Update on metastatic gastric and esophageal cancers.

Published Ahead of Print on April 27, 2015 as 10.1200/JCO.2014.60.1799 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.60.1799

JOURNAL OF CLINICAL ONCOLOGY

R E V I E W

A R T I C L E

Update on Metastatic Gastric and Esophageal Cancers Manish A. Shah From Weill Cornell Medical College of Cornell University, New YorkPresbyterian Hospital, New York, NY. Published online ahead of print at www.jco.org on April 27, 2015. Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Manish A. Shah, MD, Weill Cornell Medical College/ NewYork-Presbyterian Hospital, 1305 York Ave, 12th Floor, New York, NY 10021; e-mail: [email protected] .edu. © 2015 by American Society of Clinical Oncology

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Cancers of the stomach and esophagus are among the most challenging cancers of the GI tract to treat, associated with poor median survivals for metastatic disease and significant, sometimes prolonged, deteriorations in patient performance status as the diseases progress. However, in the past decade, we have begun to better understand disease biology and carcinogenesis, leading to the identification of subtypes of these diseases. There is also an increasing awareness of the global heterogeneity of disease and its impact on drug development. Our improved understanding of the molecular underpinnings of gastric and esophageal cancers has been accompanied with the development of novel therapeutic strategies. Recent actively investigated targets in this disease include human epidermal growth factor receptor 2, angiogenesis, MET, and immune checkpoint inhibition, with approvals of two new targeted agents, trastuzumab and ramucirumab. Improvements in our ability to deliver cytotoxic therapy, which is better tolerated and allows patients an opportunity to benefit from second- and more advanced lines of therapy, have also been observed. In this review, the current state-of-the-art management of advanced and metastatic gastric and esophageal adenocarcinomas, specifically highlighting the development of targeted therapies in these diseases, is described.

0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.60.1799

J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

INTRODUCTION

Gastroesophageal cancers, combined, are the most prevalent subtype of GI malignancies worldwide. Esophageal cancer is the eighth most common cancer in the world1 and the fifth most common GI cancer in the United States, with an estimated 18,170 new cases and 15,450 deaths in 2013.2 Esophageal cancer histology varies by location, with squamous cell carcinoma (SCC) more prevalent in the upper and middle thirds of the esophagus, and adenocarcinoma more prevalent in the lower third of the esophagus and at the gastroesophageal junction. Worldwide, SCC represents the majority of esophageal cancer cases and is predominant in the highestrisk geographic area, referred to as the esophageal cancer belt, which stretches from the Middle East to central and eastern Asia. In Western countries, there is an increasing incidence of lower esophageal adenocarcinoma accompanied by a decline in SCC, which is attributed to changes in lifestyle, including increasing obesity and the associated gastroesophageal reflux disease. Gastric cancer is a disease of historical significance, tracing through the development of modern civilization.3,4 The first documented cases of gastric cancer date back to 1600 BC, as described in the Ebers Papyrus,3 and Jean Cruveilhier was the first in modern history to anatomically describe the disease

and its natural course. In 1835, Cruveilhier described Napoleon Bonaparte’s medical history, who was thought to have a family history of the disease and reportedly died as a result of gastric cancer in 1821.3,4 Presently, gastric cancer is responsible for approximately 952,000 new diagnoses worldwide (6.8% of new cancer cases worldwide) and 723,000 deaths annually (8.8% of total).5 In 2014, an estimated 22,200 new cases of gastric cancer will have been diagnosed, and approximately 10,990 deaths resulting from this disease will occur in the United States.2 In Europe, gastric cancer ranks fifth, with an estimated 159,900 new cases per year in 2006 and 118,200 deaths (fourth most common cause of cancer-related death).6 Nearly two thirds of all cases globally occur in developing countries in Eastern Europe, South America, and Asia, with 42% of all new cases originating in China alone.7 The majority of newly diagnosed patients with gastric or esophageal cancer will present with locally advanced or metastatic disease. In the United States, the fatality-to-case ratio for gastroesophageal cancers is 0.66,2 suggesting that approximately two thirds of newly diagnosed patients will have metastatic disease at some point during the course of their illness and require systemic therapy. Many drugs are considered active in these diseases, including platinums (eg, cisplatin and oxaliplatin), fluoropyrimidines, irinotecan, taxanes, and targeted therapies © 2015 by American Society of Clinical Oncology

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Manish A. Shah

(eg, trastuzumab and ramucirumab).8 However, despite the many treatment options available, median survival for advanced gastric cancer remains a dismal 8 to 10 months.9,10 In this review, I will focus on the management of advanced gastric and esophageal adenocarcinomas. I hope to convey the fact that we are indeed making progress in our understanding of the underlying biology of these diseases and that this has translated into improved patient outcomes in the advanced setting. GASTRIC CANCER CARCINOGENESIS AND GENOMICS

Gastric cancer is a heterogeneous disease with several established risk factors (as summarized by Shah and Kelsen10; Fig 1). Gastric cancer subtypes (proximal nondiffuse, diffuse, and distal nondiffuse)10 defined by these risk factors have been molecularly classified as unique entities.11 The most relevant hereditable causes of gastric cancer include constitutional mutations in CDH1 (causing hereditary diffuse gastric cancer12) and DNA repair enzyme deficiency in Lynch syndrome.13 Individuals carrying a CDH1 mutation have an 80% lifetime risk of developing gastric cancer and are therefore recommended to undergo a risk-reducing prophylactic gastrectomy.14 However, environmental or modifiable factors are also major contributors to the development of this disease.10,15 For example, in a study of cancer risk in monozygotic and dizygotic twins, the estimated proportion of nonshared environmental factors contributing to gastric cancer risk was 62%, whereas the contribution from heritable risk was estimated to be only 28%.16 The most significant environmental risk factor is infection with Helicobacter pylori, a Gram-negative bacillus identified in 1983 as the pathogen responsible for gastric ulcers and peptic ulcer

