Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients

A. Haringhuizen1, H. van Tinteren2, H. F. R. Vaessen2, P. Baas1 and N. van Zandwijk1,*

Departments of 1 Thoracic Oncology and 2 Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Received 22 September 2003; revised 13 January 2004; accepted 20 January 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

We describe 16 months’ single-institution experience with gefitinib (‘Iressa’, ZD1839) used as ‘ultimum refugium’ for pretreated non-small-cell lung cancer (NSCLC) patients.

Patients and methods:

Toxicity, response and survival data of NSCLC patients participating in a compassionate-use program with gefitinib were reviewed. Documented disease progression and confirmation of the absence of other treatment options were requested. Oral gefitinib at a dose of 250 mg/day was given until disease progression, unacceptable toxicity or death. Cox’s proportional hazards model was used to analyze relationships between factors and probability of survival.

Results:

Rapid disease precluded treatment in eight cases. Of 92 evaluable patients, one-third had a baseline performance status (PS) of ≥2. The main side-effects of gefitinib were grade 1–2 diarrhea and skin rash. A disease control rate of 46% (objective response rate 8.7%) and 1-year survival of 29% were documented. Histology (adenocarcinoma) and a ‘never-smoking’ history were predictive of response. Number of previous chemotherapy regimens, gender, time since diagnosis and time since last chemotherapy lacked such an association. Radiotherapy during gefitinib treatment was well tolerated and was associated with prolonged survival in a patient with multiple brain metastases. Multivariate analyses revealed a significant impact of PS on survival. A ‘never-smoking’ history, adenocarcinoma/bronchoalveolar-cell carcinoma and female gender showed a trend towards better survival outcomes.

Conclusion:

Gefitinib’s single-agent activity in a group consisting of pretreated NSCLC patients is confirmed. Side-effects of gefitinib were mild. Prolonged survival was associated with good PS and less significantly with a never-smoking history, female gender and histology. Additional studies on mechanisms of tumor control and selection of target populations for this remarkable new drug are warranted.

Key words: non-small-cell lung cancer, NSCLC, gefitinib, Iressa, EGRA – tyrosine kinase inhibitor, ZD183g, bronchoalveolar-cell carcinoma


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Worldwide, lung cancer remains the most common cause of cancer death, and at the time of diagnosis the majority of patients will have advanced disease not amenable to curative approaches [1]. Apart from symptom relief, platinum-based chemotherapy, when given to patients with advanced non-small-cell lung cancer (NSCLC), provides a survival advantage of limited duration [2, 3]. Combinations of newer active agents, such as gemcitabine, paclitaxel and docetaxel, with platinum have been associated with additional improvement in survival [4, 5]. However, there are several indications that a therapeutic plateau has been reached with the current chemotherapy options, and new effective treatment approaches are urgently needed.

The epidermal growth factor receptor (EGFR) has been found to be expressed or highly expressed in a variety of solid tumors, including NSCLC [6, 7]. Molecular studies have revealed abnormal signal transduction in lung cancer cells and high EGFR expression levels have been associated with an unfavorable clinical outcome, making the receptor a promising target for anticancer therapy [8, 9].

Gefitinib, a synthetic anilinoquinazoline, is an orally available inhibitor of the tyrosine kinase domain of the EGFR [10]. The therapeutic efficacy of this molecule was first observed during phase I evaluation [1113]. Partial responses in NSCLC patients have been documented and some of these responses continued for >9 months. Antitumor activity was observed at doses lower than the maximum tolerated dose of ~700 mg/day. Two phase II randomized trials comparing gefitinib at dose levels of 250 and 500 mg/day in patients with previously treated NSCLC have recently confirmed the important single-agent activity of gefitinib and revealed that 250 mg/day was as effective as, but less toxic than, 500 mg/day [14, 15]. Here, we present a review of our 16 months’ experience with gefitinib.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
This report details a retrospective analysis of patients with pathologically proven NSCLC who were enrolled in the AstraZeneca Expanded Access Program to allow compassionate use of gefitinib. From May 2001 to September 2002, 55 males and 45 females were offered gefitinib as ‘ultimum refugium’ after failure of previous chemotherapy or if no other treatment option was available. Brain metastases were considered an exclusion criterion, but patients with performance status (PS) >2 and short life expectancy were allowed to enter the program. Oral gefitinib was given at a dose of 250 mg/day. Tablets were supplied on a 12-weekly basis for an indefinite period until disease progression, unacceptable toxicity or death. All participants gave written, informed consent and the protocol was approved by the medical ethics review committee of The Netherlands Cancer Institute.

