Gefitinib for patients with advanced non-small cell lung cancer treated on the expanded access program: a single institution experience
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ORIGINAL ARTICLE
Gefitinib for patients with advanced non-small cell lung cancer treated on the expanded access program: a single institution experience Gefitinibe no tratamento de pacientes com câncer avançado de não-pequenas células do pulmão em um programa de acesso expandido: experiência de uma única instituição Marcelo Rocha de Souza Cruz1, Artur Katz2, Rene Claudio Gansl3, Jacques Tabacoff4, Oren Smaletz5, Sergio Daniel Simon6
Objective: A retrospective analysis of patients with advanced nonsmall cell lung cancer treated with gefitinib on an expanded access program. Methods: Patients with advanced non-small cell lung cancer and Karnofsky performance status ≥ 50% were allowed to enroll. They received gefitinib 250 mg orally once a day. No other systemic anticancer treatment was allowed during the trial. Results: From June 2002 to April 2003, 31 patients were included. The age range was 38 to 84 years, with 20 men and 11 women. The median Karnofsky performance status was 80% and 25 patients had a history of smoking. Thirty patients were clinical stage IV and one patient was stage IIIB. The objective response rate was 14%. There was no complete response. An additional 36% of patients (n=10) had stable disease for more than 6 months, giving a response plus disease stabilization rate of 50%. The median progression free survival was 3.6 months, and the median overall survival was 4 months. The one year survival rate was 19%. Toxicities were mild in this cohort, with grade 1 (42%) and 2 (11%) diarrhea and grade 1 rash (16%) being the most commonly observed side effects. Conclusions: Despite the small sample, our data are similar to published trials, confirming efficacy in a setting of pretreated patients and tolerable side effects. In this study patients had to meet only a few essential eligibility criteria for enrollment, making our data reproducible and applicable to patients seen in a community setting.
gefitinib no programa de acesso expandido. Métodos: Pacientes com câncer de pulmão não-pequenas células avançado e “performance status” de Karnofsky ≥ 50% foram selecionados para receber gefitinib 250 mg uma vez ao dia. Nenhum outro tratamento sistêmico antineoplásico era permitido. Resultados: De junho/2002 a abril/2003, foram incluídos 31 pacientes com idade entre 38 e 84 anos, sendo 20 homens e 11 mulheres. O “performance status” de Karnofsky mediano foi 80% e 25 pacientes tinham história de tabagismo. Trinta pacientes apresentavam estádio clínico IV e 1 paciente apresentava estádio clínico IIIB. A taxa de resposta objetiva foi de 14%. Não houve resposta completa. Dez pacientes apresentaram doença estável por mais de 6 meses, proporcionando uma taxa de resposta mais doença estável de 50%. A sobrevida mediana livre de progressão foi de 3,6 meses, e a sobrevida global mediana foi de 4 meses. A taxa de sobrevida em um ano foi de 19%. O perfil de toxicidade em geral foi leve, com diarréia grau 1 (42%) e 2 (11%) e rash cutâneo grau 1 (16%) sendo os efeitos colaterais mais observados. Conclusões: Embora seja uma pequena amostra de pacientes, nossos dados são similares aos dados de estudos publicados, confirmando a eficácia e segurança do gefitinib em um grupo de pacientes previamente tratados. Neste estudo, os pacientes selecionados apresentavam apenas alguns critérios essenciais de elegibilidade, o que torna nossos dados reprodutíveis e aplicáveis aos pacientes atendidos na comunidade.
Keywords: Carcinoma, non-small-cell lung; Receptor, epidermal growth factor; Quinazolines/therapeutic use; Antineoplastic agents/ therapeutic use
Descritores: Carcinoma pulmonar de células não-pequenas; Receptor do fator de crescimento epidérmico; Quinazolinas/uso terapêutico; Agentes antineoplásicos/uso terapêutico
RESUMO
INTRODUCTION Lung cancer is the most common cause of cancer death worldwide (1). An estimated 173,700 persons in the
ABSTRACT
Objetivo: Relatamos uma análise retrospectiva dos pacientes com câncer de pulmão não-pequenas células avançado tratados com
Study performed at the Department of Clinical Oncology of Hospital Israelita Albert Einstein - HIAE, Sao Paulo (SP), Brazil. 1
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil.
