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Phase II Randomized Controlled Trial of an Epidermal Growth Factor Vaccine in Advanced Non–Small-Cell Lung Cancer

Elia Neninger Vinageras, Ana de la Torre, Marta Osorio Rodríguez, Mauricio Catalá Ferrer, Idania Bravo, Mario Mendoza del Pino, Daniel Abreu Abreu, Soraida Acosta Brooks, Rolando Rives, Concepción del Castillo Carrillo, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia, Tania Crombet Ramos, Gisela González Marinello, Agustín Lage Dávila

From the Hermanos Ameijeiras Hospital; National Institute of Oncology and Radiobiology; Center for Medical and Surgical Research; National Institute of Neumology; Center of Molecular Immunology, Havana; Celestino Hernández Hospital, Villa Clara; Third Congress Hospital, Pinar del Río; Maria Curie Hospital, Camagüey, Cuba; V.I. Lenin Hospital, Holguín; and Saturnino Lora Hospital, Santiago de Cuba

Corresponding author: Elia Neninger Vinageras, MD, Hospital Hermanos Ameijeiras, San Lázaro 701, PO Box 10300, Ciudad Habana, Cuba

	ABSTRACT

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Purpose We show the result of a randomized phase II clinical trial with an epidermal growth factor (EGF)-based cancer vaccine in advanced non–small-cell lung cancer (NSCLC) patients, evaluating immunogenicity, safety, and effect on survival.

Patients and Methods Eighty patients with stage IIIB/IV NSCLC after finishing first-line chemotherapy were randomly assigned to receive best supportive care or EGF vaccinations.

Results Vaccination was safe. Adverse events were observed in less than 25% of cases and were grade 1 or 2 according to National Cancer Institute Common Toxicity Criteria. Good anti-EGF antibody response (GAR) was obtained in 51.3% of vaccinated patients and in none of the control group. Serum EGF concentration showed a major decrease in 64.3% of vaccinated patients. GAR patients survived significantly more than those with poor antibody response (PAR). Also, patients whose serum EGF dropped below 168 pg/mL survived significantly more than the rest. There was a trend to an increased survival for vaccinated patients compared with controls. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with age younger than 60 years.

Conclusion Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF. There was a direct correlation between antibody response and survival. There was a direct correlation between decrease in serum EGF and survival. In patients younger than 60 years, vaccination was associated with increased survival.

	INTRODUCTION

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Lung cancer is the leading cause of death resulting from malignant diseases, but only a minority of patients are amenable of radical treatment with curative intent. For the remaining majority of patients with advanced non–small-cell lung cancer (NSCLC), palliative platinum-based chemotherapy with or without radiotherapy provides a modest survival benefit.^1-4

Epidermal growth factor receptor (EGFR), a member of a family of membrane receptors with tyrosine kinase activity, is emerging as a new target candidate for anticancer therapy as a result of its overexpression in many carcinomas (such as lung, colon, kidney, and head and neck tumors) and its relationship with several hallmark properties of malignant cells such as continuous cell proliferation, escape from apoptosis, cell migration, and angiogenesis.^5,6

Experiments in animal models⁷ provided impetus for clinical trials of EGFR inhibitors in cancer patients. Several anti-EGFR agents are already in the clinical setting: small-molecule tyrosine kinase inhibitors, monoclonal antibodies, and cancer vaccines.

Ours is an active immunotherapy approach with a vaccine containing one of the most important ligands of the EGFR coupled to a carrier protein and administered together with an adjuvant. Vaccine has shown to be immunogenic and safe in previous phase I-II clinical trials.^8-10 A direct correlation between anti–epidermal growth factor (EGF) antibody titers and survival was demonstrated in vaccinated patients, whereas an inverse association between EGF reduction and patient's survival was also found.¹⁰

In the present article, we show the result of a randomized phase II clinical trial in advanced NSCLC patients. The primary end point was the preliminary assessment of overall survival. Immunogenicity and safety were secondary end points.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients older than 18 years with histologically or cytologically proven NSCLC at stages IIIB or IV were eligible. Random assignment was performed at least 28 days after completing first-line chemotherapy, but within 2 months. All patients had measurable disease.

Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of at least 2, adequate bone marrow reserve, WBC count of at least 3,000/µL, platelet count of at least 100,000/µL, hemoglobin of at least 10 g/dL, life expectancy longer than 3 months, and normal creatinine, bilirubin, and transaminase values according to each institutional standards.

Pregnancy or lactation, secondary malignancies, or history of hypersensitivity to foreign proteins rendered patients ineligible. Disease progression to first-line chemotherapy was not an exclusion criterion.

Eighty locally advanced or metastatic NSCLC patients were recruited in nine sites from April 2002 to June 2004. Patients were then followed for 24 months. The protocol was approved by institutional review boards of all participating institutions and by the State Centre of Drug Quality Control. The trial results were validated by an independent expert review committee. All patients signed informed consent before inclusion.

