THE BEST OF ESMO 2016...DM has received honoraria for consultancy/advisory boards and symposia from...
Transcript of THE BEST OF ESMO 2016...DM has received honoraria for consultancy/advisory boards and symposia from...
esmo.org
THE BEST OF ESMO 2016
Colorectal cancer
Dr David MALKA
Gustave Roussy
Université Paris Sud
Villejuif, FRANCE
DM has received honoraria for consultancy/advisory boards and symposia from Amgen,
Bayer, Celgene, Lilly, Merck Serono, MSD, Roche, Sanofi-Aventis and Servier, and has
received research funding (to his institution) from BMS and Immune Design
DISCLOSURES
NON-METASTATIC DISEASE
Surgery for rectal cancer: 6-7 or 11-12 weeks
after chemoradiotherapy (CRT)?
W8 W10 W12 W6
TME
Lyon R90-01 Does it increase pCR rate? Sphincter
preservation? Survival?
CRT
6 vs 12 trial
• Primary end point: to increase MRI downstaging from 40% (6w) to 60% (12w)
• Patients: 237 from 21 centres (37% of them included in one centre)
Inclusion criteria?
Bhoday J et al. Abstract 4520. ESMO 2016
• MRI: at initial staging (preCRT) and at 6 +/- 12w
• Then RT then surgery at 6-8w vs12-14w
Is it clinically relevant?
RT or CRT?
6 vs 12 trial
Bhoday J et al. Abstract 4520. ESMO 2016
mrT down-staging
52 patients (43%) 6w vs. 67 patients (58%) 12w, p = 0.019
122 patients (6w arm), 115 patients (12w arm)
mrN down-staging
54 patients (44%) 6w vs. 61 patients (53%) 12w, NS
Hypothesis 40 => 60%
Bhoday J et al. Abstract 4520. ESMO 2016
6 week
n=122
12 week
n=115
p
mrTRG 1 6% 22% <0.05
CRM involvement 68% 61% NS
EMVI 50% 33% 0.001
ypT0 7.4% 20% <0.05
ypN0 42% 55% <0.05
pTRG 1 = pCR 9% 20% <0.05
• No significant difference between the 2 arms for surgical morbidity.
• 1% anastomotic leak???
Lefèvre J et al. JCO 2016
• 265 patients with T3-T4 and/or N+ rectal cancers from 24 centres
• Randomization after CRT: 7w vs11w interval before surgery
Lefèvre J et al. JCO 2016
pCR rate (ypT0N0) : 15% (7w) vs 17.4% (11w) p=0.6
+3.6% pCR
Per protocol
ITT
Lefèvre J et al. JCO 2016
Surgical morbidity 7 weeks 11 weeks
Complete and detailed data needed
6 weeks may be too early
12 weeks may be too late
7-9 weeks seems enough to reach an optimal pCR without morbidity
TO CONCLUDE
Bhoday J et al. Abstract 4520. ESMO 2016
NGS ASSESSMENT OF CETUXIMAB ADJUVANT TRIAL
Is there a place?
• Better HR than MOSAIC (0.8)
• Clinically relevant but not significant
• Subgroup analysis (unplanned)
New trial in hyper-selected RAS/BRAFWT patients?
cetuximab
No cetuximab
HR= 0.77
P=0.1
Taieb et al ESM0 2016
Does surveillance matter?
Regular CEA monitoring
Colonoscopy at year 1 and every 3–5 years
Consider CT FU in patients at higher risk
Clinical assessment 6 monthly for 2 years
Hx and colonoscopy every 5 years (up to 75)
Additional FU for patients with symptoms
Regular CEA and CT FU for Stage II-III CRC
Insufficient evidence for stage I disease
Colonoscopy at 1 year and every 5 years
Ann Oncol 2013; 24 (Suppl 6): vi64-vi72.
Ann Oncol 2013; 24 (Suppl 6): vi81-vi88.
J Clin Oncol 31:4465-4470
Does surveillance matter?