Fig 1. Model for gastric cancer carcinogenesis. Risk of developing disease is interplay among environmental, genetic, and behavioral risks. Key environmental risk is chronic infection with Helicobacter pylori, specifically CagA strain. Behavioral risks include dietary factors (eg, salt intake and tobacco use increase risk of developing gastric cancer, whereas fruit and vegetable intake and use of nonsteroidal anti-inflammatory drugs reduce risk). Genetic risk primarily comprising constitutional mutations in CDH1 or mismatch repair deficiency, although other genetic factors that can increase risk of developing gastric cancer include polymorphisms in immune cytokines that modulate infection. IL, interleukin; SNP, single-nucleotide polymorphism. 2

© 2015 by American Society of Clinical Oncology

disease. H pylori is the most common chronic bacterial pathogen in humans,17 with a high prevalence in both developing and industrialized countries. In 1994, the WHO and International Agency for Research on Cancer consensus group classified H pylori as a class I carcinogen.18 The most carcinogenic strains of H pylori carry the cytotoxinassociated gene A (CagA), which encodes for CagA,19 a key regulator of malignant transformation (as summarized by Hatakeyama20; Fig 2). CagA plays a dual role in malignant transformation, both by direct activation of pro-oncogenic signaling mechanisms as well as by generation of genomic instability. On delivery into the cell, CagA localizes to the inner plasma membrane, where it functions as a scaffolding protein and interacts with the SH2 domain– containing protein tyrosine phosphatase (SHP2).21 CagA undergoes tyrosine phosphorylation by Src family and c-Abl kinases.22 Notably, transgenic mice systemically expressing wild-type CagA spontaneously develop GI carcinomas, whereas expression of phosphorylation-resistant CagA fails to induce malignancy.23 Phosphorylation of CagA stabilizes the protein and allows for binding to SHP2 and subsequent activation of the RAS-Erk mitogenic pathway.24 Genes involved in the RAS-Erk signaling pathway include FGFR2, KRAS, EGFR, ERBB2, and MET, which are commonly amplified in gastric cancer and are actively studied targets for drug therapy.8,10 CagA also causes genomic instability by its inhibition of PAR1 activity, which alters mitosis and results in chromosomal instability.25 Finally, sustained activation of nuclear factor ␬B in H pylori–infected mucosal epithelial cells increases DNA methyltransferase levels, which mediate the hypermethylation of numerous genes, including CDH1 as well as genes involved in mismatch repair.26 Notably, both chromosomal instability and mismatch repair gastric cancer phenotypes have been reported as two of the four major gastric cancer subtypes by the Cancer Genome Atlas analysis.27 The other important subtypes of gastric cancer include genomically stable and Epstein-Barr virus (EBV) subtypes of gastric cancer (summarized in Table 1). Each subtype is molecularly unique, with implications for drug development. Gastric cancers with chromosomal instability are associated with TP53 mutation with RTK-RAS activation. The EBV type has a high prevalence (approximately 80%) of mutations in PIK3CA, overexpression of programmed death ligand 1 (PD-L1) and PD-L2, EBV–CpG island methylator phenotype (CIMP) expression, and CDKN2A silencing, as well as altered cytokine signaling. Patients with microsatellite-unstable gastric cancer present at a median age of 72 years, and their tumors exhibit moderate genomic hypermutation, gastric CIMP, MLH1 silencing, and varying mitotic pathways. Finally, the genomically stable gastric cancer subtype is enriched for Lauren’s diffuse histology, CDH1 and RHOA mutations, cell adhesion, and CLDN18-ARHGAP fusion. These new classifications have generated novel concepts for new targets and drug development in this disease.

DISEASE BIOLOGY OF ESOPHAGEAL ADENOCARCINOMA

Adenocarcinomas of the distal esophagus and gastroesophageal junction typically arise from columnar epithelial metaplasia, also known as Barrett esophagus.28 Cigarette smoking, white race, male sex, advanced age, and poor diet are predominant risk factors for adenocarcinoma.29 Conversely, infection with H pylori may lower the risk of disease development, possibly by reducing gastric acid production in JOURNAL OF CLINICAL ONCOLOGY


Update on Metastatic Gastric and Esophageal Cancers

cagA+ H. pylori

CagA

CagA CagA

gastric epithelial cell

P P SHP2

E-cadherin Fig 2. Pro-oncogenic effects of CagA on gastric epithelium. CagA deregulation of SH2 domain–containing protein tyrosine phosphatase (SHP2) activates RAS-Erk signaling, thereby promoting translocation of unbound SHP2 to nucleus. CagA also dissociates ␤-catenin from E-cadherin, thereby promoting its nuclear translocation. SHP2 also dephosphorylates parafibromin (PF), enabling formation of PF/␤-catenin complex, potentiating activation of WNT target genes. Modified with permission.20

Src β-catenin

CagA

β-catenin

SHP2 SHP2

YAP TAZ

SHP2 Ras-Erk signal

Activation

P P PF

PF Wnt signal

β-catenin

Activation

the setting of chronic infection and atrophic gastritis.30 Aneuploidy and p53 loss of heterozygosity are associated with increased risk of progression to high-grade dysplasia and/or adenocarcinoma.31 As expected, there are genetic differences between esophageal adenocarcinoma and SCC. For example, inactivating mutations of NOTCH1 were identified in 21% of SCCs but not in adenocarcinomas.32 In another analysis, esophageal adenocarcinoma was characterized by mutations in TP53, CDKN2A, SMAD4, ARID1A, and PIK3CA, as well as chromatin-modifying factors including SPG20, TLR4, ELMO1, and DOCK2.33 Functional analyses of adenocarcinoma-derived mutations in ELMO1 identified increased cellular invasion, suggesting

the potential activation of the RAC1 pathway as a mechanism of carcinogenesis. Genetic syndromes associated with esophageal cancer are rare.