Treatment Schedule
Twenty-eight days after finishing first-line chemotherapy, patients were randomly assigned to enrollment in the vaccine or in the control group. Random assignment was performed centrally through a validated simple randomization system (ASAL) version 1.2.

Patients in the vaccine group received a low-dose of cyclophosphamide (200 mg/m²) 3 days before the first vaccine dose. The EGF vaccine was administered on days 1, 7, 14, and 28, and monthly afterwards. Vaccinated patients received supportive care if required.

Patients in the control group received supportive care alone. For distant metastases with localized symptoms, diffuse brain metastases, or symptomatic bony metastasis, palliation of symptoms was performed with external-beam radiotherapy in both groups.

The EGF vaccine is produced in the Center of Molecular Immunology (Havana, Cuba), in manufacturing facilities validated according European Medicines Agency Good Manufacturing Practice standards. It is composed of human recombinant EGF produced in yeast, and chemically conjugated to the P64K Neisseria meningitides recombinant protein, produced in Escherichia coli. For protein conjugation, glutaraldehyde (0.05%) is added to the protein mixture allowing the reaction for 1 hour; then, the conjugated moiety is purified by ultrafiltration/diafiltration and sterile filtered. The vaccine is composed of the chemical conjugated EGF-P64k containing two EGF molecules per each P64k molecule. The conjugate is then mixed with Montanide ISA 51 (Seppic, Paris, France) to form water in oil emulsion immediately before injection. Each vaccine dose contained 50 µg equivalents of EGF. The product is released in the Quality Control Direction at the Center of Molecular Immunology according to manufacturer specifications, which include high-performance liquid chromatography for molecular species, potency measured as immunogenicity in vaccinated mice (in vivo test), sterility, and appearance, among others. The vaccine is administered intramuscularly.

Patient Assessment
Patient assessment was performed at baseline and every 4 weeks, and included physical exam and CBC for clinical laboratory test. Additionally, chest radiography, computed tomography (CT) scan, and abdominal ultrasound were performed at baseline and every 3 months to assess the clinical response according to the Response Evaluation Criteria in Solid Tumors (RECIST).

Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 3) after every vaccine administration. Criteria for stopping vaccinations included voluntary withdrawal, unmanageable toxicity, or worsening of the patient general conditions.

Measurements of Antibody Titers
Blood samples were collected every 14 days for 60 days and monthly thereafter. Anti-EGF antibody titers were measured through an enzyme linked immunosorbent assay (ELISA), as previously described.^5,6 EGF antibody response was not assessed in 11 patients: Seven patients were not assessed because of early death (< 2 months from enrollment), and four patients (from the control group) refused frequent sampling.

Patients were classified as having good antibody response (GAR) if they reached anti-EGF antibody titers equal or higher than 1:4,000 and at least four times their preimmunization values, and as having poor antibody response (PAR) otherwise. This good antibody response criterion was established arbitrarily in 1998 and has been used repeatedly to optimize the vaccine composition and schedule.^9-11

EGF concentration in serum was measured with a commercial ELISA (Quantikine; R&D Systems Inc, Minneapolis, MN). An arbitrary cutoff point of 168 pg/mL (half the mean of a healthy subject's value) was established to classify patients according to the extent of EGF reduction in serum. Patient survival was estimated from the time of random assignment until death.

Statistical Analysis
Survival estimations were performed according to the Kaplan-Meier method and the log-rank estimate. Pearson correlation coefficient and Fisher's exact test were used to estimate the correlation among different variables between groups. Nonassessable patients according to an external independent review committee were excluded from the survival analysis.

	RESULTS

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Patient Characteristic
Eighty IIIB/IV NSCLC patients were randomly assigned 1:1 to EGF vaccine or supportive care. All patients had finished first-line chemotherapy regimen at least 4 weeks before entering the trial. A total of 69.5% of the patients, 73.3% of vaccine group and 65% of the control group, achieved at least disease stabilization after the first-line chemotherapy, whereas 30.5% were in progressive disease at the moment of random assignment. After the revision by an external expert committee, six patients were considered nonassessable: four because of noncompliance with entry criteria and two for refusing to continue participating in the trial after random assignment, before initiating treatment.

No significant differences in demographic characteristics were found between the two treatment arms (Table 1). All patients received four to six cycles of platinum-based chemotherapy before random assignment. Radiotherapy was administered as per the physician criteria to 36 patients distributed among both groups (Table 1).

