targeted therapies in gastroesophageal malignancies dawn of a new era manish a. shah, md associate...
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Targeted therapies in Gastroesophageal Malignancies
Dawn of a new era
Manish A. Shah, MD
Associate Professor of Medicine
Weill Cornell Medical College of Cornell University
New York-Presbyterian Hospital
Director, Gastrointestinal Oncology
Center for Advanced Digestive Care
Objectives
Discussion of abstracts:
• LBA6 – Suntharalingam and colleagues• RTOG 0436 – phase III study of chemo/RT (cisplatin
and paclitaxel) with and without cetuximab for esophageal cancer treated without surgery
• LBA7 – Wilke and colleauges: • RAINBOW – phase III study of paclitaxel with or without
ramucirumab in 2nd line gastric/GEJ adenocarcinoma
The Initial Report of RTOG 0436: A Phase III Trial evaluating the addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients with Esophageal Cancer Treated
without Surgery
Suntharalingam M, Winter K, Ilson D, Dicker A, Kachnic L, Konski A, Chakravarthy B, Anker C, Thakrar
H, Horiba N, Kavadi V, Deutsch M, Raben A, Roof K,Videdic G, Pollock J, Crane C
Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA
• Why paclitaxel / Cisplatin?
Ajani J A et al. RTOG 0113: Phase II randomized trial of two nonoperative regimens of chemoradiation in localized esophageal CA. JCO 2008;26:4551-4556
Cisplatin + Paclitaxel with radiation was equivalent to cisplatin/FU + radiation, but with less toxicity.
(enrollment 2001-2005)
Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA
• Context in the CROSS preoperative studyEligibility: T1N1 – T2-3Nx (stage 1-3)Treatment: Radiation 4140 cGy + weekly taxol (50 mg/m2) and
Carboplatin (AUC 2)
van Hagen P et al. Preoperative chemoradiotheapy for esophageal or junctional cancer. NEJM 2012;366:2074-84.
• Why cetuximab?– Cetuximab: a chimeric (mouse/human) monoclonal
antibody against epidermal growth factor receptor (EGFR)
– EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer
– EGFR expression correlates with prognosis in esophagogastric ACA and SCC
– KRAS mutations occur in ~2% (0-9%) of esophageal cancers
Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006
Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA
Ove
rall
Sur
viva
l (%
)
0
25
50
75
100
Months from Randomization0 3 6 9 12 15 18 21 24
Patients at RiskRT+Chemo+CetuxRT+Chemo
159169
139158
124141
108121
94102
8283
6568
5454
5149
Failed97110
Total159169
Stratified log-rank p-value = 0.70
HR= 0.92 (0.70,1.21)RT+Chemo+CetuxRT+Chemo
RTOG 0436: Overall Survival
Median follow-up for alive patients = 24.3 months (0.1-60.7)
(n=328)
2-Year Rates:
44.0%
41.7%
• Well designed and performed study,
• Reasonable stratification
• No survival difference
Comment• Cetuximab does not improve survival or response
when combined with chemotherapy for localized unresectable esophageal cancer.
• Consistent with previous results in metastatic disease.
Comment• Cetuximab does not improve survival or response
when combined with chemotherapy for localized unresectable esophageal cancer.
• Consistent with previous results in metastatic disease.
• These data are definitive.
• Would the results be different in a pre-operative setting. Likely not!
Comment
• Why didn’t this work? (now or previously)Are esophageal cancers driven by EGFR signaling?
Dulak AM et al. Whole-exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45(5):478-=86.
TP53CDKN2AEYSARID1ASMAD4PIC3CA
EGFR mutations did not occur as top mutations. But it is more complicated –EGFR amplification did occur frequently.
Comment• What have we learned?
• Clinical response to chemo/RT is prognostic.
