficacy but adds substantial toxicity (V325
phase III trial: DCF vs. CF)
 Significantly increased RR (37% vs. 25%), TTP (5.6 vs. 3.7
months) and OS (9.2 vs. 8.6 months)
 Higher grade 3-4 neutropenia 82% vs 57% (febrile: 29% vs 12%)
WAGNER AD, ET AL. COCHRANE DATABASE SYST REV 2010
MOHAMMAD NH, ET AL. CANCER METASTASIS REV 2015
Is a third-drug needed? Recent meta-analysis
MOHAMMAD NH, ET AL. CANCER METASTASIS REV 2015
Is a third-drug needed? Recent meta-analysis
5-FU better than non-5-FU
Cisplatin better than non-cisplatin
Docetaxel better than non-docetaxel
MMC: no benefit
Anthracycline: no benefit
Other agents: no benefit
MOHAMMAD NH, ET AL. CANCER METASTASIS REV 2015
RR correlates with clinical benefit,
but it is not a OS surrogate…
R=0.48 in first-line
R=0.38 in second-line
I C H I K A W A W, E T A L . A N N O N C O L 2 0 1 6
SHITARA K, ET AL. GASTRIC CANCER 2014
Maintenance: a bridge between treatment lines
MANTRA: regorafenib vs placebo
ARMANI: early 2-line with ram
The landscape of second-line treatment
First-time may be stopped for disease progression
(80%) or treatment-related toxicity (20%)
40%
75%
Either way, a considerable number of patients are
still in good conditions after first-line therapy
HESS LM, GASTRIC CANCER 2015
KANG JH, ET AL. J CLIN ONCOL 2012
FORD HE, ET AL. LANCET ONCOL 2014
PIGF
PIGF
C
PIGF
A
B
A
D
B
E
A
D
C
C
A
D
B
C
D
Ang
sVEGFR-1
VEGFR-1
Flt1
NRP-1
VEGFR-2
Flk1/KDR
NRP-2
VEGFR-3
Flt-4
Tie
VEGF (ligand)
tyrosine kinase
APRILE G, ET AL. CRIT REV ONC HEMATOL 2015
Hypovascular tumors
Hypervascular tumors
REGARD
FUCHS C, ET AL. LANCET 2014
REGARD: Overall Survival
3.8
5.2
FUCHS C, ET AL. LANCET 2014
Adverse Events of Special Interest
Ramucirumab (N=236)
Placebo (N=115)
Any Grade
(%)
16.1
Grade ≥3
(%)
Any Grade
(%)
Grade ≥3
(%)
7.6
7.8
2.6
Bleeding/Hemorrhage *
12.7
3.4
11.3
2.6
Arteriothromboembolic *
1.7
1.3
0
0
Venous thromboembolic *
3.8
1.3
7.0
4.3
Proteinuria
3.0
0.4
2.6
0
GI perforation
0.8
0.8
0.9
0.9
Fistula (GI and non-GI)
0.4
0.4
0.9
0.9
Infusion related reaction
0.4
0
1.7
0
Cardiac failure
0.4
0
0
0
Category of event
Hypertension * †
FUCHS C, ET AL. LANCET 2014
REGARD: results and key messages
Significant benefit in OS (HR=0.77) and PFS (HR=0.48) for
ramucirumab compared to placebo
The treatment effect was generally consistent across major
subgroups
Very favorable toxicity profile, regardless of age
Ramucirumab is the first antiangiogenic drug with single
agent efficacy in GC
FUCHS C, ET AL. LANCET 2014
RAINBOW
WILKE H, ET AL. LANCET ONCOL 2014
RAINBOW: Overall Survival
7.4
9.6
VAN CUSTEM E, ET AL. ESMO 2014
WILKE, ET AL. LANCET ONCOL 2014
Adverse events related to chemotherapy
RAM + PTX (N=327)
Toxicity†
PBO + PTX (N=329)
Any Grade (%) Grade ≥3 (%) Any Grade (%) Grade ≥3(%)
Fatigue†
56.9
11.9
43.8
5.5
Neutropenia†
54.4
40.7
31.0
18.8
Neuropathy†
45.9
8.3
