Transcript
Upper GI Cancers Sam Mikhail MD Assistant Professor, Division of Medical Oncology
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Outline
§ Resectable gastric and GE junction cancer § Metastatic gastroesophageal cancer § Novel therapies
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Resectable gastric and esophageal cancer
§ Role of radiation therapy § Should we give radiation postoperative or preoperatively? § What is the optimal chemotherapy regimen?
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The CRITICS study
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Magic versus INT0116
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Surgery ECF ECF
Surgery ChemoXRT
Magic
INT0116
Cunningham D. N Engl J Med. 2006;355(1):11; McDonald JS N Engl J Med. 2001;345(10):725
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CRITICS Trial-Resectable G and GEJ cancer
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ChemoXRT
Surgery
Surgery
EOX or ECX
EOX or ECX
EOX or ECX
R
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 7
≈ 95 % ≈ 50 %
CRITICS Trial- Adherence to treatment
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ChemoXRT
Surgery
Surgery
EOX or ECX
EOX or ECX
EOX or ECX
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CRITICS Results: Overall survival
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Chemotherapy ChemoXRT 5-year OS (%) 40.8 40.9 Median OS (yrs) 3.5 3.3
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Update of the POET phase III study
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Stahl M. J Clin Oncol. 2009;27(6):851;
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
POET-updated results
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Stahl M. J Clin Oncol. 2009;27(6):851;
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The E/GEJ/G landscape
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E/GEJ/G
Treatment naive
PerioperativeECF
G/GEJ
D1 Gastrectomy
Chemo XRT
G
D2 Gastrectomy
CAPOX
E/GEJ
ChemoXRT
Surgery
CLASSIC CROSS INT0116 MAGIC
Cunningham D. N Engl J Med. 2006;355(1):11; McDonald JS N Engl J Med. 2001;345(10):725; Bang YJ Lancet. 2012;379(9813):315; Van Hagen P N Engl J Med. 2012 May;366(22):2074-84.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ POET- neoadjuvant radiation therapy + chemotherapy may improve outcomes in resectable GE cancers
§ ARTIST- Patients with G cancer and D2 gastrectomy randomized to CX
x 6 versus CX x 2 + chemoXRT + CX x 2 § 3 yr DFS (primary endpoint) was not significantly better with chemoXRT
except in node positive disease (76% vs 72%; p=0.004)
Is radiation therapy necessary
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Stahl M. J Clin Oncol. 2009;27(6):851; Park SH. J Clin Oncol. 2015;33(28):3130
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ CALGB 80101 § ECFx1→5-FU chemoXRT→ECFx2 versus § 5-FU x 1 →5-FU chemoXRT →5-FU x 2
§ EOE5 § CF x 2 versus ECX x 4 in resectable E and GE cancer § 3 year survival with CF 39% and with ECX 42%
Should we intensify Chemotherapy?
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0 1 2 3 4 5 6 7
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rvivi
ng
ECF5-FU
Overall Survival by Arm
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ Resectable gastric cancer § Prefer perioperative treatment § If first treatment is D1 gastrectomy→chemoXRT § If first treatment is D2 gastrectomy →chemo only § More is not better
§ Esophageal and GEJ cancer § Prefer neoadjuvant chemoXRT (CROSS trial regimen) § More (Radiation) is better
What does this mean for our patients
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Esophageal Cancer
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Study Design
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Results
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PFS OS
9-months OS rate
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
First line Therapy in EC
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First Line CF
ECF
DCF
EOX FOLFOX
Cis Taxol
FOLFIRI
Cis Iri
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ RR with 5-FU monotherapy=20% § Each additional therapy adds 10% RR § Each additional therapy adds 1 months in OS
Combinations versus monotherapy
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Good response rate: 45-71%
ECF
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Benefit of E unclear Toxicity OS did not seem better than two-drug combinations
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 21
PFS 5.6 m vs 3.7 m 2 yr OS 18% vs 9%
DCF vs CF
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G3/4 Toxicity Neutropenia: 82 vs 57% Complicated neutropenia: 29 versus 12% Stomatitis: 21 vs 27% Diarrhea:19 vs 8 Lethargy: 19 vs14%
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
DCF
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 23
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Good tolerability Long track record in GI cancers OS equal or better than CF PFS may be comparable to ECF
FOLFOX
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No phase III data to compare it against DCF, ECF or EOX
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FOLFOX vs ECF
CALGB 80403/ECOG 1206: Enzinger et al; ASCO 2010
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ 5-FU/Ox=5-FU/Cis § Phase III
§ PFS: 5.8 vs 3.9 m; p=0.77 § OS 10.7 vs 8.8 m; NS § >65 yrs:
§ PFS: 6.0 vs 3.1 months; p=0.029
§ OS: 13.9 versus 7.2 months
FOLFOX vs ECF
§ CX=ECX § Randomized Phase 2
§ RR:38% vs 37% PFS: 6.4 vs 6.5 m
Al-Batran J Clin Oncol. 2008;26(9):1435-42;Yun J Eur J Cancer. 2010;46(5):885-91
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ STOP AND GO approach is not preferred § Maintenance?
