V O L U M E 2 4 䡠 N U M B E R 1 䡠 J A N U A R Y 1 2 0 0 6
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Division of Thoracic Oncol-
`ogy, National Cancer Center Hospital
`East, Chiba, Japan.
`
`Submitted May 2, 2005; accepted
`October 5, 2005.
`
`Presented in part at the 40th Annual
`Meeting of the American Society of
`Clinical Oncology, New Orleans, LA,
`June 5-8, 2004.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Address reprint requests to Seiji Niho,
`MD, Division of Thoracic Oncology,
`National Cancer Center Hospital East,
`Kashiwanoha 6-5-1, Kashiwa, Chiba
`277-8577, Japan; e-mail: siniho@
`east.ncc.go.jp.
`
`© 2006 by American Society of Clinical
`Oncology
`
`0732-183X/06/2401-64/$20.00
`
`DOI: 10.1200/JCO.2005.02.5825
`
`First-Line Single Agent Treatment With Gefitinib in
`Patients With Advanced Non–Small-Cell Lung Cancer:
`A Phase II Study
`Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma,
`Nagahiro Saijo, and Yutaka Nishiwaki
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`We conducted a phase II study of single agent treatment with gefitinib in chemotherapy-naı¨ve
`patients with advanced non–small-cell lung cancer (NSCLC) to assess its efficacy and toxicity.
`
`Patients and Methods
`Patients received 250 mg doses of gefitinib daily. Administration of gefitinib was terminated if
`partial response (PR) was not achieved within 8 weeks or if tumor reduction was not observed
`within 4 weeks. In these cases, platinum-based doublet chemotherapy was given as a salvage
`treatment. We evaluated mutation status of the epidermal growth factor receptor (EGFR) gene in
`cases with available tumor samples.
`
`Results
`Forty-two patients were enrolled between March and November 2003, with 40 of these patients
`being eligible. The response rate was 30% (95% CI, 17% to 47%). The most common toxicity
`included grade 1 or 2 acne-like rash (50%) and grade 1 diarrhea (18%). Grade 2 or 3 hepatic toxicity
`was observed in 8% of patients. Four patients developed grade 5 interstitial lung disease (ILD).
`Thirty patients received second-line chemotherapy. Median survival time was 13.9 months (95%
`CI, 9.1 to 18.7 months), and the 1-year survival rate was 55%. Tumor samples were available in 13
`patients, including four cases of PR, six cases of stable disease, and three cases of progressive
`disease. EGFR mutations (deletions in exon 19 or point mutations [L858R or E746V]) were detected
`in four tumor tissues. All four patients with EGFR mutation achieved PR with gefitinib treatment.
`
`Conclusion
`Single agent treatment with gefitinib is active in chemotherapy-naı¨ve patients with advanced
`NSCLC, but produces unacceptably frequent ILD in the Japanese population.
`
`J Clin Oncol 24:64-69. © 2006 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Previous meta-analysis demonstrated that cisplatin-
`based chemotherapy yielded a modest but signifi-
`cant survival benefit over best supportive care in
`advanced non–small-cell lung cancer (NSCLC).1-4
`In the 1990s, new agents, including vinorelbine,
`gemcitabine, paclitaxel, docetaxel, and irinotecan
`became available for the treatment of NSCLC.