CYTOTOXIC THERAPY FOR ADVANCED ESOPHAGEAL SCC

There are few data specifically addressing systemic chemotherapy options for SCC of the esophagus. Virtually all of the earlier studies examined the role of chemotherapy (primarily platinum plus fluoropyrimidine– based therapy) with radiotherapy for patients with

Table 1. Gastric Cancer Subtypes Gastric Cancer Subtype EBV

Incidence (%)

Clinical and Pathologic Characteristics

9

Male sex, 81% Predominantly fundus/body Extensive DNA methylation

Microsatellite instability

22

Median age, 72 years Moderate DNA methylation

Chromosomal instability

50

Genomically stable

20

GEJ/cardia Predominantly intestinal Predominantly diffuse Early onset (median age, 59 years)

Molecular Highlights PIK3CA mutation, 80% PD-L1/2 overexpression EBV-CIMP CDKN2A silencing Altered cytokine signaling Hypermutation Gastric-CIMP MLH1 silencing Varying mitotic pathways TP53 RTK-RAS activation CDH1 and RHOA mutations CLDN18-ARHGAP fusion Cell adhesion

NOTE. As defined by Cancer Genome Atlas analysis. This was comprehensive multiplatform analysis of 295 patients who had not received prior chemotherapy or radiotherapy. These four gastric cancer groupings were identified both by unsupervised clustering and integrative clustering analyses. Abbreviations: CIMP, CpG island methylator phenotype; EBV, Epstein-Barr virus; GEJ, gastroesophageal junction; PD-L, programmed death ligand.

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Table 2. Modern Phase III Studies Evaluating Cytotoxic Therapy Study Van Cutsem et al

46

Year

Treatment

No. of Patients

RR (%)

1-Year OS (%)

Median OS (months)

P (for OS difference)

2006

CF DCF DC FLC CF IF FOLFIRI ECX FLC FLO ECF ECX EOF EOX CX CF CS CF Oxaliplatin/S1 CS

224 221 133 137 163 170 207 209 108 112 263 250 245 244 160 156 527 526 318 324

25 37 24.1 24.1 25.8 31.8 39.2 37.8 24.5 34.8 40.7 46.4 42.4 47.9 41 29 29.1 31.9 55.7 85.2

32 40 28 34 31 37 11.2 10.7 40 45 37.7 40.8 40.4 46.8 34 34 NR NR NR NR

8.6 9.2 8.2 9.6 8.7 9.0 9.5 9.7 8.8 10.7 9.9 9.9 9.3 11.2 10.5 9.3 8.6 7.9 14.1 13.1

.02

Ridwelski et al47

2008

Dank et al48

2008

Guimbaud et al49

2014

Al-Batran et al50

2008

Cunningham et al51

2008

Kang et al52

2009

Ajani et al53

2010

Yamada et al54

2014

NS NS NS NS NS NS NS .02 (v ECF) NS NS NS

NOTE. These studies have enrolled ⬎ 3,000 patients in nine trials published since 2006 and have demonstrated modest incremental improvements in patient survival. Abbreviations: CF, cisplatin plus fluorouracil; CS, cisplatin/S1; CX, cisplatin plus capecitabine; DC, docetaxel plus cisplatin; DCF, docetaxel, cisplatin, and fluorouracil; ECF, epirubicin, cisplatin, and fluorouracil; ECX, epirubicin, cisplatin, and capecitabine; EOF, epirubicin, oxaliplatin, and fluorouracil; EOX, epirubicin, oxaliplatin, and capecitabine; FLC, fluorouracil, leucovorin, and cisplatin; FLO, fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, fluorouracil, leucovorin, and irinotecan; IF, irinotecan/fluorouracil; NR, not reported; NS, not significant; OS, overall survival; RR, relative risk.

locally advanced disease. The combination of cisplatin and infusional fluorouracil is the accepted treatment standard for metatastaic SCC of the esophagus, although taxanes and irinotecan are also felt to be active (as reviewed by Ilson34). Oxaliplatin-based therapy has modest reported activity in the metastatic setting,35 although it is considered equivalent to cisplatin, given the equivalence in the locally advanced treatment setting.36 CYTOTOXIC THERAPY FOR ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA

Gastric and esophageal adenocarcinomas are chemotherapy-sensitive diseases, with several active drug therapy classes, including platinum, fluoropyrimidines, topoisomerase inhibitors, taxanes, and anthracyclines. Despite significant differences in epidemiology and molecular characteristics, cytotoxic chemotherapy combinations have not demonstrated significant differences in efficacy across these malignancies.37 However, it is clear that specific targeted agents are likely to have a greater benefit in some disease subtypes compared with others. This will be the challenge of drug development, as we enter the era of targeted therapy in gastroesophageal malignancies. Chemotherapy affords a survival advantage over best supportive care alone in both the first-38-41 and second-line settings.42-44 A metaanalysis of first-line chemotherapy versus best support care studies reported a hazard ratio (HR) of 0.39 (95% CI, 0.28 to 0.52; P ⬍ .001) for overall survival (OS) in favor of chemotherapy, translating to a benefit in weighted median average survival of approximately 6 months.45 The combination of cisplatin and fluorouracil (CF), or a triplet regimen based on this combination, in the first-line setting is a 4


standard practice (Table 2). Oxaliplatin and capecitabine are noninferior to cisplatin and fluorouracil, respectively, with perhaps a more manageable toxicity profile, and both of these agents are now established in combination chemotherapy regimens for metastatic disease.50-52 The addition of docetaxel to cisplatin plus fluorouracil is associated with an incremental OS improvement46; however, this regimen is limited by its significant toxicity.55 Further development of the docetaxel, cisplatin, and fluorouracil regimen is aimed at reducing toxicity without compromising efficacy.56-59 Combination chemotherapy for advanced gastric cancer is associated with rates of response ⱖ 40%, but most patients still have a median survival ⬍ 1 year, and survival ⬎ 2 years is rare. Herein lies the primary rationale to advance the treatment of gastroesophageal malignancies with targeted therapies. Performance status often declines after first-line therapy. Patients with esophageal cancer often have significant comorbidities, including obesity, heart disease, and emphysema, which, when coupled with progressive dysphagia and malnutrition, often limit therapeutic opportunities after first-line therapy. Patients with gastric cancer, particularly those who develop peritoneal carcinomatosis, commonly have early compromise of bowel function, resulting in significant GI symptoms and a decline in functional status, thereby limiting treatment options.9 However, the administration of second-line therapy in appropriate patients is now established as a standard care option, based on three randomized studies, each of which demonstrated a survival advantage with chemotherapy over best supportive care alone.42-44 A metaanalysis of these studies demonstrated an HR for OS of 0.73 (95% CI, 0.58 to 0.96), and in highly functioning patients (performance status, 0 to 1), the HR was 0.57 (95% CI, 0.36 to JOURNAL OF CLINICAL ONCOLOGY



Table 3. Current Studies Evaluating Targeted Therapies in Gastric and Esophageal Cancers Pathway MET

HER2

EGFR Angiogenesis

STAT3 Immune checkpoint

Agent

Clinical Trial

ClinicalTrials.gov Identifier

Line of Therapy

Onartuzumab Rilotumumab AMG337 Pertuzumab T-DM1 Trastuzumab Lapatinib Panitumumab Cetuximab Bevacizumab Ramucirumab Regorafenib Apatinib BBI608 PD-L1 PD-1

MetGastric RILOMET Phase I/II JACOB GATSBY HELOISE LOGIC/TyTAN REAL-3 EXPAND AVAGAST REGARD, RAINBOW INTEGRATE Apatinib BRIGHTER MSB0010718C (phase I) Pembrolizumab (phase I)

NCT01662869 NCT01697072 NCT01253707, NCT02016534 NCT01774786 NCT01641939 NCT01450696 NCT00680901, NCT00486954 NCT00824785 NCT00655876 NCT00548548, NCT00917384, NCT01170663 ACTRN12612000239864 NCT00970138 NCT02178956 NCT01772004 NCT02054806

First First Second/third First Second First First/second First First First Second First Third Second Second/third Second/third

NOTE. More than 5,000 patients have either recently enrolled or are planning to be enrolled onto these diverse global studies. Additional studies are actively being planned. Landscape of our therapeutic options for treatment of advanced disease will certainly change within next decade. Abbreviations: AVAGAST, Avastin in Gastric Cancer; BRIGHTER, BBI608 Plus Weekly Paclitaxel to Treat Gastric and Gastro-Esophageal Junction Cancer; EGFR, epidermal growth factor receptor; EXPAND, Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophago-Gastric Cancer; GATSBY, TDM1 Versus Taxane in Previously Treated Advanced HER2⫹ Gastric Cancer; HELOISE, Herceptin (Trastuzumab) in Combination With Cisplatin/Capecitabine Chemotherapy in Patients With HER2-Positive Metastatic Gastric or Gastro-Esophageal Junction Cancer; HER2, human epidermal growth factor receptor 2; INTEGRATE, Randomized Phase II Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Oesophagogastric Cancer; JACOB, Pertuzumab With Trastuzumab and Chemotherapy in Patients With HER2-Positive Metastatic Gastric or Gastroesophageal Junction Cancer; LOGIC, Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAINBOW, Ramucirumab Plus Paclitaxel Versus Placebo Plus Paclitaxel in Patients With Previously Treated Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma; REAL-3, Randomized Trial of EOC [epirubicin, oxaliplatin, and capecitabine] ⫾ Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer 3; REGARD, Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma; RILOMET, Rilotumumab (AMG102) With Epirubicin, Cisplatin, and Capecitabine (ECX) as First-line Therapy in Advanced MET-Positive Gastric or Gastroesophageal Junction Adenocarcinoma; STAT3, signal transducer and activator of transcription 3; T-DM1, trastuzumab emtansine; TyTAN, Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line Treatment of HER2-Amplified Advanced Gastric Cancer in Asian Populations.

