ASCO Review 2016 Upper GI Cancers

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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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 CRITICS study


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


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


CRITICS Results: Overall survival

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Chemotherapy ChemoXRT 5-year OS (%) 40.8 40.9 Median OS (yrs) 3.5 3.3


Update of the POET phase III study

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Stahl M. J Clin Oncol. 2009;27(6):851;


POET-updated results

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Stahl M. J Clin Oncol. 2009;27(6):851;


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.


§  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


§  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


§  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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Esophageal Cancer

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Study Design

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Results

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PFS OS

9-months OS rate


First line Therapy in EC

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First Line CF

ECF

DCF

EOX FOLFOX

Cis Taxol

FOLFIRI

Cis Iri


§  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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Good response rate: 45-71%

ECF

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Benefit of E unclear Toxicity OS did not seem better than two-drug combinations


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%


DCF

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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


FOLFOX vs ECF

CALGB 80403/ECOG 1206: Enzinger et al; ASCO 2010


§  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


§  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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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


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


FAST trial

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§  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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§  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


§  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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FAST: Results

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FAST: Trial. High CLND18.2 Expressers

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PFS OS


FAST: Toxicity

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§  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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Pancreas cancer: ESPAC4

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§  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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ESPAC 4: Results

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ESPAC 4

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ESPAC 4

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Thank you Questions or comments?

ASCO Review 2016 Upper GI Cancers

Healthcare

Transcript of ASCO Review 2016 Upper GI Cancers