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Phase II Trial of Erlotinib in Gastroesophageal Junction and Gastric Adenocarcinomas: SWOG 0127

Tomislav Dragovich, Sheryl McCoy, Cecilia M. Fenoglio-Preiser, Jiang Wang, Jacqueline K. Benedetti, Amanda F. Baker, Christopher B. Hackett, Susan G. Urba, Ken S. Zaner, Charles D. Blanke, James L. Abbruzzese

From the University of Arizona Cancer Center, Tucson, AZ; Southwest Oncology Group Statistical Center, Seattle, WA; University of Cincinnati Medical Center, Cincinnati, OH; University of Michigan, Ann Arbor, MI; Boston University Medical Center, Boston, MA; OR Health & Science University Cancer Institute, Portland, OR; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Tomislav Dragovich, MD, PhD, Arizona Cancer Center, 1515 N Campbell Avenue, PO Box 245024, Tucson, AZ 85724; e-mail: tdragovich{at}azcc.arizona.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas.

PATIENTS AND METHODS: Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ—63 years, ST—64 years; sex, GEJ—84% male and 16% female, ST—60 male and 40 female; Zubrod PS, GEJ—25 had a PS of 0 and 18 had a PS 1, ST—13 had a PS of 0 and 12 had a PS of 1.

RESULTS: Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor–alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization.

CONCLUSION: Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Gastric and esophageal cancers are among leading causes of cancer-related death world wide, responsible for more than 1,100,000 deaths annually.¹ In the last three decades, the United States and some Western nations witnessed a relative increase in the incidence of adenocarcinomas of the gastroesophageal junction (GEJ) and gastric cardia.²

Although many single agents lead to responses in 10% to 20% of patients, combination regimens are associated with higher response rates and longer survivals.³ Triple-combination regimens such as ECF (epirubucin, cisplatin, fluorouracil) or DCF/TCF (docetaxel, cisplatin, fluorouracil) represent the most active front-line therapies for metastatic gastric cancer.^4,5 Even with such aggressive regimens, the median survival does not reach 12 months, and treatment is often associated with significant toxicity. Despite emerging evidence that adenocarcinomas of distal esophagus and cardia (GEJ) have different clinicopathologic features as compared with distal gastric cancers, the chemotherapy approaches remain similar for both entities.⁶

Epidermal growth factor receptor (EGFR) signaling is critical for cancer cell proliferation, invasion, metastasis, and resistance to apoptosis.⁷ EGFR is overexpressed in many epithelial malignancies and therefore makes an attractive therapeutic target.⁸ An anti-EGFR monoclonal antibody is in use for treatment of refractory colorectal cancer⁹ and EGFR tyrosine kinase inhibitor erlotinib is now approved for treatment of non–small-cell lung cancer and pancreatic cancer in the United States^10,11

Erlotinib hydrochloride (erlotinib) ([6,7-bis(2-methoxy-ethoxy)-quinazolin-4–yl]–[3-ethylphenyl]amine; formerly CP-358,774) is a small-molecule, orally available reversible inhibitor of the adenosine triphosphate binding site of EGFR receptor tyrosine kinase.¹² Erlotinib was tested in epithelial malignancies such as non–small-cell lung, head and neck, hepatocellular, and pancreatic cancer.^10,11,13,14 The dose-limiting toxicities associated with erlotinib administration are skin rash and diarrhea. In a phase I study, the maximum-tolerated dose was achieved at 150 mg daily dose of erlotinib administered continuously.¹⁵

Expression of EGFR (HER1) has been detected by immunocytochemistry in more than 70% of GE cancers (unpublished results, SWOG 9008). Given the role of EGFR pathway in cancer progression and its association with poor clinical outcomes, we conducted a phase II trial of erlotinib in patients with GE adenocarcinomas.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patients with a histologic or cytologic diagnosis of adenocarcinoma of the GEJ or stomach (ST) and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria were considered eligible for the trial. The patients were stratified into two groups: GEJ versus gastric (ST) adenocarcinoma. In this study, GEJ tumors included adenocarcinomas arising within 5 cm of the anatomic GE junction (distal esophagus) or from gastric cardia. More distally located tumors were recorded as gastric. Only patients with metastatic or unresectable disease were included. Adjuvant radiation or chemoradiotherapy therapy was allowed, but no prior therapy for metastatic disease was permitted. Additional eligibility requirements included performance status on Zubrod scale of 0 to 1, the ability to take and absorb oral medications, and adequate bone marrow and hepatic and renal function. Patients had to have an absolute neutrophil count of at least 1,500 per mm³, platelets at least 100,000/mm³, serum creatinine 2x upper limit of normal or lower and bilirubin 1.5x upper limit of normal or lower, and AST and ALT 1.5x upper limit of normal or lower ( 5x upper limit of normal if due to liver metastases). Patients with a history of corneal disorders or other active ophthalmic disorder, active infections or other concomitant serious and uncontrolled medical condition were excluded from participation.