301
minimal
299
CT
300
CEA 302
CEA & CT
1211 patients
Pugh S et al. Abstract 4530. ESMO 2016
6-12-year results from the FACS trial
Intensive follow-up identified more recurrences surgically treatable with curative intent
Minimum follow-up
Intensive follow-up
CEA CT CEA + CT P value
n=301 n=300 n=299 n=302
Recurrences (%) 38 (13%) 56 (19%) 61 (20%) 48 (16%) 0.06
Surgically treatable recurrences (%) 8 (3%) 19 (6%) 28 (9%) 21 (7%) 0.008
Among recurrences, treatable (%) 21% 32% 46% 44%
Does it translate in survival?
Pugh S et al. Abstract 4530. ESMO 2016
6-12 year results from the FACS trial
Does surveillance matter? Intention to treat analysis
Log rank p = 0.45
Per protocol analysis
Log rank p = 0.36
• Of course NOT in ITT or PP
• But what is important is
survival in patients that HAVE
RELAPSED!!!
• <100 relapses out of 1200 pts
Yes, surveillance matters, especially CT, as it brings more
patients to curative-intent Tx at relapse!
News from very rare mutations/alterations!
Little is known about rare mutations in stage III colon cancer
Their prognostic value may be important to stratify clinical trials or
intensify adjuvant treatments in the future
They may have predictive value as well!!!
News from very rare mutations/alterations!
Impact of rare individual
mutations on TTR
Favors mutant Favors WT
Rare RAS and BRAF mutations are not
prognostic (except codon 61) POLE is a good prognostic factor
(sensitivity to PD(L)1i?)
Taïeb et al., Laurent-Puig et al., Domingo et al. ESMO 2016
HER2/ERBB2 is a poor prognostic
factor (sensitivity to HER2i?)
10%
4% 1%
METASTATIC DISEASE
What is the best maintenance Tx?
Capecitabine > chemotherapy stop (Luo Ann Oncol 2016)
Bevacizumab alone = marginal benefit (SAKK, PRODIGE 9)
Capecitabine + bevacizumab
largely used
> bevacizumab alone or complete stop (CAIRO3, AIO 0203)
Added value of bevacizumab vs. FP alone possible but still not proven
Maintenance with cetuximab suggested by a R ph II trial (COIN.B)
What is the best maintenance Tx?
MACBETH: Study design
R 1:1
mFOLFOXIRI +
cetuximab§ up to 8 cycles
cetuxim ab§
unt i l PD
bevacizumab §
unt i l PD
mFOLFOXIRI +
cetuximab§
up to 8 cycles mCRC pts:
ü Unresectab le disease
ü Previously unt reat ed
f or m ts disease
ü RAS and BRAF w t *
Arm
A
Arm
B
*cent ral ly assessed: KRAS 12,13,61 w t unt i l Oct 2013, then RAS and BRAF w t §administered b iw eek ly St rat i f icat ion f actor : center
Phase II randomized non-comparat ive t r ial
INDUCTION MAINTENANCE
Cremolini et al. ESMO 2016
What is the best maintenance? Macbeth (mITT population)
RASwt
Arm B (N pts=57)
Arm A (N pts=59)
Events
43
50
Median
11.2 mos
9.3 mos
95% CI
7.2-14.0
7.1-10.8
RASWT patients
Cetux seems> bev after cetux induction
In accordance with COIN B results
Still needs to be confirmed
(insufficient number of patients)
Cap (FP?) + cetux should be compared to
• FP + bev
• FP alone!
RASWT subpopulation in all studies
Tumor sidedness definition
Sigmoid
colon
Splenic
flexure
Cecum
Descending
colon
Rectum*
Hepatic
flexure
Ascending
colon
Rectosigmoid
junction
Transverse colon
Left colorectum
Whose side are you on?
Right colon
?