Baseline assessment included medical history (including prior anticancer therapy), smoking history, physical examination and vital signs, PS, complete blood cell count and blood biochemistry, chest X-ray and tumor assessment (X-rays or computed tomography scans). At follow-up (every 4–6 weeks), interval history, chest X-ray, tumor assessment, complete blood count and biochemistry were collected. Compliance with study medication and data regarding symptomatic benefit (pulmonary symptoms) and concomitant therapy were extracted from the patient records. All chest X-rays were reviewed to confirm the objective response rate and obtain a picture of any potential pulmonary toxicity elicited by gefitinib [16, 17]. Treatment-related toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [18].

Statistical methods
Retrospective analyses were made for response, survival and toxicity. Responses were measured according to RECIST (Response Evaluation Criteria in Solid Tumors; EORTC) [19]. Disease control was defined as the best tumor response of complete response (CR), partial response (PR) or stable disease (SD) confirmed and sustained for ≥4 weeks. Response rates between subgroups were compared using Fisher’s exact test. Survival and progression-free survival were defined as the period from the date of commencing gefitinib treatment to the date of death or disease progression, respectively, or last follow-up. Survival curves were constructed using the Kaplan–Meier method. Cox proportional hazard analysis was performed to explore the combined effects of variables in relation to survival. Six variables were included in the model: four patient (age, gender, PS and smoking history) and two tumor (stage and histology) characteristics. All analyses were performed using SAS® 8.2 software and S-PLUS® 6 software. Figures were created with programmes developed by Harrell [20]. The model was verified for its regression assumptions (proportional hazards, linearity, additivity) via examination of the residuals. Differences were considered significant if P <0.05.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
Eight of the 100 patients registered suffered rapid disease progression/deterioration precluding treatment with gefitinib, leaving 92 patients evaluable for response, toxicity and survival (Table 1). Median age was 58 years (range 33–76). One-third of patients had a PS of ≥2 and a majority had stage IV disease (86%) and adenocarcinoma (62%), including six cases with bronchoalveolar-cell carcinoma (BAC). Eighty-five (92.5%) patients had received prior chemotherapy. In a large majority of cases (94%) a platinum-containing combination had been used in first-line treatment. Sixty per cent had received one prior chemotherapy regimen, 21% two regimens, 8% three regimens and 2% four regimens before starting with the Expanded Access Program. Five patients with contraindications for platinum-based chemotherapy received gefitinib as first systemic treatment. In two cases, a first-line choice of gefitinib was made on the basis of congestive heart failure and psychiatric illness (phobia).


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Table 1. Patient characteristics at study entry
 
Treatment administration and toxicity
In all, 1478 weeks of treatment were analyzed (median 10.7 weeks; range 0.4–75.3). Twenty-six patients were still receiving gefitinib at the time of the present analysis. Reasons for temporary discontinuation of treatment included one patient with grade 4 toxicity (diarrhea), two with grade 3 toxicity (diarrhea and skin rash), three receiving palliative radiotherapy and one undergoing surgery for imminent myelocompression. All six patients resumed treatment within 2–33 days, and three were still receiving gefitinib in September 2002.

Overall, the toxicity of gefitinib was modest (Table 2). Common side-effects were grade 1–2 skin rash and diarrhea in 34% and 22% of patients, respectively. Less prominent were nausea/vomiting, anorexia and desquamation/itching. Gefitinib-related toxicity became apparent after 2–4 weeks of treatment and was swiftly reversible upon treatment discontinuation.