TARGETED THERAPY IN GASTROESOPHAGEAL CANCER

In the last 5 years, we have witnessed the approval of two new drugs, trastuzumab and ramucirumab, for the treatment of advanced or metastatic gastroesophageal adenocarcinoma in the first- and second-line settings. These advances are the harbingers of a new era in the treatment of advanced gastric and esophageal cancers.8 Several thousands of patients have been enrolled (or will be enrolled) onto randomized clinical trials evaluating novel treatments. It is indeed a turning point in the management of this disease, where our understanding of disease biology and the drivers of cancer propagation will be counterbalanced by novel therapeutic strategies that will, it is hoped, significantly improve patient outcomes (Table 3; Fig 3).

transmembrane signaling essential to cellular survival, replication, and proliferation and are critical for malignant transformation and maintaining the malignancy. Receptor ligand binding results in homo- and heterodimerization and tyrosine kinase activation of important oncogenic pathways, including RAS-Raf-MEK/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT.61

Best supportive care

Therapies

0.91), suggesting even a greater improvement in survival with chemotherapy in the second-line setting in patients with a preserved performance status.60

Doublet chemotherapy Triplet chemotherapy Chemotherapy + trastuzumab*

0

2

4

6

8

10

12

14

16

Time (months) HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 AND EPIDERMAL GROWTH FACTOR RECEPTOR

The ErbB family of membrane-associated proteins consists of four members, including human epidermal growth factor receptor 1 (HER1; or epidermal growth factor receptor [EGFR]) and HER2 to HER4 proteins (ErbB2 to ErbB4). These proteins are all involved in www.jco.org

Fig 3. Median overall survival (OS) observed in trials of current therapies in advanced gastric cancer. Best supportive care survival is approximately 3 to 4 months. Cisplatin/fluoropyrimidine-based doublets provide median OS of approximately 8 to 10 months, whereas triplet therapies result in perhaps slightly longer OS, at approximately 10 to 11 months. Survival of patients receiving sequential therapy (ie, doublet ¡ second-line therapy) is not captured in these data. Use of trastuzumab in human epidermal growth factor receptor 2 (HER2) –positive patients is associated with longest median survival. (*) HER2 2⫹/fluorescent in situ hybridization–positive or HER2 3⫹ population.



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Manish A. Shah

The ToGA (Trastuzumab in Combination With Chemotherapy Versus Chemotherapy Alone for Treatment of HER2-Positve Advanced Gastric or Gastro-Oesophageal Junction Cancer) study evaluated trastuzumab, a humanized monoclonal antibody that blocks HER2 activation in combination with capecitabine and cisplatin.62 Median OS improved significantly with the addition of trastuzumab (13.5 v 11.1 months; HR, 0.74; 95% CI, 0.60 to 0.91; P ⫽ .0048), and in the highly HER2 overexpressing population (immunohistochemistry, 2⫹ or 3; fluorescent in situ hybridization positive), the benefit was even greater (OS, 16.1 v 11.8 months; P ⫽ .0046).62 On the basis of this landmark study, trastuzumab in combination with chemotherapy is now the standard for HER2-positive gastric and gastroesophageal junction adenocarcinomas globally. Importantly, for the first time, patients have realized median OS of 16 months (Fig 3). In addition, nonlinear elimination pharmacokinetics were observed for trastuzumab in this study, resulting in higher clearance rates. Approximately one third of patients may have been underdosed, based on inadequate serum trough concentrations ⬍ 20 ␮g/mL.63 This difference from breast cancer is believed to be secondary to a target-mediated clearance that was clinically significant, with patients in the lowest serum trough concentration quartile subgroup having the poorer outcomes.64 The ongoing HELOISE (Herceptin [Trastuzumab] in Combination With Cisplatin/Capecitabine Chemotherapy in Patients With HER2-Positive Metastatic Gastric or Gastro-Esophageal Junction Cancer; ClinicalTrials.gov identifier NCT01450696) study is evaluating a higher trastuzumab dose in patients with a high tumor burden, testing the hypothesis that a higher maintenance dosing regimen of trastuzumab improves OS compared with the standard dosing regimen. Proximal gastric and esophageal tumors and intestinal histology are significantly more prevalently HER2 positive than diffuse gastric cancer,65,66 and the prognostic significance of HER2 expression in gastroesophageal cancer remains a subject of debate.67 Novel strategies to exploit HER2 include the use of antibodydrug conjugates to deliver cytotoxic agents with a high degree of specificity. One such molecule is trastuzumab emtansine (TDM1). This construct links trastuzumab to mytansine, a cytotoxic antimicrotubule macrolide. Its mechanism of action retains the effect of PI3K/AKT disruption as a result of targeted HER2 binding, leading to receptor inactivation by internalization and lysosomal degradation. However, once internalized, T-DM1 catabolites bind to tubulin, preventing polymerization and microtubule dynamic instability.68 With proof of principle in breast cancer,69 T-DM1 is being compared with single-agent taxane in previously treated metastatic gastric cancer (GATSBY [TDM1 vs Taxane in Previously Treated Advanced HER2⫹ Gastric Cancer] study; ClinicalTrials.gov identifier NCT01641939), with results expected in 2015. Pertuzumab represents a new class of monoclonal antibodies, acting independently of trastuzumab by targeting the extracellular dimerization domain, blocking HER2 dimerization.70 Once again, based on success in breast cancer,71 the addition of pertuzumab to trastuzumab and cisplatin plus capecitabine is being evaluated in the first-line setting in HER2-positive gastric cancer (JACOB [Pertuzumab With Trastuzumab and Chemotherapy in Patients With HER2-Positive Metastatic Gastric or Gastroesophageal Junction Cancer] study; ClinicalTrials.gov identifier NCT01774786). Lapatinib has been examined in both the first(LOGIC [Lapatinib Optimization Study in ErbB2 (HER2) Positive 6