Study Design
This was a phase II, open-label, multicenter trial administered and monitored by the Southwest Oncology Group (SWOG). Erlotinib was provided by the National Cancer Institute (National Institutes of Health, Bethesda, MD). The primary objective of this study was to assess overall response rate in two strata (GEJ and gastric cancer). Secondary objectives were (1) assessment of treatment related toxicity; (2) determination of the overall survival and time to treatment failure (TTF); and (3) exploratory analyses of biologic markers and the EGFR signaling pathway in patient samples. Patients received oral therapy with erlotinib, 150 mg/d, continuously. Four weeks of oral therapy comprised one cycle.

Treatment Assessments
Baseline assessments included medical history and physical exam including ophthalmologic and skin exams, performance status, CBC with differential and platelet count, serum chemistries, diagnostic tumor imaging, and tumor markers as clinically indicated. During the study, history, physical exam, performance status, blood counts, and chemistries were evaluated before start of each cycle. Toxicity assessment was performed every 2 weeks for the first 8 weeks, then once every 4 weeks. Toxicity assessment was based on National Cancer Institute Common Toxicity Criteria, version 2. Tumor response measurements were done after every two cycles of therapy (8 weeks). Measurable lesions were defined by RESIST criteria.¹⁶

The objectives of the correlative studies were (1) to examine the status/expression of intratumoral EGFR, transforming growth factor (TGF) -alpha and phosphorylated Akt kinase (pAKT) in this group of patients; (2) to determine whether there were EGFR mutations present or if the EGFR gene was amplified, and (3) to investigate whether any of these markers were predictive of response.

Immunohistochemistry
Formalin-fixed, paraffin-embedded tissue were cut in 4-µm sections and placed onto positively charged slides. Slides were deparaffinized in xylene, and rehydrated in decreasing concentrations of ethanol:water. The sections were incubated with an anti-EGFR monoclonal antibody (Zymed, Carlsbad, CA) at a dilution of 1:30 and anti-TGF-alpha monoclonal antibody (Oncogene Science, Cambridge, MA) at a dilution of 1:25 for 32 minutes at 37°C. For pAKT (ser473), primary antibody from Cell Signaling #9277 (rabbit polyclonal, 1:150 dilution) was used.

The sections were pretreated by protease 1 (Ventana Medical Sytems, Tucson, AZ) for 4 minutes (TGF-alpha) and 8 minutes (EGFR) respectively. Immunohistochemical staining was performed using an indirect biotin streptavidin 3,3'-diaminobenzidine method and the Ventana 320 ES automated immunostainer. Slides were lightly counterstained with Mayer's hematoxylin. EGFR-positive breast cancer tissue was used as positive control for EGFR staining, and TGF-alpha positive colon cancer tissue was used as positive control for TGF-alpha staining.

The EGFR and TGF-alpha and pAKT stained slides were read as positive or negative. Staining was scored in a semiquantitative manner. The positive cases were divided in weak staining (1+) and strong staining (2+).

EGFR Mutation Testing
Representative paraffin blocks (n = 54, eligible patient tumor biopsies) were obtained from the SWOG GI Tumor Bank. Tumor cells were microdissected from the stained sections. The microdissected tissues were treated with digestion buffer (10 mmol/L Tris-HCl pH8.0, 1 mmol/L EDTA, 1.0% Tween 20, Sigma, Aldrich, MO) containing 400 µg/mL proteinase K at 55°C for 12 hours. Samples were then heated to 95°C for 10 minutes to inactivate the proteinase K and used for polymerase chain reaction (PCR).

