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Phase II Study of Erlotinib in Patients With Malignant Pleural Mesothelioma: A Southwest Oncology Group Study

Linda L. Garland, Cathryn Rankin, David R. Gandara, Saul E. Rivkin, Katherine M. Scott, Raymond B. Nagle, Andres J.P. Klein-Szanto, Joseph R. Testa, Deborah A. Altomare, Ernest C. Borden

From the University of Arizona Cancer Center, Tucson, AZ; Southwest Oncology Group Statistical Center; Puget Sound Oncology Consortium, Seattle, WA; University of California, Davis Cancer Center, Sacramento, CA; Fox Chase Cancer Center, Philadelphia, PA; and Cleveland Clinic Foundation, Cleveland, OH

Address reprint requests to Southwest Oncology Group (S0218), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM.

Patients and Methods Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho–extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway.

Results Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho–mammalian target of rapamycin (74%), and phospho-forkhead (74%). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42%) had stable disease, 15 patients (45%) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51%), dermatologic (82%), and GI (52%); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months; 1-year survival rate was 43%; and median progression-free survival time was 2 months.

Conclusion Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.

	INTRODUCTION

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Malignant pleural mesothelioma (MPM), a neoplasm of the parietal pleura, is strongly associated with asbestos exposure. The lag time between exposure and presentation of the disease ranges between 5 and 20 years, although patients have been diagnosed more than 40 years after asbestos exposure.¹ Although the incidence of MPM in the United States is peaking as a result of regulation of occupational asbestos, it is predicted that, in Europe, the incidence of MPM will continue to increase over the early 21st century because of poorer regulation of asbestos.²

Most persons with MPM will die of their disease because of inherent resistance to chemotherapy, biologic therapy, and radiotherapy. Median survival time for untreated patients ranges from 4 to 12 months.³ The application of conventional chemotherapeutic agents has been limited by relatively low response rates and significant toxicity profiles. Platinum-based therapy remains a front-line standard, with improved outcome measures and good tolerability when novel antifolate drugs are combined with platinum.^4,5 There is currently no well-accepted standard for second-line treatment of MPM.

The epidermal growth factor receptor (EGFR) is overexpressed in many tumors; overexpression is implicated in aberrant proliferation, tumor invasiveness, and neoangiogenesis.^6-9 Studies support a role for EGFR in transformation to the malignant phenotype. Rat mesothelial cells exposed to carcinogenic crocidolite and erionite asbestos fibers had increased EGFR expression in association with cellular proliferation.¹⁰ Asbestos-exposed workers had higher levels of serum EGFR than nonexposed controls.¹¹ Human MPM highly expresses EGFR. Sixty-eight percent of tumors stained positively with the F4 antibody to the EGFR cytoplasmic domain.¹² Eleven of 14 malignant mesotheliomas (11 pleural and three peritoneal) tested for membrane expression of EGFR (Zymed antibody clone 31G7; Zymed, San Francisco, CA) were strongly positive (unpublished data). Furthermore, treatment of EGFR-expressing mesothelioma cell lines with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib¹³ and PD153035¹⁴ caused significant growth inhibition. Erlotinib (Tarceva; Genentech, South San Francisco, CA; OSI Pharmaceuticals, Melville, NY), an oral selective TKI of EGFR, has efficacy across a number of tumors types¹⁵ and is approved for advanced non–small-cell lung cancer (NSCLC) and pancreatic cancer in combination with gemcitabine.¹⁶

Given the favorable toxicity profile of this class of therapeutic agent and data suggesting EGFR as a potential therapeutic target in MPM, a phase II trial of erlotinib in advanced or recurrent MPM was undertaken. The primary objective was to measure survival outcomes, including 1-year and median overall survival; secondary objectives were to measure response rate in patients with measurable disease, to define the toxicity profile of erlotinib, and to measure tumor expression and activation of EGFR and downstream signaling molecules to explore relationships between these measures and clinical outcomes.