Gastric Cancer] study72) and second-line settings (TyTAN [Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line Treatment of HER2-Amplified Advanced Gastric Cancer in Asian Populations] study73); in neither did patient survival improve in the intent-to-treat study populations. Antibody inhibitors of EGFR (cetuximab and panitumumab) have been evaluated in gastroesophageal cancers as well in the REAL-3 (Randomized Trial of EOC [epirubicin, oxaliplatin, and capecitabine] ⫾ Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer 3)74 and EXPAND (Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophagogastric Cancer; cisplatin and capecitabine ⫾ cetuximab) studies.75 Both studies failed to demonstrate a survival advantage in an unselected patient population, and in the REAL-3 study, inferior survival was noted with the addition of anti-EGFR therapy (OS, 8.8 v 11.3 months; P ⫽ .013), possibly because of dose reductions in the concomitant cytotoxic therapy.74 The REAL-3 study demonstrates that the backbone chemotherapy regimen can significantly affect the efficacy of a particular regimen when combined with a targeted agent. Furthermore, the need for an effective biomarker is necessary to resurrect the development of EGFR inhibition in gastroesophageal cancers.

TARGETING ANGIOGENESIS

Angiogenesis, which is the formation of blood vessels, is a complex process involving numerous pathways and receptors essential for growth of solid tumor malignancies, including tumor proliferation and the development of vascular metastases. Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases are key components of cancer angiogenesis. The VEGF family consists of VEGF-A to -E and placental growth factors 1 and 2. Because of differential premRNA splicing, the single VEGF gene gives rise to several isoforms of VEGF-A.76 VEGF-A is a major regulator of angiogenesis that binds to and activates both of the VEGF receptor (VEGFR) tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR1 is expressed on endothelial and myeloid cells and promotes tumor growth and the formation of metastases, as well as inflammation. VEGFR-2 is responsible for neoangiogenesis, particularly in relation to cancer.77 Ramucirumab is a fully human immunoglobulin (Ig) G1 monoclonal antibody targeting VEGFR-2 and has demonstrated improved survival both as monotherapy (REGARD [Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma] study78) and in combination with paclitaxel (RAINBOW [Ramucirumab Plus Paclitaxel Versus Placebo Plus Paclitaxel in Patients With Previously Treated Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma] study79) in the second-line setting. Both the REGARD and RAINBOW studies were well designed and well performed. REGARD was a double-blind, placebo-controlled trial randomly assigning 355 patients at a two-to-one ratio to receive ramucirumab (n ⫽ 238) or placebo (n ⫽ 117). Patients receiving ramucirumab had a significantly improved survival, with an HR of 0.78 (95% CI, 0.603 to 0.998; P ⫽ .047). RAINBOW was a larger study, randomly assigning 665 patients at a one-to-one ratio to receive paclitaxel with or without ramucirumab; it demonstrated an HR of 0.81, with an associated median survival of 9.6 months with the addition of ramucirumab to paclitaxel JOURNAL OF CLINICAL ONCOLOGY



and 7.4 months with paclitaxel alone (P ⫽ .017). Progression-free survival (PFS) was also improved, with a highly significant HR of 0.635 (P ⬍ .001; PFS: ramucirumab plus paclitaxel, 4.4 months v paclitaxel alone,2.9months).79 Notably,ramicirumabwasevaluatedinthefirst-line setting in gastroesophageal adenocarcinoma and did not demonstrate improvedPFS,perhapsbecauseofdifferentialactivitybetweenesophageal and gastric cancers.80 Other antiangiogenic studies have been examined in gastric and gastroesopahgeal cancers. Apatinib is an oral small-molecule inhibitor of VEGFR-2 and was examined in a phase III study with two-to-one random assignment of patients to apatinib versus placebo in the thirdline setting; a total of 270 patients were enrolled. The study demonstrated an improvement in OS with apatinib, similar to that with ramucirumab (HR, 0.71; 95% CI, 0.54 to 0.94; P ⬍ .016).81 Also of relevance is the AVAGAST (Avastin in Gastric Cancer) study, the first phase III study to test the paradigm of antiangiogenic therapy in gastric and gastroesophageal cancers. The AVAGAST study was a large, international randomized phase III study of first-line chemotherapy with or without bevacizumab, an antibody inhibitor of VEGF, in advanced gastric cancer.82 Although the study was negative (median survival, 12.1 v 10.1 months; HR, 0.87; P ⫽ .1), there was some evidence of improved efficacy with the addition of antiangiogenic therapy. Patients randomly assigned to receive chemotherapy with bevacizumab had a significantly improved PFS (6.7 v 5.3 months; HR, 0.80; P ⫽ .0032) and response rates. Global disease heterogeneity was possibly responsible for the negative primary outcome of the AVAGAST study when compared with the previous phase II studies. Specifically, preplanned sensitivity analyses suggested regional differences in the extent of benefit with bevacizumab in combination with chemotherapy, with the greatest benefit seeming to be in North America, South America, and Europe (v Asia).83 Importantly, two candidate biomarkers were identified—plasma VEGF-A and neuropilin 1—from the comprehensive biomarker companion study of the AVAGAST trial. Specifically, improved patient survival was suggested in patients with plasma VEGF-A levels ⬎ the median (HR, 0.72; 95% CI, 0.57 to 0.93), or neuropilin 1 expression ⬍ the median (HR, 0.75; 95% CI, 0.59 to 0.97).84 Together, based on these studies, antiangiogenic therapy is another validated target in the management of advanced gastric and gastroesophageal junction adenocarcinomas.