2
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil.
3
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil.
4
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil.
5
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil.
6
MD, Hospital Israelita Albert Einstein - HIAE, Department of Clinical Oncology, São Paulo (SP), Brazil. Corresponding author: Artur Katz – Av. Albert Einstein 627/701 - Departamento de Oncologia Clínica - Morumbi - CEP 05651-901 - São Paulo (SP), Brazil - Tel.: (11) 3747-0491 - e-mail:
[email protected] The authors state there is no conflict of interests. Received on April 17, 2006 - Accepted on Jul 18, 2006
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United States of America will receive a diagnosis of lung cancer in 2004, and 164,440 of them will die of the disease. The prognosis for patients with lung cancer remains dismal, with a five-year survival rate of 14 percent(2). For advanced and metastatic non-small-cell lung cancer (NSCLC), systemic chemotherapy prolongs survival and improves quality of life. The currently available chemotherapy regimens only lead to complete remission in less than 1% of patients, with objective response rates ranging from 20% to 30%, and approximately 85% patients die within a year of diagnosis(3). Second and third line chemotherapy regimens provide objective responses in less than 6% patients, leading to a median survival which is seldom longer than 6 months (4). Improvement on these existing treatments for advanced NSCLC is needed, requiring the development of new agents with a different mechanism of action and an improved safety profile compared with chemotherapy. In this context, the role of the epidermal growth factor receptor (EGFR) as an important therapeutic target has been recently recognized. The epidermal growth factor receptor (EGFR) belongs to a subfamily of four closely related receptors: EGFR (ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB3), and HER4 (ErbB-4). The EGFR is a 170-kd plasma membrane glycoprotein composed of an extracellular ligand-binding domain, a transmembrane lipophilic segment, and an intracellular protein tyrosine kinase (TK) domain with a regulatory carboxyl terminal segment(5). The receptors exist as inactive monomers that homo- or hetero-dimerize (between EGFR and another member of the Erb receptor family) after ligand activation. The EGFR can also be activated by ligand-independent mechanisms(6). Activation of the EGFR TK has been identified as a key initiating event that generates a cascade of intracellular signaling events regulating cell proliferation, differentiation, survival, angiogenesis, and metastasis, all processes that are crucial to cancer progression(7). EGFR is expressed, overexpressed, or dysregulated in many human solid tumors, including breast, ovarian, NSCLC, colorectal, and head and neck cancers(8-9). Several EGFR-targeted cancer therapies are currently under development. Gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) is an orally active EGFR tyrosine kinase inhibitor (EGFR-TKI) that blocks the signal transduction pathways implicated in the proliferation and survival of cancer cells (10). In preclinical studies, gefitinib demonstrated antitumor activity against EGFR expressing NSCLC, ovarian, breast, and colon cancer cell lines(11-12) and xenograft models(13). Four phase I studies showed that gefitinib was generally well tolerated, and the main side effects were diarrhea, einstein. 2006; 4(3):207-212
asthenia and acneiform rash(10,13-15). Observations and pharmacokinetic data from these trials identified two doses for further study: gefitinib 250 mg/d is higher than the lowest dose at which clinical response was seen, and 500 mg/d is the highest dose level to be tolerated long-term by most patients. Two phase II gefitinib monotherapy studies were conducted. The IDEAL Studies (Iressa Dose Evaluation in Advanced Lung Cancer), compared 250 mg and 500 mg daily doses in patients with pretreated advanced NSCLC(16-17). The first study, IDEAL-1 Study, evaluated patients who were refractory to at least one chemotherapy regimen(16), whereas the IDEAL-2 Study included patients who had been previously treated with at least two chemotherapy regimens, including one with platin and taxane derivative compounds(17). The primary objective of both studies was to assess the objective response rate and the drugsafety profile. Disease control (including complete and partial responses and stable disease) was observed in 54% patients in IDEAL 1 Study, with 18% patients presenting objective responses (partial or complete). The median progression-free survival time was 12 weeks and the rate of progression-free patients after 4 months was 34%. Symptom improvement was observed in 39% of the cases. IDEAL 2 Study, conducted basically in the USA, included patients with higher previous exposure to chemotherapy. Objective responses were observed in 11.8% patients, with evident symptom improvement in 40%(17). These response rates for patients receiving secondline and higher therapy were encouraging, particularly when considered in the context of the retrospective analysis by Massarelli et al.(18), in which the response rate declined with each line of therapy (second line, 16.3%; third line, 2.3%). The most frequent drugrelated adverse events observed in these two trials were mild (grade 1 and 2) skin rash and diarrhea, confirming the previous findings of phase I studies.