BRAF Mutants
CIMP+
MSI+
Primary tumor not removed
Older patients
PEAK – OS – 1st line
Beva, bevacizumab; HR, hazard ratio; OS, overall survival; Pmab, panitumumab
100
80
60
40
20
0
Kap
lan-
Mei
er e
stim
ate
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
53
54
22
14
51
51
21
12
49
48
18
11
46
44
13
11
44
43
11
7
41
40
10
6
36
35
8
4
33
31
7
3
32
26
6
1
31
21
5
0
25
17
4
17
13
3
13
10
2
6
5
1
3
3
0
2
2
0
0
No. of subjects:
1:
2:
3:
4:
1: Pmab + FOLFOX left
2: Beva + FOLFOX left
3: Pmab + FOLFOX right
4: Beva + FOLFOX right
Median OS (95% CI), months
Pmab +
FOLFOX
Beva +
FOLFOX HR (95% CI)
Left 43.4 (31.6–63.0) 32.0 (26.0–47.4) 0.84 (0.22–3.27)
Right 17.5 (9.1–30.7) 21.0 (6.0–29.0) 0.45 (0.08–2.49)
Censor indicated by vertical bar
Overall survival (months)
Peeters et al. ESMO 2016
PFS – 1st (PRIME and PEAK) and 2nd (181) line
Median PFS (95% CI), months
PRIME (1st line) PEAK (1st line) 181 (2nd line)
Pmab +
FOLFOX
FOLFOX
HR
(95% CI)
Pmab +
FOLFOX
Beva +
FOLFOX
HR
(95% CI)
Pmab +
FOLFIRI
FOLFIRI HR
(95% CI)
Left 12.9
(10.0–14.6)
9.2
(7.6–10.7) 0.72
(0.57–0.90)
14.6
(11.6–17.7)
11.5
(9.3–13.0)
0.65
(0.21–2.00)
8.0
(7.3–9.1)
5.8
(5.2–7.3)
0.88
(0.69–1.12)
Right 7.5
(5.5–10.4)
7.0
(5.4–8.0)
0.80
(0.50–1.26)
8.7
(5.7–10.9)
12.6
(1.8–16.6)
0.84
(0.18–3.79)
4.8
(3.5–7.4)
2.4
(1.8–5.7)
0.75
(0.45–1.27)
Beva, bevacizumab; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; Pmab, panitumumab
Peeters et al. ESMO 2016
Response rates
Complete response + partial response (%)
PRIME (1st line) PEAK (1st line) 181 (2nd line)
Pmab +
FOLFOX
FOLFOX Pmab +
FOLFOX
Beva +
FOLFOX
Pmab +
FOLFIRI
FOLFIRI
Left 68 53 64 57 50 13
Right 42 35 63 50 13 3
Beva, bevacizumab; Pmab, panitumumab
Peeters et al. ESMO 2016
Whose side are you on? (CALGB all RASWT) 80405: Overall Survival by Biologic
(Right Sided Primary) Arm
N
(Events)
Median
(95% CI)
HR
(95% CI) Adjusted p
Bev 78
(58)
29.2
(22.4-36.9) 1.36
(0.93-1.99) 0.10
Cetux 71
(56)
13.7
(11.3-19.0)
80405: Overall Survival by Biologic
(Left Sided Primary) Arm
N
(Events)
Median
(95% CI)
HR
(95% CI)
Adjusted
p
Bev 152
(119)
32.6
(28.3-36.2) 0.77
(0.59-0.99) 0.04
Cetux 173
(119)
39.3
(32.9-42.9)
Venook et al. ESMO 2016
Whose side are you on? (FIRE.3 and CRYSTAL all RASWT)
Heinemann et al. and Van Cutsem et al. ESMO 2016
Whose side are you on? (FIRE.3 and CRYSTAL all RASWT)
Heinemann et al. and Van Cutsem et al. ESMO 2016
Whose side are you on? (FIRE.3 and CRYSTAL all RASWT)
Whose side are you on? (FIRE.3 and CRYSTAL all RASWT)
Whose side are you on? Conclusion
• In LEFT-SIDED RASWT • 2+anti-EGFR >2+bev for shrinkage and disease control
• Option: 3+bev (FOLFOXIRI+bev) in fit patients
• In RIGHT-SIDED RASWT
• Poor prognosis pts (BRAFmt in 20-30%!)
• BOTH 2+BEV OR 2+ANTI-EGFR REMAIN POSSIBLE
• 3+bev (FOLFOXIRI+bev) may be the good choice in fit patients
→ Clinical trials still needed
Do we have to change our practice based on unplanned subgroup analyses of
1st (2nd) line, non-strategic trials?
esmo.org
MIR-31-3P IS A PREDICTIVE BIOMARKER OF CETUXIMAB RESPONSE IN FIRE-3 CLINICAL TRIAL P. Laurent-Puig, M.L. Grisoni, V. Heinemann, K. Fontaine, C. Vazart, V. Decaulne, F.