Exons 18, 19, and 21 of EGFR gene were amplified by PCR (MJ Research, Johannesburg, South Africa) in a 12.5-µL reaction volume containing 10 mmol/L Tris-Cl (pH 8.0), 50 mmol/L KCL, 2 mmol/L MgCl₂, 6 mmol/L each primers (exon 18: forward 5'-CTTTCCAGCATGGTGAGG-3', reverse 5'-GGCCAGGGACCTTACCTTAT-3'; exon 19: forward 5'-TGCCAGTTAACGTCTTCCTTC-3', reverse 5'-CCACACAGCAAAGCAGAAAC-3'; exon21: forward 5'-CCATGATGATCTGTCCCTCA-3', reverse 5'-AATGCTGGCTGACCTAAAGC-3'), 200 µmol/L deoxyribonucleotide triphosphates (dNTPs), and 0.5 Units of Platinum Taq DNA Polymerase High Fidelity (Invitrogen, Carlsbad, CA). Amplification was carried out for 35 cycles (1 minute at 94°C, 2 minutes at 55°C, and 3 minutes at 72°C). PCR products were purified using Qiaquick PCR purification kit (Aiagen, Valencia, CA). Mutations were detected by direct sequencing of the amplified products in both sense and antisense directions using a thermosequenase phosphorus-33–labeled terminator cycle sequencing kit (USB, Cleveland, OH).

EGFR Fluorescence In Situ Hybridization Analysis
Fluorescence in situ hybridization (FISH) for the detection of EGFR gene amplification and ploidy status was performed with ASR DNA probes produced by Vysis Inc (Downers Grove, IL). The probe for EGFR hybridizes to the band region 7p12 and was directly labeled with Spectrum Orange (a proprietary fluorophore; Vysis); the chromosome probe targeted the centromere of chromosome 7 (7p11.1-q11.1, D7Z1 locus) and was labeled with Spectrum Green. The slides were heated overnight at 56°C, deparaffinized in xylene, rehydrated in ethanol, and air dried.

They were fixed in 4% paraformaldehyde for 60 minutes, rinsed in phosphate-buffered saline (PBS) and H₂O, and immersed in 0.2 N HCl for 20 minutes. After a neutralizing rinse, the slides were placed in Vysis Pretreatment Solution (sodium thiocyanate) at 81°C for 30 minutes followed by digestion with Vysis Protease solution (0.5 mg protease/mL) or Proteinase K at 20 µg/mL. The slides were then rinsed and dehydrated. The probes and the specimen DNA were denatured simultaneously at 80°C and the slides incubated overnight at 37°C in a humid chamber.

The cover slips were soaked off in a posthybridization wash buffer of 2 X SSC, 0.3% NP40 at room temperature and unbound probe washed off at 73°C. The slides were rinsed in 2 X SSC, 0.1% NP40 and air dried. 4,6-diamidino-2-phenylindole (DAPI) in an aqueous mounting medium was applied to counter stain the nuclei. The slides were stored at –20°C until evaluated on an Olympus BX-51 fluorescent microscope through two dual band pass filters, one for enumerating the Spectrum Orange against DAPI and one for enumerating Spectrum Green against DAPI.

Signals for each probe were enumerated in individual nuclei if the signals were bright, distinct, and easily assessable against a background that was dark and relatively free of fluorescent particles and haziness.

Plasma Protein Analyses
Plasma from the patients enrolled in the trial was obtained from the SWOG GI Tumor Bank and stored at –80°C until utilized. Enzyme-linked immunosorbent assays (ELISAs) for EGF were obtained from R&D Systems (Minneapolis, MN) and TGF-alpha ELISA kits were be purchased from Oncogene Research Products (San Diego, CA). ELISAs were performed according to manufacturer's recommended protocol. Each sample was assayed in triplicate. Results were analyzed to determine if there is a difference in expression of EGF and TGF-alpha between responders and nonresponders either pretreatment with erlotinib.