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Table 2. Toxicity of gefitinib
 
In addition to existing pathology, interstitial pulmonary abnormalities were discovered in seven patients. In five of these patients this coincided with obvious tumor progression, in one with tumor progression and infection, and in one with a documented infection (Table 3). One asymptomatic patient developed interstitial pulmonary changes during the first 4 weeks on treatment. Upon prolongation of gefitinib therapy, X-ray changes disappeared and an objective response was achieved that is still continuing (>14 months).


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Table 3. Characteristics of patients reviewed for interstitial lung disease (ILD)
 
Response to treatment and survival analysis
The objective response rate was 8.7% [1 CR, 7 PR; exact 95% confidence interval (CI) 3.8–16.4%). The duration of the response ranged from 1.2 to 15.8+ months. Thirty-four patients (37%) experienced SD, amounting to a disease control rate of 45.7% (Table 4). Responses were documented in patients with adenocarcinoma only (P = 0.0221), were more frequent among never-smokers (P = 0.0015) and did not show any relation (univariate analysis) to gender, age, number of prior chemotherapy regimens, time since last chemotherapy, time since diagnosis or stage of disease.


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Table 4. Response, survival and histology
 
Fifty-eight of the 92 patients had died at the time of analysis and 34 were censored. After a median follow-up of 8 months, the median survival was 4.9 months (95% CI 3.3–5.7) and 1-year survival 29% (95% CI 17–40%) (Figure 1). Median progression-free survival was 1.6 months (95% CI 1.3–2.0) for the whole group, 4.1 months (95% CI 3.2–5.0) for patients with SD and 8 months (95% CI 3.3–15.9) for the responders. Multivariate regression modeling showed that only patients with PS 2–4 had a significantly worse prognosis (hazard ratio 12.0; 95% CI 2.7–54), while there was a trend toward better survival for females, never-smokers and patients with adenocarcinoma/BAC. Age and disease stage were not significantly associated with overall survival (Figure 2).



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Figure 1. Survival and histology.

 


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Figure 2. Hazard ratios (mortality) and 95% (blue) and 99% (red) confidence bars for the effects of potential predictors (age was included as a continuous variable; 25th and 75th quartiles are presented) [20].

 
Despite radiological signs of disease progression, clinical benefit was documented in 21 patients. Twenty-four patients had palliative radiotherapy while receiving gefitinib and tolerated this approach without extra toxicities. In two cases this concerned brain irradiation for isolated brain recurrence; the first patient progressed after 5 months and the second continues to respond in the brain and chest after more than 9 and 14 months, respectively. Five patients developed bone metastases while the disease in the chest responded or was unchanged (one PR, four SD).


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Our experience with gefitinib is in line with recent reports by others [14, 15], confirming durable single-agent activity combined with a mild toxicity profile in a significant proportion of patients for whom no other treatment options existed. Cardiac, renal or hematological toxicities were not seen and the main side-effects were grade 1–2 acneiform skin rash and diarrhea. The occurrence of skin disorders is explained by the fact that EGFR is also expressed in the basal layer of the skin; inhibition of the receptor will disturb normal biology and result in skin rash [21]. A comparable mechanism might be responsible for diarrhea.

Interstitial lung disease (ILD) attributed to gefitinib has recently attracted attention [16, 17]. Retrospectively, we diagnosed ILD in one patient. The interstitial abnormalities discovered were asymptomatic and transient. Other patients with interstitial pulmonary abnormalities had obvious tumor progression (lymphangitis). ILD is a complex entity that accompanies different disorders such as cardiac failure, pulmonary metastases/lymphangitis and infections and is seen relatively frequently following chemotherapy and radiotherapy [22, 23]. Therefore, a causal relationship between ILD and gefitinib cannot be easily made. Recently analyzed trials (‘Iressa’ NSCLC Trial Assessing Combination Treatment; INTACT 1 and 2) studying the addition of gefitinib to standard chemotherapy showed a low incidence of ILD in both the gefitinib (1.1%) and placebo arms (0.9%) [24, 25]. Our data, and more importantly the experience with 37 000 patients in the AstraZeneca global Expanded Access Program, also revealed a low percentage (0.36%) of potential pulmonary complications, suggesting that the first report on ILD might have overestimated this problem [16].