Rousseau, B. Courtieu, F. Liebaert, A. Jung, D. Neureiter, R. Thiébaut, S. Stintzing
Treatment effect on PFS, OS and ORR
• Overall: Hazard/Odds ratios [95% CI] not adjusted
p=0.046
HR=0.57 [0.37 ; 0.87] p=0.003
HR=1.13 [0.66 ; 1.96] p=0.61
HR (97.5%CI)
p=0.048
HR=0.80 [0.58 ; 1.12] p=0.13
HR=1.33 [0.82 ; 2.14] p=0.18
HR (97.5%CI)
Low
n = 229
High
n = 111 OR=1.23 [0.54 ; 2.80] p=0.62
OR=4.13 [1.99 ; 8.61] p=0.0002
p=0.028
Favors cetux Favors beva Favors cetux Favors beva Favors beva
• In miR-31-3p subgroups: Hazard/Odds ratios adjusted on age, number of organs and BRAF status2
MiR-31-3p is predictive of treatement effect on PFS, OS and ORR
OR (95%CI) Favors cetux
OS
HR=0.70 [0.53 ; 0.92] p=0.011
HR=0.71 [0.53 ; 0.93] p=0.014
ITT RAS WT1
mITT
ORR
OR*=1.28 [0.83 ; 1.99] p=0.32
OR*=1.66 [1.07 ; 2.59] p=0.03
PFS
HR=0.93 [0.74 ; 1.17] p=0.54
HR=0.92 [0.73 ; 1.16] p=0.46
1Heinemann et al. Lancet Oncology 2014
*Missing data included as non-responders
Interaction test
Treatment effect on early tumor shrinkage (ETS) at 6 weeks
Favors beva Favors cetux
Interaction test: p=0.029
MiR-31-3p is predictive of treatment effect on early tumor shrinkage cetuximab gives an earlier response than bevacizumab in low miR-31-3p expressors
High n = 111 Low n = 229
Responders:
ETS at 6 weeks < -30 %
Odds ratio [95% CI] adjusted on age, number of organs and BRAF status
Favors beva Favors cetux
beva responders
25%
cetux responders
56%
beva responders
28%
cetux responders
35%
n = 47 n = 51 n = 104 n = 77 Excluding patients with missing response
OR = 4.11 [2.14 ; 7.92] p=0.00002 OR = 1.16 [0.46 ; 2.92] p=0.76
Treatment effect on depth of response (DoR)
Favors beva Favors cetux
Interaction test p=0.0006
MiR-31-3p is predictive of treatment effect on depth of response cetuximab gives an deeper response than bevacizumab in low miR-31-3p expressors
High n = 111 Low n = 229
OR=6.05 [2.77 ; 13.22] p=0.000006 OR=0.84 [0.35 ; 2.02] p=0.70
Responders:
depth of response > -30 %
beva Responders
53%
cetux responders
53%
n = 47 n = 51
beva responders
53%
cetux responders
86%
n = 104 n = 77 Excluding patients with missing response
Odds ratio [95% CI] adjusted on age, number of organs and BRAF status
Favors beva Favors cetux
Bevacizumab n=151 Correlation test: cor=0.12 , p=0.159
Cetuximab n=128 Correlation test: cor=0.28 , p=0.002
Depth of reponse by miR-31-3p expression
Non Responders
20%
Stable disease
-30%
Responders
CUT OFF
Low High
CUT OFF
Low High
MiR-31-3p & sidedness
MiR-31-3p expression groups by sideness
Twofold increase in the percent of patients with right sided tumors who
have high miR-31-3p expression.