Vaccination reduced the EGF concentration, which decreased below the threshold of 168 pg/mL in 64.3% of vaccinated patients. Mean EGF concentration in nonvaccinated patients was significantly higher than in vaccinated patients. A significant inverse correlation was observed between the anti-EGF antibody titers and the EGF concentration in vaccinated but not in the control patients (Fig 1).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kinetics of anti–epidermal growth factor (EGF) antibody (Ab) titers and EGF concentrations in serum from patients from (A) the vaccine group and (n = 32 for antibody titers; n = 28 for sera EGF concentration) and (B) the control group (n = 37 for antibody titers; n = 17 for sera EGF concentration). Left y-axis represent anti-EGF antibody titers (sera dilution in log scale), right y-axes represent serum EGF concentration (pg/mL).

There was also a strong correlation between the decrease in EGF concentration and survival. Vaccinated patients with minimal EGF concentration below 168 pg/mL survived significantly longer (mean, 20.44 months; median, 13 months) than those who did not reach such reduction (mean, 6.01 months; median, 5.6 months; Fig 2).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Survival functions for (A) vaccinated with good anti–epidermal growth factor (EGF) antibody response (GAR; n = 20), vaccinated with poor anti-EGF antibody response (PAR; n = 18), and controls (n = 37; log-rank P = .0002); and (B) vaccinated patients with sera EGF concentrations 168 pg/mL (n = 17), more than 168 pg/mL (n = 17), and controls (n = 37; log-rank P = .0024).

When comparing vaccinated patients with controls (Fig 3A), the vaccine group achieved a mean survival of 12.73 months (median, 6.47 months) whereas the control arm survival was 8.52 months (median, 5.33 months). There was a trend toward a survival advantage for the vaccine group, which was not significant at this sample size. However, this trend became significant when patients were stratified by age. Vaccinated patients age 60 years or younger survived significantly longer (mean, 18.53 months; median, 11.57 months) than controls (mean, 7.55 months; median, 5.33 months; P = .0124; Fig 3B). In the subset of patients older than 60 years, there were no significant differences in survival between vaccinated and controls (P = .4382). Age per se had no significant influence in survival within the control group.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Survival functions for (A) whole patient population (vaccinated, n = 37; controls, n = 37; log-rank P = .098), and (B) patients younger than 60 years (vaccinated, n = 22; controls, n = 28; log-rank P = .0124).

	DISCUSSION

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Despite current advances in cytotoxic chemotherapy, the prognosis for patients with NSCLC continues to be poor, with the exception of the small, selective subgroup of patients with good performance status, minimal or absent weight loss, and disease suitable for a high-dose radiation therapy.^12,13 Patients with unresectable NSCLC are usually considered to have incurable disease. In that sense, the development of new, more effective drugs is deemed mandatory.¹⁴ Recently, novel molecular approaches for lung cancer treatment have been tested in clinical trials.¹⁵

Because EGFR is associated with malignant transformation, it has been considered a very appealing target for the treatment of epithelial tumors.¹⁶ Inhibitors of the EGFR signaling pathway include monoclonal antibodies against EGFR and small-molecule receptor tyrosine kinase inhibitors, which are discussed widely in many reports.^14-17

The EGF vaccine is a novel approach to disrupt EGFR signaling. This active immunotherapeutic procedure has been broadly evaluated in small phase I trials intended to optimize vaccine composition, dose, and schedule. Here, we report for the first time to our knowledge the results of a controlled, randomized phase II trial, designed to preliminary assess the clinical benefit of the EGF vaccine as second-line therapy of advanced NSCLC patients compared with a control group receiving best supportive care. Secondarily, safety and immunogenicity were evaluated.

The vaccine was very well tolerated. Most common adverse events consisted of chills, headache, fever, asthenia, injection-site pain, nausea, and vomiting. This safety profile is in agreement with those previously reported.^8-11 However, one patient who achieved a very high anti-EGF antibody response together with a significant decrease in EGF concentration in sera developed a skin rash. After vaccination, this patient achieved a complete tumor remission, still sustained 44 months after random assignment.

Regarding immunogenicity, 51.3% of vaccinated patients were classified as having GAR, whereas no controls did. Conversely, EGF concentration in sera was significantly decreased in vaccinated patients compared with controls.

Immunization with EGF vaccine resulted in a significant inverse correlation between anti-EGF antibodies titers and EGF serum concentration in the study arm, but not in the controls. This result confirms that EGF vaccination provokes an immune-deprivation of the circulating EGF.

In previous trials, we established that there exists a significant increase in survival for good responders compared with poor responders. This fact was consistently repeated in the currently reported phase II trial. EGF serum concentration inversely correlates with survival, pointing to it as a good surrogate end point that should be further validated in a larger patient population. However, because recent studies have highlighted the existence of biologic factors involved in sensitivity or resistance to EGFR inhibitors,¹⁸ EGFR gene copy number as well as mutations in the EGFR and in K-ras genes must also be evaluated in the forthcoming studies.

There was an increase in overall survival of all vaccinated patients compared with controls, but the difference still did not reach statistical significance, which could be an effect of the small sample size. A larger randomized phase III trial, already ongoing, will further assess this effect.