OBJECTIVE To report here a retrospective analysis of a single institution experience of patients with advanced NSCLC treated with gefitinib on an expanded access program (EAP). METHODS The enrolled patients were on an open-label EAP available at our institution in Brazil. All patients gave informed consent approved by the Institution Research Board. The primary objective was to evaluate overall survival (OS). Secondary objectives were to estimate
Gefitinib for patients with advanced non-small cell lung cancer treated on the expanded access program: a single institution experience
progression-free survival (PFS), response rate, and stable disease rates. Patients with histologically or cytologically confirmed advanced NSCLC with metastatic or recurrent disease not curable with surgery or radiotherapy at study entry were allowed to enroll. They could have a Karnofsky performance status (KPS) > 50%. Patients with brain metastases were not eligible for this program. All patients treated by the EAP were considered for inclusion in this analysis. Patients received gefitinib 250 mg orally once daily. Treatment was continued uninterrupted until disease progression, death, unacceptable toxicity or withdrawal of consent. No other systemic anticancer treatment was allowed during the trial, but use of palliative radiotherapy for isolated bone metastases was permitted. Baseline assessments were performed within 2 weeks before study entry. After starting treatment, patients were assessed for toxicity after the first four weeks. Patients were evaluated every 12 weeks regarding efficacy. A 14-day dose interruption was allowed for resolution of possible gefitinib toxicity. Specifically for diarrhea, this 14-day dose interruption allowed resolution of diarrhea as well as correction of hydration and use of antimotility agents. With appropriate supportive care (antimotility agents for diarrhea and topical or systemic antibiotics for skin rash), gefitinib could be restarted at the same dose. Objective response rates (complete response, partial response, stable disease, or progressive disease) were assessed according to the World Health Organization (WHO) criteria. For the analysis of OS and PFS, measurement started on the day that treatment with gefitinib began. For OS, the cut-off was either on the date of death or on the date last seen alive. For PFS, the patient time ended at disease progression or death. For those not experiencing either endpoint, the patient’s time ended when the patient was last seen alive and free from progression. Toxicity data were captured only if they were classified as serious adverse events (SAEs). A SAE was an adverse event occurring while on treatment with gefitinib or within 30 days after discontinuation of gefitinib and was associated with death, a life-threatening event, persistent or significant disability/incapacity, or inpatient hospitalization. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0.
RESULTS Between June 2002 and April 2003, the EAP included 31 patients. Of the 31 patients who were treated with gefitinib, 28 were considered assessable for response.