OS by miR-31-3p subgroups and sidedness Left High
Left Low
Right High n = 69
n = 191 n = 26 Low
High
Left Right
HR=2.85 [1.19 ; 6.85]
HR=0.52 [0.34 ; 0.79]
Right Low
n = 41 n = 111
n = 229
n = 260 n = 67
miR by treat p=0,09 miR by treat p=0,64
Both miR-31-3p and sidedness are predictive: • Right-High pts: OS benefit with bev • Left-Low pts: OS benefit with cetux
Sidedness by treat p=0,001
Sidedness by treat p=0,371
Sidedness by treat p=0,001
miR by treat p=0,046
Interaction
test p-value
_ bevacizumab _ cetuximab
2nd line FOLFIRI +/- regorafenib
O’Neil. et al. - ESMO® 2016 - Abs. 464 PD
R A B D O M I Z E D
N = 240
Screening :
Obtain archival tissue for correlative
studies in all patients, and fresh
biopsy (optional) in subset1
mCRC following 1 prior
oxaliplatin-containing regimen
Primary
endpoint :
PFS
Secondary
endpoints :
ORR, DCR, OS, PK,
safety, and tolerability
FOLFIRI†
+ Placebo
†Day 1–2, Day 15–16
Regorafenib 160 mg*
+ FOLFIRI
*Day 4–10, Day 18–24
R A B D O M I Z E D
2 to 1
phase I - Schulteis et al. Ann Oncol 2013
Repeat cycles2 until
documented tumor
progression or
unacceptable toxicity or
study withdrawal or
death
Obtain whole blood
sample1 Irinotecan pharmacokinetic
blood samples,
D1–3, cycles 1 and 21
Obtain blood samples on Day 21 cycle
2 and at end of treatment visit for
correlative studies1
R
2nd line FOLFIRI +/- regorafenib 1L Anti VEGF/ Anti EGFR / no targeted Tx: 65% / 8% / 28%
PFS (primary endpoint) 6.5 vs 5.3 mo, p=0.0473
OS: 13.8 vs 11.7 mo (NS)
• Positive Phase 2 study
• Confirms the role of
antiangiogenics in the
2nd-line setting
O’Neil. et al. - ESMO® 2016 - Abs. 464 PD
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22
HR = 0,72
Log-rank test, p=0,473
Pro
gre
ssio
n f
ree
surv
ival
time (months) No. at risk
A 120 102 81 59 40 22 13 11 7 6 2 1
B 61 47 38 22 14 7 3 3 2
2nd line FOLFIRI +/- regorafenib
O’Neil et al, ESMO 2016
PFS OS
Folfiri Regorafenib 6,5 mo 13,8 mo
Folfiri 5,3 mo P = 0,0473 11,7 mo P = NS
Tabernero et al, Lancet 2015
Folfiri Aflibercept 6,9 mo 13,05 mo
Folfiri 4,67 mo P < 0,001 12,06 mo P = 0,0032
Folfiri Ramucirumab 5,7 mo 13,3 mo
Folfiri 4,5 mo P = 0,0005 11,7 mo P = 0,0219
Bennouna et al, Lancet Oncol 2012
Folfiri Bevacizumab (TML) 5,7 mo 11,2 mo
Folfiri 4,1 mo P < 0,0001 9,8 mo P = 0,0062
O’Neil. et al. - ESMO® 2016 - Abs. 464 PD
2+-line Tx
• FOLFIRI can combine with regorafenib, improves ORR, and is
tolerable with a modified regorafenib regimen
• Sorafenib-irinotecan combo: interesting results but what
development in the future?
• TAS 102 confirms its efficacy and good tolerability in Asia
Samalin et al., Kim et al., O’Neil et al ESMO 2016
LUME: NINDETANIB IN LAST-LINE
Negative for OS but positive for PFS???
PFS: 2.60 vs 1.41 mo
HR 0.57, P<0.0001
Investigator assessment
Van Cutsem et al. ESMO 2016
CCTG CO.23: NAPABUCASIN IN LAST-LINE
Negative for all-comers but positive for Stat3+ patients
Jonker et al. ESMO 2016
L2 Phase III ongoing…
Acknowledgments
Julien Taïeb
Publiclin team
Chiara Cremolini Per Pfeiffer
Florence Huguet Jérémie Lefèvre
Marc Peeters Ian Chau
Heinz Joseph Lenz Pierre Laurent-Puig
Volker Heinemann Claus-Henning Khöne
Eric Van Cutsem Ramon Salazar