Second Line Treatment for
Gastroesophageal Cancers:
Are We Helping People Feel
Better and Live Longer?
Johanna Bendell, MD
Director, GI Oncology Research
Associate Director, Drug Development Unit
Sarah Cannon Research Institute
Nashville, TN
Second Line Therapy for
Gastroesophageal Cancers – A Difficult
Situation
After progression on first line therapy, only
roughly 20% of patients receive second-line
therapy with a median overall survival of 5.6
months (Chau, GI ASCO 2004)
Patients are sick
– Symptomatic – weight loss, anorexia, pain, difficulties
eating (with or without prior local intervention), N/V
Do we have data to show second line therapy
can help?
Randomized Second Line Trials
to Date
Study
Treatment
N
OS
Treatment
Group
OS
Control
Group
QoL
AIO
ThussPatience
2011
Irinotecan
vs. BSC
40
4.0 mo
HR 0.48
[0.25,0.92]
2.8 mo
50% vs. 7%
improvement
in tumorrelated
symptoms
Park
2011
Irinotecan or
docetaxel
vs. BSC
202
5.1 mo
HR 0.63
[0.47,0.86]
3.8 mo
N/A
WJOG4007
Ueda 2012
Irinotecan
vs.
Paclitaxel
219
9.5 mo
(paclitaxel)
8.4 mo
(irinotecan)
N/A
GRANITE-1
Van Cutsem
2012
Everolimus
vs. BSC
656
5.39 mo
HR 0.90
[0.75-1.08]
4.34 mo
N/A
Trial Design
Arm A (n=84):
Docetaxel 75mg/m2 IV every 3
weeks for up to 6 cycles
+ ASC
Adenocarcinoma
of esophagus,
esophagus-gastric
junction or
stomach refractory
to platinum and
fluoropyrimide
Stratified by:
Assess every 3
weeks for 18
weeks, then
every 6 weeks
RANDOMISE
1:1
n=168
Arm B (n=84):
Active symptom control
May include: Radiotherapy,
analgesia, anti-emetics,
steroids
1.Disease status (Locally advanced vs metastatic);
2. Site of disease (Esophagus vs GEJ vs Stomach);
3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months);
4. ECOG PS ( 0/1 vs 2)
COUGAR-02
Well-designed with good stratification
factors
Screening vs. number enrolled show how
difficult these trials are to accrue
– Many are ineligible (sick population)
– Refusal of study (vs. BSC)
Restaging at 3 and 6 cycles for docetaxel
patients, as indicated for BSC patients (no
TTP endpoint)
Included QUALITY OF LIFE
This is a difficult population to
treat
Docetaxel
BSC
23%
36%
Death
15%
38%
PD
40%
2%
Tox
31%
N/A
Treatment
N/A
14%
Completed
18 weeks
Reason off
These patients are
sick
Most do not complete
treatment plan
Toxicity
Toxicity rates
relatively low for q 3
week docetaxel
Only significant
differences are
neutropenia and
febrile neutropenia
Relatively low
neuropathy and
thrombocytopenia
Due to low amount of
chemotherapy given?
Median number of
cycles of docetaxel
given was 3
Overall survival
100
Median survival: 5.2 months (95% CI 4.1-5.9) for Docetaxel
3.6 months (95% CI 3.3-4.4) for ASC
Percentage surviving
75
Hazard ratio 0.67 (95% CI 0.49-0.92), p=0.01
Docetaxel
ASC
50
25
0
0
2
4
6
8
10
12
14
16
18
8
2
5
1
4
1
Months from randomisation
No. at Risk:
Docetaxel
ASC
84
84
69
70
53
38
33
19
25
13
17
9
10
6
Who really received benefit???
Patients who had disease progression 3-6
months after first line therapy
– Longest disease free interval
– Selection of patients who respond to therapy
better
Patients with ECOG 0
We Help Them Live Longer, But Do
We Help Them Feel Better?
