gastric cancer: second and later line therapy · eox xp flo folfiri fufiri s-1 ... p = 0.007 ford h...
TRANSCRIPT
GASTRIC CANCER: Second and Later Line Therapy
David H. Ilson, M.D., Ph.D.
Attending Physician
Memorial Sloan-Kettering Cancer Center
New York
Disclosure
Consulting
– AMGEN
– Bayer
– Lilly/Imclone
– Pieris
– Roche Genentech
– Astra Zeneca
– Bristol Myers Squibb
Esophago-Gastric Cancer: Metastatic Disease
• CIV 5-FU + cisplatin
• 4-5 day 5-FU infusion
• RR 20-30%
• Med S 8-9 months
• Capecitabine = CIV 5-FU, Oxaliplatin = Cisplatin
• Superior toxicity for CRC scheduling (every 2 week schedule)
• 2 Drug regimens preferred
Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use?
Oxali:
EOX or
EOF
Cape:
ECX or EOX XP FLO FOLFIRI FUFIRI
S-1 Cis DCF ECF
Pts 489 513 160 109 209 170 305 221 126
%RR 44% 45% 41% 34% 39% 32% 54% 36% 45%
TTP, months
6.7 6.5 5.6 5.5 5.3 5.0 6.0 5.6 7.4
OS, months
10.9 10.4 10.5 10.7 9.5 9.0 13.0 9.2 8.9
Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol
19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997
Second Line Chemo Gastric Cancer Phase III Trials Improved Survival
Docetaxel
vs
BSC Docetaxel
or
Irinotecan
vs
BSC Paclitaxel
vs
Irinotecan
Patients 84 84 133 69 111 112
RR % 7% -- 13%
17%/10%
-- 21% 14%
PFS 12.2 wks NS NS NS 3.6 mo 2.3 mo
OS 5.2 mo 3.6 mo 5.3 mo
(5.2-6.5)
3.8 mo 9.5 mo 8.4 mo
Significance HR 0.67
P = 0.01
HR 0.657
P = 0.007
Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012 Ueda JCO 31: 4438;
2013
Docetaxel/Irinotecan vs BSC Docetaxel vs BSC
Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012
Second Line Chemo Gastric Cancer Phase III Trials Taxanes or Irinotecan Improve Survival
Targeted Agents
The only success story to date is HER2 and VEGF
The only validated biomarker is HER2
No biomarker selection for VEGF directed therapy
Immunotherapy
– MSI high status
– PDL-1
– Candidate gene signatures
HER2
Trastuzumab has modest first line activity
– TOGA: Cape-Cis + trastuzumab improved RR, PFS, OS
– JACOB: Cape-Cis-Trastuzumab + Pertuzumab Failed--ESMO
Lapatinib failed to improve OS + Cape-Ox first line (LOGIC)
Second line: trastuzumab emtansine (TDM-1) was no better than paclitaxel
Up front and acquired resistance are likely
Bang Lancet 376: 1302; 2010, Hecht JCO 34: 443; 2016, Thuss-PatientceLancet Oncol 18: 540; 2017
2:1 RANDOMIZATION
Locally advanced or
metastatic gastric cancer or
GEJ adenocarcinoma
With disease progression on or after
• 4 months of 1st-line platinum or
fluoropyrimidine-based
chemotherapy or
• 6 months of adjuvant chemotherapy
Second Line, VEGFR2, Ramucirumab: 1000
patients on two multinational, double-blind
phase III trials
©2014 Eli Lilly and Company
REGARD2
Monotherapy plus BSC (n=355)
PRIMARY ENDPOINT:OVERALL SURVIVAL
Ramucirumab**†
+ BSC (n=238)
Placebo + BSC
(n=117)
*8 mg/kg IV every 2 weeks, or placebo, plus PTX (80 mg/m2 days 1, 8, and 15 of a 4-week cycle); no prior paclitaxel use
**8 mg/kg IV every 2 weeks or placebo†Until disease progression, unacceptable toxicity, or death
1:1 RANDOMIZATION
Locally advanced or
metastatic gastric cancer or
GEJ adenocarcinoma
With disease progression on or after
4 months of 1st-line platinum and
fluoropyrimidine-based chemotherapy
No prior paclitaxel use
RAINBOW1
Combination therapy (n=665)
PRIMARY ENDPOINT:OVERALL SURVIVAL
Ramucirumab +
paclitaxel*†
(n=330)
Placebo +
paclitaxel*†
(n=335)
BSC: best supportive care; GEJ: gastroesophageal junction.
1. Wilke H et al. Lancet Oncol 2014;15:1224–1235
2. Fuchs CS et al. Lancet 2014;383:31–39
REGARD: Monotherapy, Progression-free survival
Months
Pro
gre
ssio
n-f
ree s
urv
ival (%
)
1.3 MONTHS
2.1MONTHS
CI: confidence interval; HR: hazard ratio; PFS: progression-free survival.
Fuchs CS et al. Lancet 2014;383:31–39
©2014 Eli Lilly and Company
REGARD: Overall survival
Months
Overa
ll surv
ival (%
)
5.2MONTHS
3.8MONTHS
Overa
ll surv
ival (%
)
CI: confidence interval; HR: hazard ratio; OS: overall survival.