	PATIENTS AND METHODS

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Inclusion Criteria
Patients 18 years of age or older with histologically proven epithelial, sarcomatous, or biphasic mesothelioma (by local pathology review) not amenable to extrapleural pneumonectomy were eligible for enrollment. Patients with measurable and nonmeasurable disease were eligible. Prior radiation or surgical procedures for MPM for diagnostic or therapeutic purposes were allowed. Only chemotherapy-naive patients were eligible for enrollment. A Zubrod performance status of 0 to 1 and adequate hematologic function (absolute neutrophil count 1,500/mL, platelets 100,000/mL), hepatic function (serum bilirubin 1.5x the upper limit of normal and ALT and AST 1.5x the upper limit of normal unless the liver was involved with tumor, in which case ALT and AST were 5x the upper limit of normal), and renal function (serum creatinine 2x the upper limit of normal) were required. Chronic anticoagulant therapy with warfarin compounds was allowed with frequent monitoring of the international normalized ratio. Exclusion criteria included severe comorbid disease or a significant cardiac history, pregnant or breastfeeding, history of significant corneal diseases, or GI tract disease affecting ability to take or absorb oral medication.

The study was approved by the institutional review boards of the respective institutions. All patients gave written informed consent.

Study Design
Treatment consisted of single-agent erlotinib administered orally at 150 mg/d on days 1 through 28 of each 28-day dosing cycle. No a priori limit on the number of treatment cycles per patient was made. Sequential dose modifications to 100 mg and 50 mg daily were allowed. Dose delay until toxicity resolved to grade 1 and dose modification were made for grade 2 skin toxicity, grade 2 diarrhea, or other significant grade 2 nonhematologic toxicities at the discretion of the treating physician. Grade 2 keratitis persisting for more than 2 weeks required dose delay until the toxicity resolved to grade 1. Dose delay and modification were required for grade 3 or greater hematologic and nonhematologic toxicities.

Patient history, physical examination, and laboratory analyses were assessed before beginning cycle 1 of therapy and before each subsequent treatment cycle. Tumor measurements were performed after every two treatment cycles. For patients with measurable disease, tumor response was judged by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.¹⁷ Patients were withdrawn from study for disease progression or symptomatic deterioration, unacceptable toxicity, or treatment delay of greater than 3 weeks or if more than two dose modifications were required.

Statistical Analysis
The primary statistical end point of the study was 1-year survival, with assumptions based on historical survival data from front-line chemotherapy trials in mesothelioma citing 1-year survival rates of 50% for pemetrexed plus cisplatin, 38% for single-agent cisplatin in the comparator arm,⁴ and 41% for single-agent vinorelbine.¹⁸ Patients with both measurable and nonmeasurable disease were assessable for the primary end point. This single-stage phase II design was based on the assumption that a 1-year survival probability of 55% or more would be of further interest and that further testing would not be pursued if the 1-year survival probability was 35% or lower. Fifty-five eligible patients were to be enrolled. If 26 or more patients survived past 1 year, it would be concluded that erlotinib would warrant further study. This design has a significance level of P = .07 and a power of 94%. Kaplan-Meier curves were used to show overall and failure-free survival.

Immunohistochemical Analysis
Immunohistochemical (IHC) staining was performed on paraffin sections that were 3- to 5-µm and obtained from surgical specimens fixed in formaldehyde. One slide was reserved for staining with hematoxylin and eosin. Slides were deparaffinized, hydrated in water, and subjected to antigen retrieval in citrate buffer 10 mmol/L, pH 6.0, using a microwave oven. Preparations were incubated in 3% H₂O₂ for 20 minutes, washed with H₂O or phosphate-buffered saline, and blocked with 10% serum for 30 minutes.