QoL forms (EORTC QLQ-C30, STO22, EQ5D)
planned in both arms q 3 weeks for 18 weeks,
then q 6 weeks
Number of QoL forms expected/returned lower
in the control arm – potential source of bias, but
common in these types of studies
Arm A (Docetaxel)
Arm B (ASC)
QLQ-C30
Form
Number
Received
Number
Expected
Number
died/not
expecting QOl
n(%)~
Baseline
3 weeks
6 weeks
9 weeks
12 weeks
18 weeks
24 weeks
Total
n(%)*
82(98)
62 (81)
49 (68)
45 (68)
34 (55)
29 (60)
17 (52)
318 (72)
84
77
72
66
62
48
33
442
0
7 (8)
12 (14)
18 (21)
22 (26)
36 (43)
51 (61)
Number
Received
Number
Expected
Number
died/not
expecting QOl
n(%)~
n(%)*
76 (90)
50 (68)
38 (57)
25 (45)
29 (64)
13 (45)
11 (65)
242 (65)
84
73
67
55
45
29
17
370
0
11 (13)
17 (20)
29 (35)
39 (46)
55 (65)
67 (80)
Quality of life (EORTC QLQ-C30)
•
•
•
•
Standardised AUC analysis
Comparison using O’Brien global rank procedure
No significant differences in function or global health scale
Symptom score for pain significantly better in chemotherapy arm
Global health
p=0.53
CT ASC
Pain
p=0.0008
COUGAR-2
Chemotherapy benefits patients in the
second line setting
– We now see docetaxel and irinotecan work
– But overall benefit is still around 1.5 mo
But need to think about who will really
benefit
– Can we get better at selecting the appropriate
patient?
– Longer PFI, better PS
– Patients who respond better and feel better
live longer
COG
Gefitinib in advanced esophageal cancer
progressing after chemotherapy
Gefitinib 500mg od
(n=225)
Patients progressing
following chemotherapy
Simple randomisation
Planned:
18 months to recruit 450 patients
Primary endpoint:
Overall survival - powered to detect an
increase in 1 year survival from 10 to
18%, 82.5% power, 5% significance level.
Secondary endpoints:
PFS, toxicity & PROs
ASCO GI 24th Jan 2013
Placebo (n=225)
• Multi-centre
• Double-blind – patients,
clinicians and trial office
staff blinded to trial
treatment
• Treated until progression
• Regular CT scans
13
COG
No benefit for overall survival
– 3.73 vs. 3.6 mo, HR 0.90 [0.74,1.09]
PFS
– 1.60 vs. 1.17 mo, HR 0.795 [0.657,0.962]
– Was there a subgroup who had benefit?
Is there a biomarker? Studies ongoing…
Did anyone feel better?
– EORTC QLQ-C30
– EORTC QLQ-OG25
Quality of Life
Planned assessments at baseline, 4, 8,
and 12 weeks then until progression
Prespecified PRO: global QoL, dysphagia,
difficulty eating, odynophagia
Primary evaluation at 4 weeks
– Not surprisingly for this patient population,
only 70% alive and progression free at 4
weeks (82.5% placebo vs. 74.7% geftinib
compliance)
50
Placebo
Gefitinib
40
30
20
10
s
12
w
ee
k
w
ee
ks
8
w
ee
ks
4
Ba
se
lin
e
0
COG patients with measurable disease at baseline
placebo
gefitinib
150
100
Progressive disease
Progressive disease
50
20
0
Stable disease
Stable disease
Partial response
Partial response
-30
-50
-100
COG 2012
Odynophagia is improved
in the gefitinib arm at 4
weeks, and stays
consistently better with
time out to 12 weeks
This points to a group of
patients who appear to
benefit from gefitinib
There was a group with
tumor shrinkage at 4
weeks
– RR 3.1 vs 0.4%
– DCR (8 weeks) 26 vs. 16%
(p = 0.014)
Can we identify who they
are?
It always comes down to the
biomarker question…
But what are the biomarkers?
REAL-3
– Mutations/pathway dysregulation not common
– EXPAND biomarkers pending
Though we do see EGFR overexpression (50-70%)
Squamous vs. adenocarcinoma
– Different responses to EGFR inhibitors?