36.2
4.6
Decreased appetite
Abdominal pain†
40.1
36.1
3.1
6.1
31.9
29.8
4.0
3.3
Leukopenia†
33.9
17.4
21.0
6.7
Diarrhea
32.4
3.7
23.1
1.5
Epistaxis
30.6
0
7.0
0
Vomiting
26.9
3.1
20.7
3.6
WILKE H, ET AL. LANCET ONCOL 2014
Time to deterioration in EORTC QLQ C-30 Scales
WILKE H, ET AL. LANCET ONCOL 2014
RAINBOW: results and key messages
Significant benefit in OS (median OS + 2 months), PFS and RR
for ramucirumab and paclitaxel compared to paclitaxel alone
The treatment effect was generally consistent across major
subgroups
Toxicity moderately increased, but QoL was overall improved
WILKE H, ET AL. LANCET ONCOL 2014
Apatinib
A new small TK inhibitor that highly
and selectively inhibit VEGFR2
MTD 850 mg/day administered orally
DING J, DRUG METAB DISPOS 2013
LI J ET AL, J CLIN ONCOL 2013
Apatinib: phase III trial
Multicenter, randomized (2:1), double-blind, placebo-controlled phase 3 trial
Apatinib
Asian 74.5%, China 47%
Strat factor: #metastatic sites (1-2 vs >2)
850 mg/die q28d
(n=181)
Highly pretreated
GC patients
(n=273)
Primary endpoint: OS
(crossover permitted)
Secondary endpoints: PFS, ORR,
DCR, QoL, safety
R 2:1
Matching placebo
(n=92)
QIN S, ASCO 2014
Angiogenic inhibitors in third-line…
LI J ET AL, J CLIN ONCOL 2016
PAVLAKIS N ET AL,
ASCO GI 2015
Benefit (HRs) from antiangiogenics in GC
Second-line
First-line
HR 0.9 AVAGAST
HR 1.0 Yoon (ram)
HR 1.1 AVATAR
Perioperative
HR 1.06 STO3/MAGIC-B
HR 0.8 REGARD
HR 0.8 RAINBOW
Third-line
HR 0.7 Li (apatinib)
HR 0.68 INTEGRATE (rego)
Will the ramucirumab first-line study
change the forecast?
Rainbow
Rainfall
Ramucirumab + paclitaxel vs paclitaxel*
CDDP and 5-FU +/- ramucirumab
*WILKE H ET AL, LANCET ONCOL 2015
Who should be excluded from second-line?
Almost all PS 2+ patients?
Patients who experienced severe toxicity
in first-line?
Patients over 80? Or those who do not
need and desire further treatments?
Second-line chemotherapy: prognostic factors
709 patients from 15 Italian Centres treated with II-line chemotherapy
from Jan/2005 to Dec/2014
Second-line PFS
Second-line OS
HR
95%CI
p
HR
95%CI
p
Age >70 vs. ≤70 years
0.9
0.7-1.0
0.115
0.9
0.8-1.0
0.096
ECOG PS 0 vs. 1
0.4
0.3-0.5
<0.001
0.3
0.3-0.5
<0.001
ECOG PS 0 vs. 2
0.5
0.4-0.6
<0.001
0.5
0.4-0.7
<0.001
Single agent vs. triplet
1.4
1.0-1.8
0.037
1.4
1.0-1.8
0.042
Doublet vs. triplet
1.5
1.1-2.0
0.009
1.4
1.0-1.8
0.046
Haemoglobin ≥12 vs. <12 g/dL
0.9
0.8-1.1
0.259
0.8
0.7-0.9
0.030
Neutrophils/lymphocytes ratio <2.8 vs. ≥2.8
0.7
0.6-0.9
<0.001
0.6
0.5-0.8
<0.001
Fontanella C et al. ECC Meeting 2015 (abstr. 2357)
Second-line chemotherapy: prognostic factors
709 patients from 15 Italian Centres treated with II-line chemotherapy
from Jan/2005 to Dec/2014
Second-line PFS
Second-line OS
HR
95%CI
p
HR
95%CI
p
Age >70 vs. ≤70 years
0.9
0.7-1.0
0.115
0.9
0.8-1.0
0.096
ECOG PS 0 vs. 1
PS matters!