Fuchs CS et al. Lancet 2014;383:31–39
©2014 Eli Lilly and Company
5.2
3.8
5.2
3.6
Ramucirumab vs PBO (BSC)
(N = 355)
Docetaxel vs ASC
(N = 131)
Docetaxel or Irinotecan vs
BSC
(N = 202)
Irinotecan vs BSC
(N = 40)
5.3
Median OS in Randomized Second-Line Gastric Cancer Studies Presented/Published in 2009-2013
Ford HER, et al. The Lancet Oncology. 2014;15(1):78-86.
Kang JH, et al. J Clin Oncol. 2012;30(13):1513-1518.
Thuss-Patience PC, et al. Eur J Cancer. 2011;47(15):2306-2314.
0 1 2 3 4 5 6
Median OS (months) by study arm
Active Treatment BSC
3.8
4.0
2.4
RAINBOW: Paclitaxel + Ramucirumab,
Progression-free survival
Months
Overa
ll surv
ival pro
babili
tyP
rogre
ssio
n-f
ree s
urv
ival (%
)
4.4MONTHS
2.9MONTHS
CI: confidence interval; PBO: placebo; PTX: paclitaxel; RAM: ramucirumab.
Wilke H et al. Lancet Oncol 2014;15:1224–1235
©2014 Eli Lilly and Company
RAINBOW: Overall survival
Months
Overa
ll surv
ival
9.6MONTHS
7.4 MONTHS
CI: confidence interval; PBO: placebo; PTX: paclitaxel; RAM: ramucirumab.
Wilke H et al. Lancet Oncol 2014;15:1224–1235
©2014 Eli Lilly and Company
RAINBOW: Improved tumor response rate
Wilke H et al. Lancet Oncol 2014;15:1224–1235
Disease control:
Ramucirumab + paclitaxel 80%
Placebo + paclitaxel 64% (p<0.0001)
©2014 Eli Lilly and Company
Recent Negative Second Line Trials
DREAM: DHP-107 (Oral Taxane) vs paclitaxel, PFS, 238 pts
GOLD; Paclitaxel + / - PARP Inhibitor Olaparib, OS, 644 pts
– Trend toward improved OS in ATM negative pts
BRIGHTER: Paclitaxel + / - STAT3 inhibitor BBI608
EGFR Inhibition: Irinotecan + / - Nimotuzumab
Ongoing Second or Later Line Trials
TAS102: Placebo vs TAS102 third or later line
Integrate II: Placebo vs Regorafenib third line
Apatinib vs Placebo
Blocking CTLA-4 and PD-1
T cellTumor cell
MHCTCR
PD-L1PD-1
- - -T cell
Dendritic
cell
MHCTCR
CD28
B7 CTLA-4- - -
Activation
(cytokines, lysis, proliferation,
migration to tumor)
B7+++
+++
CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)
anti-CTLA-4anti-PD-1
Tumor Microenvironment
+++
PD-L2PD-1
anti-PD-1
- - -
PD-L1 and PD-L2 Expression Are
Elevated in Gastric Cancer
CIN = chromosome instability; EBV = Epstein-Barr virus; GS = gnomically stable; MSI = microsatellite instability.
Presented with permission from Bass A. Comprehensive molecular characterization of gastric cancer. Presented
at: TCGA Symposium, May 13, 2014.
PD-L2 (PDCD1LG2)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
mR
NA
Ex
pre
ssio
n (
RN
A S
eq
RP
KM
)(lo
g2
)
CIN EBV GS MSI
Molecular Subtype
PD-L1 (CD274)
7
6
5
4
3
2
1
0
mR
NA
Ex
pre
ssio
n (
RN
A S
eq
RP
KM
)(lo
g2
)
CIN EBV GS MSI
Molecular Subtype
Immunotherapy Pivotal Trials
Second or Later Line
– Pembrolizumab vs Paclitaxel (KEYNOTE 61) Failed
– Pembrolizumab vs Physician Choice (KEYNOTE 181)
– Avelumab vs Physician Choice (Javelin 300) Failed
Pembro, Nivo only superior to no therapy and best supportive care
Atezolizumab, Durvalumab / Tremelimumab, phase I-II
Modulation agents: IDO inhibitors, co stimulatory pathways, others + anti PD-1, PD-L1
Gastric Cancer: Summary
Metastatic Disease
– Two drug alternatives (FOLFOX, FOLFIRI, Cape-Cis or Oxali) less toxic
– Second Line: taxane or irinotecan
Targeted therapies
– VEGFR2: Ramucirumab improves outcome second line, alone or with paclitaxel
Paclitaxel + Ramucirumab benchmark 9.6 month OS
Concern about second line paclitaxel alone control arms
– HER2: Trastuzumab emtansine no better than paclitaxel
Genomic data: resistance pathways, networks
Checkpoint Inhibitors: clear signal of activity in late line therapy
– MSI high, PDL-1 positive: U.S. approval for Pembrolizumab
– Checkpoint inhibitors NO BETTER than chemotherapy in second and third line
– IT better only against no therapy