Antibodies to EGFR clone 31G7 (Zymed), phospho-EGFR (Cell Signaling Technology, Beverly, MA), human epidermal growth factor receptor 2 (HER2) clone CB11 (Ventana Medical Systems Inc, Tucson, AZ), phospho–extracellular signal-regulated kinase (ERK) 1/2 (Biosource International, Camarillo, CA), phospho-Akt Ser473, phospho–mammalian target of rapamycin (mTOR) Ser 2448, phospho-forkhead (FKHD) Ser256, phospho-4EBP1 Thr65 (Cell Signaling Technology), and phosphatase and tensin homolog (PTEN; Zymed) were used. The antibodies were detected with biotinylated secondary antibodies. Negative controls for phospho-Akt were incubated with primary antibody preabsorbed with blocking peptide (Cell Signaling Technology). Other negative controls were incubated with their respective immunoglobulin isotype. Tissue sections were stained with diaminobenzidine chromagen and counterstained with hematoxylin. Surrounding non-neoplastic stroma and/or normal tissues served as internal negative controls for each slide. The slides were scored semiquantitatively. A score of 0 indicated no staining, 1+ indicated weak positivity with focal staining, 2+ indicated clearly positive and homogenous staining, and 3+ indicated intense and homogenous immunostain. For the purposes of this study, only the two latter scores were considered clearly positive.

	RESULTS

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Patients
Patient recruitment was undertaken from May 1, 2002 through April 15, 2003. Sixty-four patients were registered. One patient was ineligible because of a concomitant second neoplasm diagnosed immediately after registration. Median patient age was 69.5 years (range, 44.5 to 90.2 years). Forty-seven patients (75%) were male, and 16 (25%) were female. Performance status was 0 in 21 patients (33%) and one in 42 patients (67%). Histologic subtype was epithelial in 28 patients (44%), sarcomatous in two patients (3%), and biphasic in seven patients (11%); for 26 patients (41%), the subtype was not specified. A formal central pathology review was not performed. Three patients (5%) had prior radiation, and 21 patients (33%) had prior surgery. Thirty-three patients (52%) had measurable disease.

Response and Survival
Response was not able to be determined in four of 33 patients with measurable disease because of lack of disease assessment before death or withdrawal from study (two patients), inconsistency in type of scans for repeat tumor measurement (one patient), and lack of follow-up tumor assessment (one patient). Twenty-nine of 33 patients were assessed for response. There were no objective responses (0%; 95% CI, 0% to 11%). Fourteen patients (42%; 95% CI, 25% to 61%) had stable disease, which was documented at least 6 weeks after registration and before progression or symptomatic deterioration (range, 1.5 to 16.8 months), and 15 patients (45%) had disease progression.

Of the 63 eligible patients with follow-up, 55 have died, with a median overall survival time of 10 months (95% CI, 5 to 13 months) and 1-year survival estimate of 43% (95% CI, 31% to 55%; Fig 1A). Sixty-two patients have experienced progression or died. Median progression-free survival time was 2 months (95% CI, 2 to 4 months), with a 1-year progression-free survival rate of 6% (95% CI, 0% to 12%; Fig 1B). For 14 patients with stable disease, median time to progression was 4 months (95% CI, 3 to 5 months).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Kaplan-Meier overall survival curve for 63 eligible patients. (B) Kaplan-Meier progression-free survival curve for 63 eligible patients.

Grade 1 to 3 nonhematologic adverse events noted in 10% of patients attributed to erlotinib are listed in Table 1. Grade 1 to 2 events were most commonly anorexia (36%), fatigue/malaise (48%), diarrhea (44%), nausea (25%), skin rash (64%), pruritus (28%), dry skin (30%), and mouth dryness (20%). Grade 3 events included fatigue/malaise (5%), diarrhea (8%), and rash (18%). One grade 5 adverse event of dyspnea with development of a lobar infiltrate on chest x-ray was reported, without radiographic evidence of interstitial lung disease, although computed tomography imaging was not obtained.

View this table: [in this window] [in a new window]   Table 1. Grade 1 to 3 Nonhematologic Toxicity ( 10% frequency)

Ten patients (16%) were removed from protocol as a result of treatment-emergent adverse events as follows: grade 2 to 3 skin rash (three patients); grade 1 diarrhea (one patient); grade 1 rectal bleeding with grade 1 decreased hemoglobin (one patient); grade 3 uveitis (one patient); grade 2 elevated creatinine (one patient); grade 1 fever requiring dose delay (one patient); grade 3 fatigue, diarrhea, and weakness despite dose reduction (one patient); and grade 3 fatigue, anorexia, and nausea (one patient).