IMMUNE CHECKPOINT INHIBITION

It has become clear that cancers are recognized by the immune system, which can suppress and even eliminate malignant clones, resulting in substantial patient benefit and perhaps even long-term response. There is emerging evidence that immunosurveillance is significantly altered in gastroesophageal malignancies.85-87 PD-L1 is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prevention of autoimmunity.88 Engagement of PD-L1 on dendritic cells with the programmed death 1 (PD-1) receptor on T cells delivers an inhibitory signal that promotes T-cell anergy or apoptosis.89 Tumor cells often overexpress PD-L1 (or PD-L2), resulting in T-cell anergy and escape from immunosurveillance. Blockade of the interaction between PD-L1 or PD-L2 on tumor cells and PD-1 on T cells reverses T-cell suppression within tumors, thereby promoting effective antitumor immune responses. In esophwww.jco.org

ageal cancer, tumor-infiltrating lymphocytes correlated with improved survival,86,87 and expression of PD-L1 and PD-L2 was associated with poor survival in esophageal carcinoma.85,86 Notably, 43% of esophageal SCCs and 70% of esophageal adenocarcinomas express PD-L1,86 and its expression is independently associated with worse survival.85 There has been early demonstration of activity of PD-1 and anti–PD-L1 antibody immune checkpoint inhibitors in upper GI malignancies. Modest activity has been demonstrated with the PD-L1 antibody MEDI14736 in advanced gastric cancer.90 Pembrolizumab is a highly selective, humanized monoclonal IgG4␬ isotype antibody against PD-1 that successfully blocks the negative regulatory signaling of the PD-1 receptor expressed on T cells91 and received US Food and Drug Administration approval in September 2014 for its activity in melanoma.92 Pembrolizumab also seems to have substantial activity in patients with advanced gastric cancer expressing PD-L1, as reported at the European Society for Medical Oncology 2014 meeting.93 Of the 39 patients enrolled, 19 were from the Asia-Pacific region, and 20 were from other areas of the world. At a median follow-up of approximately 6 months, the overall response rate was 31% (Asians, 31.6%; nonAsians, 30%), suggesting activity of this novel strategy to inhibit the immune checkpoint.

MET AND HEPATOCYTE GROWTH FACTOR

The MET receptor signaling pathway is essential during embryogenesis in the regulation of cell survival and distant migration of epithelial and myogenic precursors cells. Aberrant MET activation in malignant tumors such as renal or upper GI carcinomas occurs through receptor overexpression, upregulation of stromal ligand production of hepatocyte growth factor (HGF; or scatter factor), and gene amplification.94 Intracellular signaling pathways activated by MET include the PI3KAKT and RAS-MAPK pathways. Activation of the MET pathway results in stimulation of cell-cell detachment, migration, and invasion.95 MET also interacts with EGFR family receptor tyrosine kinases, including EGFR. In preclinical models, cells expressing both HER2 and MET demonstrated ligand-independent MET phosphorylation and downstream signaling activation via HER2 signaling.96 MET is amplified in approximately 2% to 10% of gastric adenocarcinomas and is associated with depth of tumor invasion, lymph node metastasis, and unfavorable prognosis.95,97 A much higher percentage (40% to 50%) of gastric adenocarcinomas stain positively for MET by immunohistochemistry. It is unclear at the current time which of these two biomarkers is the better predictor of response to MET-targeted therapy. Two agents targeting MET signaling in advanced gastric cancer (rilotumumab and onartuzumab) are currently in phase III trials for the treatment of advanced gastric cancer. Rilotumumab is a fully humanized IgG2 monoclonal antibody against HGF; it recently demonstrated encouraging activity in an early-phase clinical trial.98 Patients randomly assigned to rilotumumab plus chemotherapy (epirubicin, cisplatin, and capecitabine) had a significantly improved PFS, with an HR of 0.60 (80% CI, 0.45 to 0.79; P ⫽ .016).98 In this prospective study, patients who were MET positive and randomly assigned to placebo and chemotherapy had a median OS of 5.7 months, confirming the earlier studies suggesting that MET activation is an important adverse prognostic factor for gastroesophageal © 2015 by American Society of Clinical Oncology


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malignancies. Rilotumumab is under phase III evaluation with epirubicin, cisplatin, and capecitabine in the first-line setting (RILOMET-1 [Rilotumumab (AMG102) With Epirubicin, Cisplatin, and Capecitabine (ECX) as First-line Therapy in Advanced MET-Positive Gastric or Gastroesophageal Junction Adenocarcinoma]; ClinicalTrials .gov identifier NCT01697072), with results expected in 2015. Onartuzumab is a monoclonal antibody that binds the MET receptor, preventing HGF binding and receptor activation. It is unique in that it is the first monovalent antibody examined as an anticancer agent, because divalent antibodies to MET activate the receptor.99 Initial clinical activity in non–small-cell lung cancer was quite encouraging,100 leading to registration studies across multiple malignancies. The phase III MetGastric trial (ClinicalTrials.gov identifier NCT01590719) enrolled patients with previously untreated HER2negative and MET-positive metastatic gastric adenocarcinomas to receive modified FOLFOX6 (infusional fluorouracil, leucovorin, and oxaliplatin) plus onartuzmab or placebo, with results expected in 2015.