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Months from Randomization0 3 6 9 12 15 18 21 24
Patients at RiskcCRResidual Disease
10485
10479
9871
8759
7649
6541
5234
4427
4024
Failed6162
Total10485 HR= 1.59 (1.11,2.26)
cCRResidual Disease
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Months from Randomization0 3 6 9 12 15 18 21 24
Patients at RiskcCRResidual Disease
7043
7034
6225
5619
5116
4512
387
307
297
Failed2835
Total7043 HR= 3.67 (2.22,6.07)
cCRResidual Disease
Implications:
Our best approach to improving survival in this disease is to improve response to therapy.
– PET directed therapy
CALGB 80803: PET directed chemo + chemo/RT
– Targeted therapy
RTOG 1010: Trastuzumab with chemo/RT
– Improve our understanding of tumor biology
RTOG 0436: 85% tissue collected
RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PAC) Versus Placebo
and PAC in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy
H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky,
Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe
Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro
*On behalf of the RAINBOW Investigators
LBA7
Treat until disease
progression or
intolerable toxicity
• Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1st line platinum/fluoropyrimidine based chemotherapy• Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycleN = 330
Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
SCREEN
RANDOMIZE
Survival and safety
follow-up
RAINBOW: Study Design
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
1:1
RAINBOW: Overall Survival
0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM+PAC
PBO+PAC
Months
Ove
rall
Su
rviv
al P
rob
ab
ility
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PAC PBO + PACPatients / Events 330 / 256 335 / 260Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31,
8.38) 6-month OS 72% 57%12-month OS 40% 30%
RAM + PAC 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0PBO + PAC 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
Δ mOS = 2.3 months
Comment
• Well performed international study – kudos to the investigators and to Lilly.
• Why did it work?
AvagastOverall Survival : Cis/Cape +/- Bevacizumab
XP + Placebo
XP + Bev
HR = 0.87
95% CI 0.73–1.03
p = 0.1002
Survival rate
3 9 15 18 21 240
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
6 12
Study month
10.1
12.1
Bevacizumab plus CT for Advanced Gastroesophageal Adenocarcinoma (GC): Combined U.S. experience*
Smyth, et al. ASCO 2011 (Abstract 4056)
Tumor Characteristics
US cohortAVAGAST
Chemo + Bev arm p value
n % n %
Site
Gastric 64 (41) 333 (86)
<0.0001GEJ 92 (59) 54 (14)
Lauren's Classification*
Diffuse 42 (27) 176 (46)
<0.0001**Intestinal 81 (52) 155 (40)
Mixed 35 (9)
Not reported 33 (21)
Liver metastasis 81 (52) 130 (34) <0.0001
*Data from 4 investigator initiated U.S. phase II studies of chemotherapy plus bevacizumab for the treatment of metastatic/unresectable gastric cancer were pooled. Sites involved were: 1) Memorial Sloan-Kettering Cancer Center, 2) Dana-Farber/Harvard Cancer Center, 3)Yale Cancer Center, and 4) Stanford Comprehensive Cancer Center.
Patient characteristics by region AVAGAST Study
Characteristic, % Asia Europe Pan-America
Age <65 72 68 77
≥65 28 32 23
ECOG PS 0–1 97 91 96
≥2 3 9 4
Primary site Stomach 94 78 84
GEJ 6 22 16
Disease status Metastatic 99 95 92
Locally advanced 1 5 8
Prior gastrectomy Yes 32 23 27
No 68 77 73
Measurable lesion Yes 73 88 77
No 27 12 23
Liver metastasis Yes 27 37 42
No 73 63 58
*1 additional patient had an ECOG PS of 4 There was an imbalance of >10% between the regions
Avagast vs. RamicirumabAvagast Rainbow
Study Design 1st line 2nd line
Backbone chemotherapy
Cisplatin/ capecitabine Paclitaxel
Demographics N = 774 N = 665