IHC Analysis: EGFR, Phospho-EGFR, HER2, and Phospho-ERK
For 57 patients, there was sufficient tumor tissue for EGFR and phospho-ERK analysis, with 50 and 56 tumors with sufficient material for phospho-EGFR and HER2 analysis, respectively (Appendix Table A1, online only). Seventy-five percent of tumors stained with 2+ to 3+ intensity for EGFR, and 96% of tumors had 2+ to 3+ staining intensity for phospho-EGFR (cytoplasmic rather than membrane based). Ninety-five percent of tumors did not show any membrane staining intensity for HER2; the remaining 5% showed 1+ intensity. Phospho-ERK staining was generally mild to moderate in intensity, with 71% of tumors showing 1+ to 2+ staining intensity. There was no significant correlation between EGFR and phospho-ERK expression and stable disease versus progression. Figure 2 shows hematoxylin and eosin staining of an epithelial subtype tumor with corresponding IHC for EGFR, phospho-EGFR, and HER2.

View larger version (138K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Hematoxylin and eosin (H & E) –stained section of epithelial malignant pleural mesothelioma. (B) Epidermal growth factor receptor (EGFR; 3+). (C) Phospho-EGFR (p-EGFR; 3+ nuclear, negative membrane). (D) Human epidermal growth factor receptor 2 (HER2; 3+ cytoplasmic, negative membrane).

View larger version (111K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Hematoxylin and eosin (H & E) –stained section of epithelial malignant pleural mesothelioma and corresponding immunohistochemistry for phospho-Akt (P-AKT, 2+), blocking peptide for phospho-Akt, phosphatase and tensin homolog (PTEN; 1+), phospho–mammalian target of rapamycin (P-mTOR; 2+), phospho-forkhead (P-FKHD; 2+), and phospho-4EBP1 (P-4EBP1; 2+).

	DISCUSSION

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MPM can act indolently without treatment or with palliative measures only. A median survival of 7 months has been reported for patients treated with palliative surgery, radiotherapy, or chemotherapy used only as a radiation sensitizer.¹⁹ This variable natural history likely contributed to the 12-month survival rate of 43%, which did meet the criterion established a priori to consider erlotinib of interest for further study. However, the short median time to progression (2 months), which does not compare favorably to reported median times to progression of 5.7 months for pemetrexed plus cisplatin and 3.9 months for cisplatin alone,⁴ suggests a lack of clinical efficacy for this drug in MPM. The results are in concert with a similar lack of efficacy reported in a trial of front-line gefitinib in MPM.²⁰ In contrast to the current study design, response rate was the primary study end point. Although two of 43 patients had objective responses, this low level of activity was not considered to be clinically relevant. The failure-free survival time of 2.6 months (95% CI, 1.5 to 4.0 months) was similar to that reported in this study of erlotinib. One-year survival rate for patients treated with gefitinib was 32% (95% CI, 3.5% to 10.3%), which is somewhat lower than the rate reported here for erlotinib, although CIs for both studies were large. Similar to data reported here, EGFR was strongly expressed in 97% of patient tumors.

In the current study, only 48% of patients had measurable disease, which is likely related to the use of RECIST criteria rather than the modified RECIST measurement system developed to better measure changes in pleural thickness rather than in bidimensionally measurable lesions.²¹ This limited the number of patients for response but not survival assessments.

The lack of efficacy reported here was despite the high expression of EGFR in the majority (75%) of tumors. In NSCLC, EGFR expression by IHC was only a moderately good predictor of response to EGFR TKI, whereas in contrast, response to EGFR inhibition correlates with activating EGFR mutations^22,23 and EGFR gene amplification, which in some studies predicts for response as well as survival.²⁴ In gliomas as well, EGFR gene amplification has predicted for sensitivity to EGFR TKI.²⁵ We did not test for EGFR mutations or gene amplification; however, a mutational analysis of 62 human mesotheliomas found no EGFR exon 19 polymorphisms and no point mutation for codons 858, 861, and 719 (known to comprise the majority of tyrosine kinase domain mutations noted in gefitinib-responsive NSCLC).²⁶ These data, together with the lack of clinical efficacy of EGFR TKIs, suggest that MPM lacks an important mechanism by which other tumor types are sensitive to EGFR inhibition.