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Three patients died within 7 days of starting treatment. The age range was 38 to 84 years, with 20 men and 11 women. The median KPS was 80%, and 25 patients had history of smoking. Thirty patients were clinical stage IV and 1 patient was stage IIIB. Patient characteristics are summarized in table 1. Table 1. Patients characteristics (n=31) Age (years) Range Gender Male Female
38-84 Number of patients 20 11
Karnofsky Performance Status (%) 50 60 70 80 90 100
3 4 8 8 6 2
Tum or stage IIIB IV
1 30
Histology Adenocarcinoma Bronchoalveolar carcinoma Squamous-cell carcinoma Large-cell carcinoma NSCLC (not otherwise specified)
14 4 2 5 6
Number of prior chemotherapy regimens 0 1 >2 3 History of smoking Yes No
3 9 19 4 25 6
Gefitinib was given as first-line treatment for 3 patients, second-line treatment for 9 patients, and third-line or further for 19 patients. The objective response rate was 14% (4 patients presented partial response). There was no complete response. An additional 36% of patients (n=10) had stable disease for more than 6 months, giving a response plus disease stabilization rate of 50%. The median progression free survival (PFS) was 3.6 months, and the median overall survival was 4 months. The one year survival rate was 19%. Data for survival and response rate are summarized in table 2. Table 2. Survival and response rate (n=28) OR CR PR SD Median PFS Median OS 1 year suvival rate
50% (n=14) 0 14% (n=4) 36% (n=10) 3,6 months 4 months 19%
OR = overall response; CR = complete response; PR = partial response; SD = stable disease; PFS = progression free survival; OS overall survival
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Table 3. Characteristics of patients with NSCLC and long term survival using gefinitib Patient Nunber 1 2 3 4 5 6
Gender
Age
Histology
No. of Prior regimens
Smoking status
Duration of therapy
Overall survival
Male Male Male Female Female Female
41 35 52 43 85 88
Adeno BAC BAC Adeno BAC SCC
3 1 1 1 0 0
Never Smoker Never Smoker Smoker Smoker Never Smoker Smoker
18+ mo 16 mo 29+ mo 24+ mo 18+ mo 14 months
18+ mo 16 mo 29+ mo 24+ mo 18+ mo 16+ mo
Adeno = Adenocarcinoma; BAC = Braonchoalveolar carcinoma; SCC = squamous-cell carcinoma; mo = months; + denotes still on therapy and/or alive.
The treatment duration was less than 6 months for 17 patients; 6 to 9 months for 7 patients; 9 to 12 months for 1 patient and more than 12 months for 6 patients. The long-term survivors (more than 12 months alive) achieved a life span ranging from 425 to 870 days (table 3). Toxicity was generally mild in this cohort of patients, with grade 1 (42%) and 2 (11%) diarrhea and grade 1 rash (16%) being the most commonly observed side effects. One patient was removed from treatment due to interstitial lung disease.
DISCUSSION We report here a single-center experience of patients receiving gefitinib on an expanded access program. Despite the small sample, our data are similar to the IDEAL 1 trial (16) . IDEAL 1 is a multicenter, randomized, double-blind but not placebo-controlled trial of two dose levels of gefitinib (250 versus 500 mg/ day). Response rates were 10.4% in the IDEAL 1 trial versus 14% in our trial, while disease stabilization occurred in 35.9% versus 36%, PFS was 2.7 months versus 3.6 months, median survival was 7.6 months versus 4 months. Other important findings from IDEAL studies were also addressed (19). The association of response with adenocarcinoma cell type is likely and occurred in the cases containing features of bronchioloalveolar carcinoma. Smoking status (never versus current or former) seems to be an independent predictor of response, where never smokers have better response (29%) than current or former smokers (4.6%). The association of response and female gender was also observed. These variables were well documented and should be validated in future studies. It is unknown why adenocarcinoma histology was associated with better survival than squamous-cell carcinoma, especially because the latter expresses EGFR more commonly. The IDEAL 1 investigators suggested that compared with other histologies, the adenocarcinomas may have a more indolent course(16). Early EGFR overexpression has been demonstrated in the bronchial epithelium of high-risk smokers(20). It is einstein. 2006; 4(3):207-212