Asia 376 (49%) 223 (33.5%)
Non-Asia 398 (51%) 442 (66.5%)
Results OS
Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)
10.5 12.1 moHR 0.99 (0.73-1.34)
Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)
5.9 8.5 moHR 0.73 (0.59-0.91)
Results PFS
Asia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)
Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)
Pan-America 4.4 5.9 (HR 0.65)
Avagast vs. RamicirumabAvagast Rainbow
Study Design 1st line 2nd line
Backbone chemotherapy
Cisplatin/ capecitabine Paclitaxel
Demographics N = 774 N = 665
Asia 376 (49%) 223 (33.5%)
Non-Asia 398 (51%) 442 (66.5%)
Results OS
Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)
10.5 12.1 moHR 0.99 (0.73-1.34)
Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)
5.9 8.5 moHR 0.73 (0.59-0.91)
Results PFS
Asia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)
Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)
Pan-America 4.4 5.9 (HR 0.65)
Avagast vs. RamicirumabAvagast Rainbow
Study Design 1st line 2nd line
Backbone chemotherapy
Cisplatin/ capecitabine Paclitaxel
Demographics N = 774 N = 665
Asia 376 (49%) 223 (33.5%)
Non-Asia 398 (51%) 442 (66.5%)
Results OS
Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)
10.5 12.1 moHR 0.99 (0.73-1.34)
Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)
5.9 8.5 moHR 0.73 (0.59-0.91)
Results PFS
Asia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)
Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)
Pan-America 4.4 5.9 (HR 0.65)
Biomarkers- pVEGFA and NRPCandidate Biomarkers for Bevacizumab Efficacy in Gastric Cancer
Van Cutsem E [Shah MA]. JCO 2012;30:2119-2127
Implications
• Targeting the angiogenesis pathway in gastric/ GEJ adenocarcinoma is now validated
• Ramicirumab + paclitaxel is a viable, safe, effective treatment option following 1st line therapy.
• Is VEGFR2 specific inhibition any different than blocking VEGF-A?
What have we learned• Disease biology is important, as shown by
gastric cancer heterogeneity.
Genetic Risk
Environment
Behavior
Family History:CDH1MMRAPCTP53
H. Pylori cag A strain
Tobacco use/ diet (salt) (fruits/vegetables)
Immune SNPsIL1, IL4, etc.
Proximal non
diffuse
Gastric
Cancer
Distal non
diffuse
Gastric CA
Diffuse Gastric CA
Are we at the Dawn of a new era?
Pathway Agent Clinical Trial Randomization Patients
METOrnartuzumab METGASTRIC
FOLFOX +/- ornatuzumab 800
Rilotumumab RILOMET ECX +/- rilotumumab 450
HER2
Pertuzumab JACOB XP-T +/- pertuzumab 780
Trastuzumab HELOISEXP-T (standard) vs.
XP-T (high dose) 400
TDM-1 GATSBYTDM-1 vs taxane
(2nd line) 412
Lapatinib TyTANPaclitaxel +/- lapatinib
(2nd line) 261
EGFRPanitumumab REAL-3 EOX +/- panitumuamb 574
Cetuximab EXPAND XP +/- cetuximab 904
Angiogenesis
Ramucirumab REGARDRamucirumab vs. BSC
(2nd line) 355
Ramicirumab RAINBOWPaclitaxel +/-
Ramucirumab (2nd line) 665
Regorafenib INTEGRATERegorafenib vs BSC
(2nd line) 150
Targeted Successes
Target Study Setting Clinical Benefit
HER2 TOGA 1st line HER2 positive
HR 0.74 (2.7 month)
VEGFR2 REGARD 2nd line monotherapy
HR 0.78 (1.4 month)
RAINBOW 2nd line combination
HR 0.81 (2.3 month)
Dawn of …. more of the same?Target Study Why does it work? Why does it not?
HER2 TOGA HER2 drives tumor growth and proliferation
?
VEGFR2 REGARD Blocks VEGFR2 ?
RAINBOW Blocks VEGFR2 ?
Angiogenesis Bevacizumab Inhibits VEGF-A ?
Mictrotubules Taxanes Arrests cell division
?
DNA Synthesis Fluoropyrimidines Stops DNA /RNA synthesis
?
DNA Damage Platinum Accumulation of DNA damage
?
We are in a New Era !
• Greater emphasis on obtaining tissue and biospecimens
• Greater tools at our disposal– [put your – omic here]
Focus our efforts on understanding how therapy works understanding why therapy doesn’t work why therapy stops working