0.4
0.3-0.5
<0.001
0.3
0.3-0.5
<0.001
ECOG PS 0 vs. 2
0.5
0.4-0.6
<0.001
0.5
0.4-0.7
<0.001
Single agent vs. triplet
1.4
1.0-1.8
0.037
1.4
1.0-1.8
0.042
Doublet vs. triplet
1.5
1.1-2.0
0.009
1.4
1.0-1.8
0.046
Haemoglobin ≥12 vs. <12 g/dL
0.9
0.8-1.1
0.259
0.8
0.7-0.9
0.030
Neutrophils/lymphocytes ratio <2.8 vs. ≥2.8
0.7
0.6-0.9
<0.001
0.6
0.5-0.8
<0.001
Fontanella C et al. ECC 2015 (abstr. 2357)
Second-line chemotherapy: prognostic factors
709 patients from 15 Italian Centres treated with II-line chemotherapy
from Jan/2005 to Dec/2014
Second-line PFS
Second-line OS
HR
95%CI
p
HR
95%CI
p
Age >70 vs. ≤70 years
0.9
0.7-1.0
0.115
0.9
0.8-1.0
0.096
ECOG PS 0 vs. 1
PS matters!
0.4
0.3-0.5
<0.001
0.3
0.3-0.5
<0.001
ECOG PS 0 vs. 2
0.5
0.4-0.6
<0.001
0.5
0.4-0.7
<0.001
Single agent vs. triplet
First-line benefit matters!
1.4
1.0-1.8
0.037
1.4
1.0-1.8
0.042
Doublet vs. triplet
1.5
1.1-2.0
0.009
1.4
1.0-1.8
0.046
Haemoglobin ≥12 vs. <12 g/dL
0.9
0.8-1.1
0.259
0.8
0.7-0.9
0.030
Neutrophils/lymphocytes ratio <2.8 vs. ≥2.8
0.7
0.6-0.9
<0.001
0.6
0.5-0.8
<0.001
Fontanella C et al. ECC 2015 (abstr. 2357)
Second-line chemotherapy: prognostic factors
709 patients from 15 Italian Centres treated with II-line chemotherapy
from Jan/2005 to Dec/2014
Second-line PFS
Second-line OS
HR
95%CI
p
HR
95%CI
p
Age >70 vs. ≤70 years
0.9
0.7-1.0
0.115
0.9
0.8-1.0
0.096
ECOG PS 0 vs. 1
PS matters!
0.4
0.3-0.5
<0.001
0.3
0.3-0.5
<0.001
ECOG PS 0 vs. 2
0.5
0.4-0.6
<0.001
0.5
0.4-0.7
<0.001
Single agent vs. triplet
First-line benefit matters!
1.4
1.0-1.8
0.037
1.4
1.0-1.8
0.042
Doublet vs. triplet
1.5
1.1-2.0
0.009
1.4
1.0-1.8
0.046
Haemoglobin ≥12 vs. <12 g/dL
0.9
0.8-1.1
0.259
0.8
0.7-0.9
0.030
0.7
0.6-0.9
<0.001
0.6
0.5-0.8
<0.001
Organ function and
Neutrophils/lymphocytes
ratio <2.8 vs. ≥2.8
laboratory matter!
Fontanella C et al. ECC 2015 (abstr. 2357)
Have we got any algorhytm?
L O R D I C K F, N A T R E V C L I N O N C O L 2 0 1 5
First-line choice
Maintenance?