FUTURE DIRECTIONS

We are entering a transformative era in the management of advanced and metastatic gastric and esophageal adenocarcinomas. Historically, these diseases have been among the most difficult to manage in oncology, with low median survivals and prolonged deteriorations in quality of life as the diseases move forward. Drug development has been a challenge, with the recognition of the impact of global disease heterogeneity. However, current combination cytotoxic regimens are easier to administer and are more tolerable, resulting in improved outcomes. Long-term survivors are rare but possible, and many studies have REFERENCES 1. Pennathur A, Gibson MK, Jobe BA, et al: Oesophageal carcinoma. Lancet 381:400-412, 2013 2. Siegel R, Ma J, Zou Z, et al: Cancer statistics, 2014. CA Cancer J Clin 64:9-29, 2014 3. Santoro E: The history of gastric cancer: Legends and chronicles. Gastric Cancer 8:71-74, 2005 4. Guggenheim DE, Shah MA: Gastric cancer epidemiology and risk factors. J Surg Oncol 107: 230-236, 2013 5. Ferlay J, Soerjomataram I, Ervik M, et al: GLOBOCAN 2012 v1.0: Cancer incidence and mortality worldwide—IARC CancerBase No. 11. http:// globocan.iarc.fr 6. Jackson C, Cunningham D, Oliveira J, et al: Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20: iv34-iv36, 2009 (suppl 4) 7. Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin 61:69-90, 2011 8. Shah MA: Gastrointestinal cancer: Targeted therapies in gastric cancer—The dawn of a new era. Nat Rev Clin Oncol 11:10-11, 2014 9. Power DG, Kelsen DP, Shah MA: Advanced gastric cancer: Slow but steady progress. Cancer Treat Rev 36:384-392, 2010 10. Shah MA, Kelsen DP: Gastric cancer: A primer on the epidemiology and biology of the disease and an overview of the medical manage8


reported 15% to 20% of patients alive with metastatic disease for ⱖ 2 years. Chemotherapy treatment after progression with first-line therapy is feasible, with response rates similar to those seen in other solid tumor malignancies, and randomized studies support its use as standard practice in appropriate patients. Most importantly, with our improved understanding of disease biology, we have begun to appreciate that cancers of the stomach and esophagus are not identical. Although long recognized as histologically distinct, diffuse gastric cancer has been unequivocally distinguished from intestinal gastric cancer at the molecular level, and proximal and distal gastric cancers have also been found to be molecularly unique. These distinctions may not be important when using a blunt therapeutic instrument such as chemotherapy (which kills indiscriminately, mostly based on cellular division); however, the diagnostic precision will undoubtedly be increasingly relevant as we enter the era of targeted therapies for gastroesophageal malignancies. The integration of targeted therapy, especially antiangiogenic and antiHER2 therapy, has demonstrated encouraging results in phase II and III studies, respectively. Definitive large multicentered randomized trials will further define the role of targeted agents combined with chemotherapy. In the face of a still tragic disease, the evolution of treatments and our improved understanding of the biologic basis of the disease serve as sources of optimism. Much work is still required, but the horizon for the treatment of gastric and esophageal cancers has certainly never been brighter. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the author are available with this article at www.jco.org.

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cancer and adenocarcinoma of the gastroesophageal junction: Results of a phase II trial. Ann Oncol 18:1673-1679, 2007 57. Al-Batran SE, Hartmann JT, Hofheinz R, et al: Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: A phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 19:1882-1887, 2008 58. Tebbutt NC, Cummins MM, Sourjina T, et al: Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: The AGITG ATTAX trial. Br J Cancer 102:475-481, 2010 59. Shah MA, Stoller R, Shibata S, et al: Random assignment multicenter phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF) versus DCF with growth factor support (GCSF) in metastatic gastroesophageal adenocarcinoma (GE). J Clin Oncol 28:304s, 2010 (suppl; abstr 4014) 60. Iacovelli R, Pietrantonio F, Farcomeni A, et al: Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer. A systemic review and meta-analysis of published studies. PLoS One 9:e108940, 2014 61. Karamouzis MV, Grandis JR, Argiris A: Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 298: 70-82, 2007 62. Bang YJ, Kim YW, Yang HK, et al: Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial. Lancet 379:315-321, 2012 63. Hofmann M, Stoss O, Shi D, et al: Assessment of a HER2 scoring system for gastric cancer: Results from a validation study. Histopathology 52: 797-805, 2008 64. Kyi C, Shah MA: A case report of trastuzumab dose in gastric cancer. J Gastrointest Oncol 4:E19-E22, 2013 65. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of Her2positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010 66. Rüschoff J, Dietel M, Baretton G, et al: HER2 diagnostics in gastric cancer: Guideline validation and development of standarized immunohistochemical testing. Virchows Arch 457:299-307, 2010 67. Tafe LJ, Janjigian YY, Zaidinski M, et al: Human epidermal growth factor receptor 2 testing in gastroesophageal cancer: Correlation between immunohistochemistry and fluorescence in situ hybridization. Arch Pathol Lab Med 135:1460-1465, 2011 68. LoRusso PM, Weiss D, Guardino E, et al: Trastuzumab emtansine: A unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 17:6437-6447, 2011 69. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER-2 positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012 70. Lynce F, Swain SM: Pertuzumab for the treatment of breast cancer. Cancer Invest 32:430438, 2014 71. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2positive metastatic breast cancer (CLEOPATRA Study): Overall survival results from a randomized,



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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Update on Metastatic Gastric and Esophageal Cancers The following represents disclosure information provided by author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Manish A. Shah Research Funding: sanofi-aventis (Inst)

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