Proteomics
Plasma samples were thawed, added to a C16 hydrophobic interaction protein chip and analyzed on the Protein Biology System 2 SELDI-TOF mass spectrometer (Ciphergen Biosystems, Freemont, CA.). Proteins below 20,000 mass/charge range were ionized with alpha-cyano-4-hydroxy-cinnamic acid as a matrix. Spectra was analyzed using Ciphergen's bioinformatics software. Initially, a comparison of pre- to post-treatment samples was performed to see whether any clustering patterns exist to segregate pre- from post-treatment samples. In addition, pretreatment samples were compared between responders and nonresponders to see whether any clusters distinguish these groups. Finally, plasma from responders was compared pre- and post-treatment to see whether any unique clusters were identified.

Statistical Design
The primary objective of this trial was to assess the erlotinib efficacy as measured by overall response probability. Erlotinib would not be of further interest if the true confirmed response probability was 5% or less, but of considerable interest if it was 20% or more. A two-stage design was implemented separately within each stratum. If at least one confirmed response was observed among the first 20 subjects, an additional 20 patients were to be accrued to that stratum. Five or more confirmed responses out of the total 40 patients was considered evidence that the treatment regimen is of further interest in gastric or GEJ cancer. This design has a power of 92% when the true response rate is 20%, and a significance level is .05. A sample of 40 patients was sufficient to estimate the 6-month survival time, and 6-month treatment failure to within ± 16% in the stratum.

	RESULTS

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Patient Characteristics
From June 1, 2002, to August 16, 2003, a total of 70 patients were enrolled in this study, 44 to GEJ stratum and 26 to gastric stratum. Two of 70 registered patients were found to be ineligible. Forty-three patients with GEJ and 25 with gastric cancer received study treatment. The gastric stratum was permanently closed on August 15, 2003, because of lack of sufficient antitumor activity.

Table 1 lists the demographic information and patient characteristics for each of the two strata (GEJ and gastric). Patients in both strata were well balanced in terms of age, performance status, and prior surgery. There was a predominance of males in the GEJ stratum. More patients in GEJ stratum received prior radiation therapy (37%) then in gastric stratum (12%). A higher number of patients in gastric stratum discontinued study treatment because of toxicity or death (Table 1).

View larger version (9K): [in this window] [in a new window]   Fig 1. Overal survival (Kaplan-Meier estimates). GE, gastroesophageal.

View larger version (9K): [in this window] [in a new window]   Fig 2. Time to treatment failure. GE, gastroesophageal.

Biologic Markers
Available tumor biopsies (n = 42, from eligible patients) were stained for EGFR, pAKT, and TGF-alpha (Table 4). Given the small number of responders and overall high frequency of positive staining for all three markers, the tested immunohistochemistry markers had no strong predictive value.

Plasma EGF levels, as determined by ELISA, did not differ significantly between responders and nonresponders, and no significant correlation between plasma EGF and response to erlotinib or EGF and disease strata was observed (data not shown). TGF-alpha levels were undetectable in majority of samples. Proteomic analyses were conducted to detect any identifiable protein peaks that would differ in plasma samples taken from responders versus nonresponders. A total of 41 plasma samples, including one from a patient with complete response, three from patients with partial response, and three from patients with stable disease were analyzed. No significant changes in detectable protein peaks were detected when sample profiles were compared (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This phase II trial examined the efficacy and safety of single agent erlotinib in patients with advanced GE adenocarcinoma.

Erlotinib was well tolerated in patients with adenocarcinoma of the GEJ. The tolerability was somewhat inferior in patients with gastric cancer, where 16% discontinued because of toxicity. It is unclear what accounted for this difference because patients were well balanced in terms of performance status, organ function, and prior therapy.

The findings from our study suggest that the GEJ and gastric tumors differ in terms of their sensitivity to EGFR blockade. The two entities also differ in terms of etiology, with GEJ adenocarcinomas associated with Barrett's esophagus, and distal gastric adenocarcinomas associated with Helicobacter pylori infection.^6,17 Our observation could have a molecular basis because different molecular pathways targeted by EGFR inhibitors may be differentially expressed in proximal versus distal adenocarcinomas. Several small studies of EGFR kinase inhibitors in esophageal and gastric cancer have been reported recently in abstract form.^18-20 In a phase II trial of gefitinib (500 mg/d), Ferry et al¹⁸ reported a response rate (RR) of 12%. In another study using gefitinib plus celecoxib, Van Groeningen et al¹⁹ reported 10% RR in patients with metastatic esophageal cancer. The predominant histology in these trials was esophageal adenocarcinoma. In contrast, Doi et al²⁰ reported on lack of efficacy of gefitinib, mostly in patients with distal gastric carcinoma. More recently Janmaat et al²¹ reported on modest activity (RR 2.85%) of gefitinib in esophageal carcinoma patients (n = 36), with female sex and squamous cell histology as positive predictors. Another explanation is that gefitinib and erlotinib may have a different repertoire in terms of receptor inactivation, with erlotinib being potentially more active at the vIII, truncated receptor form.^22,23