Second-line choice
PS 0 AND
Not biologically old
Motivation
PS, age, comorbidities,
previous tolerance, type
of previous CT, need for
remission, motivation,
supportive context,
tumour biology…
RAM + paclitaxel
RAM single agent
chemo single agent
CLINICAL TRIALS
PS 2+ OR
Biologically old
No motivation
BSC
OHTSU A ET AL, J CLIN ONCOL 2013
DUTTON SJ ET AL, LANCET ONCOL 2014
LORDICK F ET AL, LANCET ONCOL 2013
WADDELL T ET AL, LANCET ONCOL 2013
FOLFOX
+ placebo
560 pts
HER-2 negative,
MET-positive GC
R
FOLFOX
+ onartuzumab
Trial YO28322
ECX
+ placebo
450 pts
HER-2 negative,
MET-positive GC
RILOMET-1 study
R
ECX
+ rilotumumab
Selection of Met-positive patients
Met
status
Negative
Positive
Eligible
for
YO28322
✗
✓
IHC
Score
Staining Criteria
0
No or equivocal staining in tumor cells
or <50% tumor cells with membrane
and/or cytoplasmic staining
1+
>50% tumor cells with WEAK or higher
membrane and/or cytoplasmic staining
but <50% tumor cells with moderate or
higher staining intensity
Positive
✓
2+
>50% tumor cells with MODERATE or
higher membrane and/or cytoplasmic
staining but <50% tumor cells with
strong staining intensity
Positive
✓
3+
>50% tumor cells with STRONG or
higher membrane and/or cytoplasmic
staining intensity
Rapresentative IHC Images
Immunoistochimica o biologia molecolare?
Se Atene piange, Sparta non ride
24 November 2014
KWAK E ET AL, ASCO GI 2015
Why did this happen?
TOGA
ToGA trial design
Phase III, randomised, open-label, international, multicentre study
3,807 pts screened
810 HER2-positive
HER2-positive
advanced GC
(n=584)*
 Primary endpoint
−
XP or FP
(n=290)
R
XP or FP
+ trastuzumab
(n=294)
OS
 Secondary endpoints
−
PFS, TTP, ORR, clinical benefit rate, DoR, QoL, safety, pain intensity, analgesic
consumption, weight change, pharmacokinetics
*594 patients randomised, 10 patients never received treatment
‡Chosen at investigator’s discretion: 87.5% of pts received capecitabine
BANG YB, ET AL. LANCET 2010
BANG YB, ET AL. LANCET 2010
BANG YB, ET AL. LANCET 2010
Possible strategies
to overcome trastuzumab resistance
•
•
•
•
Enhancing HER-2 inhibition
(TDM-1, pertuzumab, neratinib)
Simultaneously targeting different HER receptors
(lapatinib, neratinib, afatinib)
Blocking downstream effectors
(everolimus, MK-2206, AZD5363)
Hitting different pathways
(onartuzumab, AMG337, linsitinib)
Zev A. Wainberg et al. Clin Cancer Res 2010;16:1509-1519
SATOH T ET AL, J CLIN ONCOL 2014
PFS HER2 3+
OS HER2 3+
GATSBY trial
TDM-1
2.4 mg q7 or
3.6 mg q21
HER2 positive
pretreated GC pts
(n=300)
Primary endpoint: OS
(crossover permitted)
R 2:1
Paclitaxel
or Docetaxel
Secondary endpoints: PFS, ORR,
DCR, QoL, safety
KANG YK, ET AL. ASCO GI 2016
KANG YK, ET AL. ASCO GI 2016
KANG YK, ET AL. ASCO GI 2016
No efficacy of HER-2 inhibition beyond PD:
why?