The preferred dimerization partner of EGFR is HER2.²⁷ Preclinical studies have shown that tumors with high HER2 expression were more sensitive to gefitinib.²⁸ In a clinical study of gefitinib in NSCLC, sensitivity to gefitinib did not correlate with HER2 expression by IHC.²⁹ In this study, 5% of tumors had only weak expression of HER2 by IHC, which is in concert with reports that MPM lacks membrane expression of HER2,^30,31 although contrasting with a report of 28 of 29 MPM tumors with immunoreactivity.³² Given lack of IHC expression, it is unlikely that the HER2 gene would be amplified and that growth and proliferation in MPM is driven by the EGFR/HER2 receptor signaling mechanism.

Because EGFR signals through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/ERK effector pathways, activation of ERK and the phosphatidylinositol 3-kinase/Akt pathway was analyzed. Preclinical studies with gefitinib showed that persistent activation of these pathways was associated with resistance to this agent.^33,34 In NSCLC, phospho-ERK positivity was a negative predictor of clinical response to gefitinib.³⁵ In this study, phospho-ERK staining was mainly mild to moderate in intensity, and no correlation between stable disease and expression was noted.

Constitutive activation of Akt, which triggers antiapoptotic signaling, modulates angiogenesis, increases invasion and metastasis, and inhibits cell cycle arrest,^36,37 is often the consequence of PTEN mutation. In gliomas, Akt activation has been associated with resistance to treatment with erlotinib.²⁵ In NSCLC, reports differ on the relationship between Akt activation and response to EGFR TKI.^38-40 In this study, most tumors had Akt activation unrelated to loss of PTEN, which is consistent with a report showing no mutations in 18 MPM tumors studied.⁴¹

This study provides evidence of Akt pathway activation in MPM. There is a growing understanding of molecular predictors of sensitivity to mTOR inhibition beyond Akt phosphorylation status, including hypoxia-inducible factor expression in renal cell carcinoma⁴² and PTEN expression in breast carcinoma.⁴³ Molecular analysis for correlates of sensitivity may elucidate whether the Akt pathway is a relevant target in MPM.

	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.

Employment: N/A Leadership: N/A Consultant: Linda L. Garland, Genentech; David R. Gandara, Genentech Stock: N/A Honoraria: Linda L. Garland, Genentech Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Linda L. Garland, Cathryn Rankin, Ernest C. Borden

Administrative support: Ernest C. Borden

Provision of study materials or patients: Linda L. Garland, Saul E. Rivkin

Collection and assembly of data: Linda L. Garland, Cathryn Rankin, Katherine M. Scott, Deborah A. Altomare

Data analysis and interpretation: Linda L. Garland, Cathryn Rankin, David R. Gandara, Raymond B. Nagle, Andres J.P. Klein-Szanto, Joseph R. Testa, Deborah A. Altomare

Manuscript writing: Linda L. Garland, Cathryn Rankin, David R. Gandara, Ernest C. Borden

Final approval of manuscript: Linda L. Garland, Cathryn Rankin, David R. Gandara, Saul E. Rivkin, Raymond B. Nagle, Andres J.P. Klein-Szanto, Joseph R. Testa, Deborah A. Altomare, Ernest C. Borden

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Callaleh Bonugli for assistance as protocol coordinator of this study, Lena McKinney for administrative coordination of tumor studies, and Erika Dexter for tumor immunohistochemistry.

	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, CA46441, CA20319, CA45808, CA58861, CA13612, CA45807, CA45377, CA11083, CA35431, CA37981, CA46368, CA27057, CA67575, CA45560, CA35090, CA35178, CA58882, CA42777, CA58416, CA12644, CA16385, CA46113, CA22433, and CA76462.

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

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Submitted November 15, 2006; accepted March 19, 2007.

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