Several peptide, gene-, and cell-based vaccines are been evaluated in the clinical setting.¹⁹ The MUC-1–based L-BLP25 tested in a similar patient subset showed a survival trend in favor of L-BLP25 in a subgroup of patients with locoregional stage IIIB.²⁰ Belagenpumatucel-L, an allogeneic tumor cell vaccine that incorporates a TGF-β antisense gene, was well tolerated and showed a survival advantage in 75 NSCLC patients.²¹ A third vaccine composed of autologous tumor cells genetically modified to secrete granulocyte macrophage colony-stimulating factor (GVAX), demonstrated clinical activity in advanced-stage NSCLC,²² whereas autologous dendritic cell derived exosomes loaded with MAGE antigens resulted in long-term stability of disease in the very same setting.²³ The preliminary encouraging results justified further phase III evaluation for L-BLP25, the TGF-β antisense gene vaccine, and GVAX.¹⁹

The effect of EGF vaccination on survival was significant for the group of patients younger than 60 years. In this age group, vaccinated patients survived significantly longer than controls. A better result of vaccination procedures in younger people are to be awaited. In fact, a similar response pattern has been described for some prophylactic anti-infectious vaccines. Senescence of the immune systems appears rather early in life, as a contraction of the naïve T-cell pool, which in turn limits the response to antigens encountered de novo in older individuals.²⁴ The impact of "immuno-senescence" on the humoral response to this vaccine should be assessed in a larger patient sample. The effect of aging on the cellular response elicited by the vaccine should also be characterized.

In summary, our results confirm the immunogenicity and safety of the EGF vaccine in what we believe is the first randomized trial in this area. The previous association among high anti-EGF antibody titers, decrease in EGF concentration and survival was also verified. Therefore, both antibody response and EGF concentration decrease could be proposed as surrogate markers to optimize vaccination dosage and schedules. Additionally, this trial finds for the first time to our knowledge a survival advantage for all vaccinated patients compared with controls in the younger age cohort.

The finding of long-term stabilization of the disease in some patients points to the possible role of nontoxic immunotherapy in gradually shifting advanced cancer into a chronic disease, compatible with years of good-quality life. Vaccine optimization by means of the use of a different vaccine schedule as well as by immunizing at multiple sites is being already evaluated. New clinical trials to reevaluate this approach in larger patient series and to optimize vaccination schedules are ongoing.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Elia Neninger Vinageras, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia, Tania Crombet Ramos

Administrative support: Marta González Dueñas, Gisela González Marinello, Agustín Lage Dávila

Provision of study materials or patients: Elia Neninger Vinageras, Ana de la Torre, Marta Osorio Rodríguez, Mauricio Catalá Ferrer, Idania Bravo, Mario Mendoza del Pino, Daniel Abreu Abreu, Soraida Acosta Brooks, Concepción del Castillo Carrillo, Marta González Dueñas, Carmen Viada

Collection and assembly of data: Elia Neninger Vinageras, Ana de la Torre, Marta Osorio Rodríguez, Mauricio Catalá Ferrer, Idania Bravo, Mario Mendoza del Pino, Daniel Abreu Abreu, Soraida Acosta Brooks, Rolando Rives, Concepción del Castillo Carrillo, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia

Data analysis and interpretation: Elia Neninger Vinageras, Rolando Rives, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia, Tania Crombet Ramos, Agustín Lage Dávila

Manuscript writing: Elia Neninger Vinageras, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia, Tania Crombet Ramos, Gisela González Marinello, Agustín Lage Dávila

Final approval of manuscript: Elia Neninger Vinageras, Ana de la Torre, Marta Osorio Rodríguez, Mauricio Catalá Ferrer, Idania Bravo, Mario Mendoza del Pino, Daniel Abreu Abreu, Soraida Acosta Brooks, Rolando Rives, Concepción del Castillo Carrillo, Marta González Dueñas, Carmen Viada, Beatriz García Verdecia, Tania Crombet Ramos, Gisela González Marinello, Agustín Lage Dávila

	Glossary Terms

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EGF (epidermal growth factor):

The ligand for EGFR (see EGFR).

EGFR (epidermal growth factor receptor):

Also known as HER-1, EGFR belongs to a family of receptors (HER-2, HER-3, HER-4 are other members of the family) and binds to the EGF, TGF-β, and other related proteins, leading to the generation of proliferative and survival signals within the cell. It also belongs to the larger family of tyrosine kinase receptors and is generally overexpressed in several solid tumors of epithelial origin.

Immunotherapy:

A therapeutic approach that uses cellular and/or humoral elements of the immune system to fight a disease.

	NOTES

 
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

	REFERENCES

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Submitted April 20, 2007; accepted December 11, 2007.

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