• Chemo does not take care of hetero cell
clones
• Novel genomic events (Met amp, KRAS mut,
PI3KCA mut)
• Different protein expression level
• Loss of HER-2 expression/amplification (p
value)
FGFR3 may be implicated in trastuzumab resistance
PIRO G, ET AL. SUBMITTED TO CLIN CANCER RES
JACOB (BO25114): trial design
Phase III, randomised,
double blind, international,
multicenter study
HER2-positive
advanced GC
780 pts
XP or FP
+ trastuzumab
+ pertuzumab
R
Primary endpoint: OS
Secondary endpoints: PFS, ORR, clinical benefit,
DoR, QoL, safety, pharmacokinetics
Accrual completed on Jan 12, 2016; Interim OS analysis after 351 events
XP or FP
+ trastuzumab
+ placebo
4% of all Breast cancer harbour a RARA/Erbb2 coamplification due to locus
closeness
COURTESY OF SK GARATTINI
Cell lines
RARA/Her2+ cell lines respond to retinoic acid
COURTESY OF SK GARATTINI
Maximum Percent Change From Baseline
in Tumor Sizea (RECIST v1.1, Investigator Review)
Change From Baseline in Sum of
Longest Diameter of Target Lesion, %
100
80
60
41% of patients
experienced a decrease in
tumor burden
40
20
0
-20
-40
-60
-80
-100
39 pts (20 non-Asian)
Median age 63
KPS 0-1
67% at least 2 CT-lines
MURO K ET AL, ESMO 2014
Nivolumab:
the CHECKMATE odyssey
Nivolumab monotherapy well tolerated, antitumor activity in
heavily pretreated pts with GC/GEC. Objective responses
occurred in pts with PD-L1-positive and -negative tumors
Le DT
Pembrolizumab:
the KEYNOTE saga
Doi T
Pembro had manageable toxicity and durable antitumor activity in
pts with heavily pretreated, PD-L1+ advanced esophageal
carcinoma. Phase II and III trials in pts with esophageal carcinoma
are ongoing
Avelumab:
the JAVELIN story
Avelumab showed an acceptable safety profile and clinical activity
in GC/GEJ pts. Objective responses and disease stabilization
observed in both groups. Median PFS was longer in PD-L1+ pts.
Chung H
ASCO GI 2016
MOHLER M. ASCO GI 2016
Should soft tissue be the issue?
PD-L1 expression: how much is enough?
O H I G A S H I Y, E T A L . C L I N C A N C E R R E S 2 0 0 5
THRUMURTHY SG, ET AL. NAT REV CLIN ONCOL 2015
F A N O T T O V, E T A L . E S M O G I 2 0 1 6 , S U B M I T T E D
L O R D I C K F, E T A L . N A T R E V C L I N O N C O L 2 0 1 6
2010s…Lauren’s classification revisited
RIQUELME I, ET AL. ONCOTARGET 2015
2014: a new molecular classification for GC
TCGA NETWORK. NATURE 2014
How does this work?
Samples characterized using six molecular platforms:
•
•
•
•
•
•
array-based somatic copy number analysis,
whole-exome sequencing,
array-based DNA methylation profiling,
mRNA sequencing,
microRNA (miRNA) sequencing,
reverse-phase protein array (RPPA)
VAN BEEK J, ET AL. J CLIN ONCOL 2004
CD274 = PD-L1
PDCD1LG2 = PD-L2
HURWITZ H, ET AL. J CLIN ONCOL 2015
FANG WL, ET AL. ONCOTARGET 2015
Mutational load in different tumors
LAWRENCE MS, ET AL. NATURE 2013
EGFR inhibitors,
HER-2 inhibitors,
MET inhibitors,
FGFR2 inhibitors,
…and many others
should we rethink
the all story?
M A T S U O K A T, E T A L . W O R L D J G A S T R O E N T E R O L 2 0 1 4
M A T S U O K A T, E T A L . W O R L D J G A S T R O E N T E R O L 2 0 1 4
In the meantime…
TCGA
The Cancer
Genome
Atlas
ACRG
The Asian
Cancer
Research
Group
CRISTESCU R, ET AL. NAT MEDICINE 2015
CRISTESCU R, ET AL. NAT MEDICINE 2015
TCGA and ACRG complement each other
The ACRG complements the TCGA stratification
approach, and supplements it by incorporating two
key molecular mechanisms related to TP53 and EMT,
in order to further stratify patients with gastric
cancer.
L O R D I C K F, E T A L . N A T R E V C L I N O N C O L 2 0 1 6
West does better with antiangiogenics,
East with HER-2 inhibitors
….and do not forget epigenetics
K I A N Y, E T A L . A N N O N C O L 2 0 1 6
Dal curare al prendersi cura
Care with compassion
Dynamic model of palliative care
PARTRIDGE AH, ET AL. J CLIN ONCOL 2013
Ambulatorio Cure Simultanee
Oncologo Medico
Medico palliativista
Medico nutrizionista
Psicologo
Infermiera (Case Manager)
HUI AND BRUERA. J CLIN ONCOL 2010
≈ 12 months time period
PARIKH RB, ET AL. N ENGL J MED 2013

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