What does this mean for our patients?
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Novel therapies
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Immune Therapy in UGI cancers
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Immune therapy
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Abstract Agent setting Tumor type N Efficacy Toxicity
4009 Avelumab Phase IB, Maintenance or 2nd line
G/GEJ 151 RR: 2nd line 18.2% (PD L1+ve)
4010 Nivo +/- Ipi (N3/N1+I3/N3+I1)
I/II E/G/GEJ 160 mOS:5 vs 6.9m vs 4.8 m
G3/4: 5, 35 and 13%
4011 Ipi vs BSC II maintenance s/p 1st line
mG/GEJ 143 irPFS: 2.9 vs 4.9 m; p=0.097
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Immune therapy trials
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Study Agent Phase Tumors Line of therapy Pembrolizumab + Ramucirumab I Gastric, GEJ 2-3 MEDI4736 + Ramucirumab I Gastric, GEJ 2-3
KN-062 Pembrolizumab Pembrolizumab + cisplatin + 5-FU Cisplatin + 5-FU
III Gastric, GEJ 1st
KN-181 Pembrolizumab vs investigator’s choice
III Esophageal, GEJ 2nd
KN-180 Pembrolizumab II Esophageal, GEJ 3rd
KN-061 Pembrolizumab vs paclitaxel III Gastric, GEJ 2nd
MPDL3280A I Solid tumors NA MEDI4736 MEDI4736 + Tremelimumab Tremelimumab
I/II Gastric, GEJ refractory
CM-032 Nivolumab Nivolumab + Ipilimumab
I/II Solid tumors
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FAST trial
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ CKDN 18.2: § Member of the claudin family § Structure component in tight junctions
§ Seals intercellular spaces § Expressed in 70-90% of gastric, pancreatic and bile duct cancers § Not expressed in healthy tissue except for stomach mucosa but not
accessible for antibody
FAST: EOX +/- IMAB362, an anti-CLDN18.2 ab in pts with G and GEJ adenocarcinoma
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ Chimeric IgG1 antibody highly specific to CLDN18.2 § ADCC § CDC § Induced pro-inflammatory cytokines and T-cell infiltration
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FAST: EOX +/- IMAB363, an anti-CLDN18.2 ab in pts with G and GEJ adenocarcinoma
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ Randomized phase II study § Locally advanced or metastatic gastric, esophageal and GEJ
adenocarcinoma § CLDN18.2 positive by IHC (2 or 3+)
Trial Design
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FAST: Results
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FAST: Trial. High CLND18.2 Expressers
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PFS OS
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FAST: Toxicity
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ Phase III study of DHP107 (200 mg/m2 po bid d1, 8 & 15 q4 w) or IV paclitaxel (175 mg/m2 infused d1 q3 w) in the 2nd line setting in 236 pts with mGC
§ mOS (ITT) was 9.7 m for DHP107 vs 8.9 m for paclitaxel (HR = 1.04; 95% CI 0.76–1.41; p = 0.824).
§ ORR was 17.8% for DHP107 vs 25.4% for paclitaxel § Nausea, vomiting, diarrhea and mucositis were more common with
DHP107; peripheral neuropathy was more frequent with paclitaxel
DREAM Study: Oral Paclitaxel
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Pancreas Cancer
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Pancreas cancer: ESPAC4
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
§ Gem 1,000 mg/m2 weekly 3 weeks on/1 week off + capecitabine 1,660 mg/m2/day 3 wks on/1 week off vesus gemcitabine alone
Pancreas Cancer: ESPAC 4 trial
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
ESPAC 4: Results
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
ESPAC 4
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
ESPAC 4
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Thank you Questions or comments?
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