`Several phase III trials comparing doublet platinum-
`based chemotherapies demonstrated no signifi-
`cant difference with respect to response rate,
`survival, or quality of life.5,6 Nonplatinum or trip-
`let platinum-based combination chemotherapies
`have been investigated, but none of these pro-
`duced longer survival than standard doublet
`platinum-based chemotherapy.7-9
`
`Recently, molecular-targeted agents have
`been introduced for the treatment of NSCLC. Ge-
`fitinib is an orally active epidermal growth factor
`receptor (EGFR) tyrosine kinase inhibitor, which
`displays activity against recurrent NSCLC after
`platinum-based chemotherapy. Two international,
`randomized phase II trials in patients with advanced
`or metastatic NSCLC after platinum-based chemo-
`therapy demonstrated response rates of 12% to 18%
`(28% in the Japanese population).10,11 Two interna-
`tional, randomized, double-blinded, placebo-
`controlled phase III trials investigated the role
`of gefitinib combined with platinum-based chemo-
`therapyregimens,includingcarboplatinandpaclitaxel,
`or cisplatin and gemcitabine in chemotherapy-naı¨ve
`patients with advanced NSCLC.12,13 Surprisingly,
`there were no improvements in overall survival,
`
`64
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`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`AVENTIS EXHIBIT 2079
`Mylan v. Aventis, IPR2016-00712
`
`

`
`First-Line Single Agent Gefitinib in NSCLC
`
`time to progression, or response rate. There are no data available
`regarding first-line treatment with single agent gefitinib against
`NSCLC in the Japanese population. Here, we conducted a phase II
`study of single agent treatment with gefitinib in chemotherapy-naı¨ve
`patients with advanced NSCLC. If a failure with gefitinib treatment
`was perceived, standard platinum-based doublet chemotherapy was
`performed as salvage. The primary end point of this phase II trial was
`response rate, and the secondary end points were toxicity, survival,
`and response rate of salvage chemotherapy.
`
`PATIENTS AND METHODS
`
`Patient Population
`Patients were required to have histologically or cytologically confirmed
`stage IIIB (malignant pleural or pericardial effusion and/or metastasis in the
`same lobe) or stage IV NSCLC. Recurrences after surgical resection were
`permitted. Other criteria included: (1) age 20 years or older, but younger than
`75 years; (2) Eastern Cooperative Oncology Group performance status (PS) 0
`or 1; (3) measurable disease; (4) PaO2 ⱖ 60 mmHg; (5) adequate organ
`function (ie, total bilirubin ⱕ 2.0, AST and ALT ⱕ 100 U/L, serum creatinine
`ⱕ 1.5 mg/dL, leukocyte count 4,000 to 12,000/mm3, neutrophil count ⱖ
`2,000/mm3, hemoglobin ⱖ 9.5 g/dL, and platelets ⱖ 100,000/mm3); (6) no
`prior chemotherapy or thoracic radiotherapy; (7) no interstitial pneumonia or
`pulmonary fibrosis, as determined by chest x-ray; (8) no paralytic ileus or
`vomiting, (9) no symptomatic brain metastases, (10) no active infection; (11)
`no active concomitant malignancy; (12) no pregnancy or breast-feeding; (13)
`no severe allergy to drugs. Patients with PaO2 less than 60 mmHg were
`excluded, because those patients might have pulmonary fibrosis, which is a risk
`factor of interstitial lung disease (ILD).14 All patients were required to provide
`written informed consent and the institutional review board at the National
`Cancer Center approved the protocol.
`
`Treatment Plan
`Treatment was started within a week after enrollment in the study.
`Patients received 250 mg of gefitinib orally daily. In the event of grade 3 or
`more and/or unacceptable toxicities, gefitinib was postponed until these tox-
`icities were improved to grade 2 or less. Dose reduction was not performed. If
`treatment was postponed four times or more, the treatment was terminated.
`Therapy was continued unless the patient experienced unacceptable toxicity or
`progressive disease, partial response (PR) was not achieved within 8 weeks, or
`the sum of the longest diameters of the target lesions decreased less than 10%
`within 4 weeks. If the gefitinib treatment failed according to these criteria,
`platinum-based doublet chemotherapy was performed as a salvage regimen.
`Previous trials of gefitinib for pretreated patients with NSCLC reported
`that most responding patients showed rapid tumor regression within 4 or 8
`weeks.11 Furthermore, most responses by gefitinib were extreme shrinkage of
`the tumor. Minor response, as frequently seen by the treatment with cytotoxic
`agents, was seldom experienced. Stable disease with gefitinib corresponded to
`no tumor reduction or slight progression. If patients with stable disease con-
`tinued the treatment with gefitinib until progressive disease became obvious,
`those patients might not be able to receive platinum-based salvage chemother-
`apy because of poor PS due to progressive disease. Platinum-based combina-
`tion chemotherapy is the standard care for patients with advanced NSCLC
`and good PS. Platinum-based chemotherapy was thought to be essential
`for patients with no response from the first-line single agent treatment with
`gefitinib. Therefore, we implemented these early stopping criteria for
`treatment with gefitinib.