present at the stage of basal cell hyperplasia and persists through squamous metaplasia, dysplasia, and carcinoma in situ. The question is whether EGFR overexpression is necessary for gefitinib response. Recent evidence suggests that gefitinib response occurs across a wide range of EGFR expression levels (21-23). Exploratory analysis of tumor biopsies taken from patients in the IDEAL 1 and 2 trials used a reproducible immunohistochemical assay to estimate the correlation of EGFR membrane staining intensity (no staining, weak, moderate, or strong staining [0, 1+, 2+, 3+, respectively]) with the probability of objective tumor response or symptom improvement, with the null hypothesis that membrane staining intensity is not predictive of clinical outcome(24). The mean proportion of cells staining 2+ or 3+ was 31.3% for patients with response and 37.5% for those without response. Furthermore, in both IDEAL trials, five (15%) of 34 patients had response with less than 10% detectable staining. The mean percentage with 3+ staining was 32.1% for patients with and 22.8% for patients without symptom improvement. Therefore, the results of this analysis did not reveal a consistent association between EGFR membrane staining and either objective response or symptom improvement. More important than EGFR overexpression, determination of specific mutations in the EGFR gene has been recently reported to correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib(25). In cell lines, overexpression of other factors may predict for resistance to gefitinib. Overexpression of the antiapoptotic protein Bcl-2 decreased the response to gefitinib treatment(23). Evaluation of the mitogenactivated protein kinase/extracellular signal regulated kinase and phosphatidylinositol 3’-kinase/ Akt pathways showed considerable inhibition of these pathways by gefitinib in the highly sensitive control A431 cells (a vulvar squamous-cell carcinoma cell line), whereas one or both of these pathways remained active upon anti-EGFR treatment in NSCLC cell lines (NCIH460,NCI-A431 and A549). In addition, treatment with specific inhibitors of mitogen-activated protein kinase or phosphatidylinositol 3’-kinase resulted in a
Gefitinib for patients with advanced non-small cell lung cancer treated on the expanded access program: a single institution experience
smaller effect on proliferation than simultaneous treatment with both inhibitors, whereas induction of apoptosis was observed only when both pathways were blocked. Together, these data suggest that persistent activity of either of these signaling pathways is involved in the lack of sensitivity of NSCLC cell lines to EGFR inhibitors. Hence, a better understanding of the effect of gefitinib on the downstream signaling of the human epidermal growth factor pathways will shed further light on the mechanisms of resistance to gefitinib, which may lead us to the next step forward in the treatment of NSCLC with these targeted agents. Regarding gefitinib toxicity, the majority of our patients tolerated therapy well, with grade 1 rash (16%) and mild diarrhea (42% grade 1; 11% grade 2) being the most common toxicities. Specifically for diarrhea, the 14day dose interruption allowed by the EAP was sufficient for resolution of diarrhea as well as correction of hydration and use of antidiarrheal agents. With appropriate supportive care, gefitinib could be restarted at the same dose. This is again consistent with the observations of the IDEAL investigators(16-17). Two hundred and nine patients were assessed for safety and tolerability in the IDEAL 1 trial, 103 of whom received gefitinib at the 250mg dose level. In the cohort receiving a 250 mg/day dose, most adverse events were mild (CTC grade 1/2), there was no evidence of cumulative toxicity, and most were reversible. Adverse events were often seen before the end of the first month of treatment(16). In the 250-mg/day group, 15.5% of patients had adverse events requiring a short treatment interruption, and none required a dose reduction. The main reasons for dose interruptions were skin reactions, gastrointestinal disturbances, and elevated transaminases. Only 1.9% of patients stopped treatment because of these events. Twenty-four percent of patients on the 250-mg/day regimen took antipropulsive or antidiarrheal agents, and diarrhea resolved in 84% of patients. Skin disorders, including rash, pruritus, dry skin, and acne, were generally mild. They usually resolved during treatment or with temporary therapy interruption, or following treatment cessation. Concurrent rash and diarrhea occurred in 15.5% of patients(16). These results confirm the efficacy and safety of gefitinib treatment in a setting of pretreated patients without any prospect of improvement until now. In this study patients had to meet only a few essential eligibility criteria for enrollment in the expanded access program, which makes our data reproducible and applicable to patients attending in a community setting.
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