– SCC head and neck respond
– Lordick, et al, R ph II SCC esophagus,
RR 19 vs. 13%,
PFS 5.7 vs. 3.6 mo,
OS 9.5 vs. 5.5 mo
Chau 2011
Randomized Second Line Trials to Date
Study
Treatment
N
OS
Treatment
Group
OS Control
Group
QoL
AIO
ThussPatience 2011
Irinotecan vs.
BSC
40
4.0 mo
HR 0.48
[0.25,0.92]
2.8 mo
50% vs. 7%
improvement in
tumor-related
symptoms
Park
2011
Irinotecan or
docetaxel vs.
BSC
202
5.1 mo
HR 0.63
[0.47,0.86]
3.8 mo
N/A
WJOG4007
Ueda 2012
Irinotecan vs.
Paclitaxel
219
9.5 mo
(paclitaxel)
8.4 mo
(irinotecan)
N/A
COUGAR-2
Ford 2013
Docetaxel vs.
BSC
168
5.3 mo
HR 0.67
[0.49,0.92]
3.6 mo
No diff global
QoL but pain
improvement
GRANITE-1
Van Cutsem
2012
Everolimus
vs. BSC
656
5.39 mo
HR 0.90
[0.75-1.08]
4.34 mo
N/A
COG
Dutton 2013
Gefitinib vs.
BSC
450
3.73 mo
HR 0.90
[0.74,1.09]
3.6 mo
Improvement in
odynophagia,
social function
MOVING FORWARD…
T-DM1 structure
T-DM1 is a novel ADC
Trastuzumab
Target expression: HER2
Monoclonal antibody: Trastuzumab
Cytotoxic agent: DM1
Highly potent cytotoxic agent
T-DM1
Linker: MCC
Systemically stable
Average drug:
antibody ratio ≅3.5:1
Trastuzumab Emtansine: Phase II Study of 2L
treatment for HER2+ Metastatic Gastric
Cancer
Phase II
n=100
2L Her2 positive mGC
PS: 0 -1
IHC 3+ or IHC 2+/ISH+
Prior Ctx + prior HER2
N=412
Stratified by:
region, PS,
prior gastrectomy,
prior HER2-targeted tx
2
T-DM1 3.6 mg/kg q3 wk
2
T-DM1 2.4 mg/kg/wk
1
Chemotherapy**
• Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100
* Dose selection based on PK/safety/efficacy
** Investigator’s choice between paclitaxel 80 mg/m 2/wk and docetaxel 75 mg/m2 q 3 wk
REGARD: Randomized Phase
III Trial 2nd Line Ramicirumab
vs. Placebo
Ramucirumab IV
q 2 weeks
Second line
metastatic gastric
and GEJ
adenocarcinoma
R
Press release 10/12: met primary endpoint
of OS and secondary endpoint of PFS
Press release 1/23/13: OS 5.2 vs. 2.6 mo
PFS 2.1 vs. 1.3 mo
1:1
Placebo
q 2 weeks
Primary EP: OS
N = 355
22
RAINBOW: Randomized Phase
III Trial 2nd Line Paclitaxel +/Ramicirumab
Second line
metastatic gastric
and GEJ
adenocarcinoma
Paclitaxel 80 mg/m2
d1, 8, 15 +
Ramucirumab IV
q 2 weeks
R
1:1
Paclitaxel 80 mg/m2
d1, 8, 15 +
Placebo
q 2 weeks
Primary EP: OS
N = 665
23
Second Line Treatment of
Gastroesophageal Cancers
Consistent trials showing some benefit to chemotherapy
COUGAR trial shows docetaxel is an appropriate
chemotherapy choice
COG trial shows gefitinib overall does not improve
survival endpoints
However, both trials show suggestion of subpopulations
that may benefit more
– COUGAR – longer PFI, better PS
– COG – subpopulation with improved QoL factors
Drug development in this setting needs to be more
targeted to the right population
– We are doing this
– TDM1 for HER2 positive patients
– Inclusion of biomarker studies and QoL in trials for this
population