We have examined some of the known biologic surrogates of EGFR pathway activation, such as intratumoral staining for EGFR, pAKT and TGF-alpha. Although most of these markers were overexpressed in responders, the number of responders was relatively small, and the overall prevalence of the overexpressors high so that strong correlation could not be established. No specific patterns or protein peaks were identified using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) that would distinguish between responders and nonresponders.

Recently, in a retrospective analysis, three different somatic mutations involving EGFR tyrosine kinase domain and also EGFR gene amplifications were found to be associated with tumor response to gefitinib in patients with non–small-cell colon cancer.^24,25 Guo et al²⁶ recently reported on the presence of EGFR mutations (encompassing exons 18 through 21) in one of 10 specimens from esophageal adenocarcinoma, and in three of 57 specimens from squamous cell carcinomas. We examined the DNA extracted from tumor biopsies for the presence of the mutations involving exons 18, 19, and 21 and for EGFR gene amplification (FISH). No specific mutations or evidence for gene amplification were detected in any of the samples. Although it is possible that GE tumors contain mutations in unexamined regions of the EGFR gene, mutations and gene amplification seen in lung adenocarcinomas appear to be absent from GE carcinomas.

In summary, the results of this study demonstrated antitumor activity of erlotinib in patients with distal esophageal/GEJ adenocarcinomas, but not in patients with distal gastric tumors. Further investigation of erlotinib either alone or in combination with chemotherapy and/or radiation therapy is of interest in patients with esophageal and GEJ adenocarcinomas.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Tomislav Dragovich Genentech (A) Ken S. Zaner Genentech (A) Genentech (A)

Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Tomislav Dragovich, Susan G. Urba, Amanda F. Baker, Cecilia M. Fenoglio-Preiser, Charles D. Blanke, James L. Abbruzzese Administrative support: Charles D. Blanke, James L. Abbruzzese Provision of study materials or patients: Susan G. Urba, Ken S. Zaner Collection and assembly of data: Sheryl McCoy, Amanda F. Baker, Christopher B. Hackett, Cecilia M. Fenoglio-Preiser Data analysis and interpretation: Tomislav Dragovich, Sheryl McCoy, Jacqueline K. Benedetti, Amanda F. Baker, Jiang Wang, Christopher B. Hackett, Cecilia M. Fenoglio-Preiser, Charles D. Blanke Manuscript writing: Tomislav Dragovich, Cecilia M. Fenoglio-Preiser Final approval of manuscript: Sheryl McCoy, Susan G. Urba, Ken S. Zaner, Jacqueline K. Benedetti, Amanda F. Baker, Cecilia M. Fenoglio-Preiser, Charles D. Blanke, James L. Abbruzzese Other: Jiang Wang (Sequencing)

 

	ACKNOWLEDGMENTS

 
We thank John Crowley, PhD, from the SWOG Stats Office for his assistance with protocol design as a part of SWOG Young Investigator Initiative; Wendy Tate, MS, from the Arizona Cancer Center for her assistance with SELDI TOF analyses; and Chris Hackett and John Bishop from University of Cinncinatti for their assistance with EGFR PCR and FISH assays.

	NOTES

 
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA27057, CA76448, CA13612, CA46441, CA86780, CA04919, CA42777, CA35090, CA35178, CA67663, CA35176, CA63848, CA35128, CA45808, CA45450, CA76447, CA45807, CA12644, CA58658, CA16385, CA67575, CA58686, CA45560, CA11083, CA22433, CA63850, CA58882, CA35192, CA14028, CA35431, CA58723.

Presented in part at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium, January 27-29, 2005, Hollywood, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted April 21, 2006; accepted August 17, 2006.

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