Initially patients were advised to stop gefitinib therapy when palliative radiotherapy for brain or bone metastases was judged appropriate. Later in the program, discontinuation of gefitinib was avoided in those patients, who still had symptomatic benefit or intrathoracic disease control while developing metastases. With the combination gefitinib and radiotherapy, excellent symptomatic responses were seen without significant extra- or intracranial toxicity. For example, one patient with isolated brain recurrence is responding >9 months after radiotherapy (plus gefitinib). Other studies, including phase I experience in children with glioblastoma multiforme, also suggest that the response on radiotherapy is enhanced by gefitinib. At the same time an increasing number of observations indicate that gefitinib alone is also effective in NSCLC patients with brain metastases [2630]. Recent experimental studies have provided evidence for release of growth factor activity by ionizing radiation and an enhanced antitumor effect if ionizing radiation was followed by gefitinib, for which inhibition of growth factors and DNA repair are being held responsible [3136]. These observations call for larger trials designed to evaluate and define the role of gefitinib in the treatment of brain metastases in NSCLC patients, either as single agent or in combination with radiation therapy.

An objective response rate of almost 9% and a disease control rate of >45% in a group of NSCLC patients with poor prognostic characteristics confirms the important single-agent activity of gefitinib. Our population was not restricted to patients with PS 0–2 or a life expectancy of >12 weeks. In a univariate analysis, adenocarcinoma and a non-smoking history were predictive for response, which partly confirms observations by others, who found BAC histology and non-smoking history to be predictive of response [37]. We noted the longest survival among the (small) subgroup of patients with BAC. Erlotinib, another EGFR inhibitor, has also shown prominent activity in patients with BAC [38]. Given the fact that EGFR expression is strongest in squamous-cell carcinomas, this is an intriguing observation, suggesting that mechanisms other than receptor blocking may provide clues about successful treatment with gefitinib. The IDEAL (‘Iressa’ Dose Evaluation in Advanced Lung cancer) 1 study that identified adenocarcinoma as a prognostic factor received a similar comment [39]. HER2 co-expressing with EGFR may be the underlying mechanism for prominent effects of gefitinib in BAC [40]. However, our group of patients suggests that the effect of histology on survival is less important than PS, and confirms that prolonged symptom and disease control is possible without response. Thus, efficacy cannot be determined by response status alone, and the identification of a validated marker of gefitinib activity will be a leap forward in the use of this remarkable drug in daily practice.

Docetaxel, with a response rate of 7% and a survival gain of 7 weeks (median survival 7.5 months versus 4.6 months with best supportive care alone) in pretreated patients with a PS 0–2, has been accepted as a standard second-line treatment for NSCLC [41]. Our data suggest that gefitinib, when given to patients failing on platinum-based chemotherapy with a reasonable performance status, might have similar efficacy. This underlines the need for a randomized comparison of these two drugs.

In conclusion, gefitinib’s single-agent activity and mild toxicity profile are confirmed in a NSCLC population for whom no other treatment options existed. Efficacy was especially prominent in patients with adenocarcinoma (BAC) and no smoking history. Asymptomatic, transient interstitial pulmonary abnormalities were observed in one patient, and additional data are needed to validate the relationship between gefitinib and ILD. Excellent results with gefitinib given concurrently with radiotherapy merit additional studies on combined treatment.


    Acknowledgements
 
‘Iressa’ is a trademark of the AstraZeneca group of companies. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries. ® indicates USA registration. S-PLUS is a registered trademark of Insightful Corporation.


    FOOTNOTES
 
* Correspondence to: Dr N. van Zandwijk, Department of Thoracic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Tel: +31-20-5122958; Fax: +31-20-5122572; E-mail: n.v.zandwijk@nki.nl Back


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 Discussion
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