`
`Study Evaluations
`Pretreatment evaluations consisted of a complete medical history, deter-
`mination of performance status, physical examination, hematologic and bio-
`chemical profiles, arterial blood gas examination, ECG, chest x-ray, bone scan,
`and computed tomography (CT) scan of the chest, ultrasound or CT scan of
`the abdomen, and magnetic resonance imaging or CT scan of the whole brain.
`
`Evaluations performed included a weekly chest x-ray for 4 weeks, and once
`every 2 weeks for biochemistry, complete blood cell, platelet, leukocyte differ-
`ential counts, physical examination, determination of performance status, and
`toxicity assessment. Imaging studies were scheduled to assess objective re-
`sponse every month.
`Response and Toxicity Criteria
`Response evaluation criteria in solid tumors (RECIST) guidelines were
`used for evaluation of antitumor activity.15 The target lesions were defined as
`ⱖ 2 cm in the longest diameter on CT scans. A complete response (CR) was
`defined as the complete disappearance of all clinically detectable tumors for at
`least 4 weeks. A PR was defined as an at least 30% decrease in the sum of the
`longest diameters of the target lesions for more than 4 weeks with no new area
`of malignant disease. Progressive disease (PD) indicated at least a 20% increase
`in the sum of the longest diameter of the target lesions or a new malignant
`lesion. Stable disease was defined as insufficient shrinkage to qualify for PR and
`insufficient increase to qualify for PD. Toxicity was graded according to the
`National Cancer Institute Common Toxicity Criteria version 2.0.
`Mutation Analysis of the EGFR Gene
`Tumor specimens were obtained during diagnostic or surgical proce-
`dures. Biopsied or surgically resected specimens were fixed with formalin or
`100% methanol, respectively. Tumor genomic DNA was prepared from
`paraffin-embedded sections using laser capture microdissection in biopsied
`specimens or macrodissection in surgically resected specimens at Mitsubishi
`Chemical Safety Institute LTD. Exons 18, 19, and 21 of the EGFR gene were
`amplified and sequenced as previously described.16
`Statistical Analysis
`In accordance with the minimax two-stage phase II study design by
`Simon,17 the treatment program was designed to refuse response rates of 10%
`(P0) and to provide a significance level of .05 with a statistical power of 80% in
`assessing the activity of the regimen as a 25% response rate (P1). The upper
`limit for first-stage drug rejection was two responses in the 22 assessable
`patients; the upper limit of second-stage rejection was seven responses within
`the cohort of 40 assessable patients. Overall survival was defined as the interval
`between enrollment in this study and death or the final follow-up visit. Median
`overall survival was estimated by the Kaplan-Meier analysis method.18 Fisher’s
`exact test was used in a contingency table.
`
`RESULTS
`
`Patient Population
`A total of 42 patients were enrolled in this study between March
`and November, 2003, with 40 of these patients being eligible. One
`patient was found ineligible due to anemia, the other because spinal
`magnetic resonance imaging could not confirm a positive bone scan.
`Patient characteristics are listed in Table 1. Sixty percent of patients
`were male; median age was 61 years. The most common histologic
`subtype was adenocarcinoma (75%). Most patients (93%) had stage
`IV disease or recurrence after surgical resection. Eighty percent of
`patients were current or former smokers.
`Efficacy
`One patient (3%) has been receiving gefitinib after 22 months.
`Four patients suspended gefitinib for 11, 14, 27, or 29 days, because
`of liver dysfunction (n ⫽ 3) and fever due to urinary tract infection
`(n ⫽ 1). Thirty-nine patients terminated gefitinib because of progres-
`sive disease (n ⫽ 20), no tumor reduction within 4 weeks (n ⫽ 12), not
`achieving PR within 8 weeks (n ⫽ 1), toxicities including pulmonary
`(n ⫽ 3), nausea and vomiting (n ⫽ 1), rash (n ⫽ 1), or hepatic
`dysfunction (n ⫽ 1).
`There were 12 PRs in 40 eligible patients, and the objective re-
`sponse rate was 30% (95% CI, 17% to 47%; Table 2). All but one
`
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`
`

`
`Niho et al
`
`Table 1. Patient Characteristics
`
`Characteristic
`
`Patients enrolled
`Patients eligible
`Sex
`Male
`Female
`Age, years
`Median
`Range
`Performance status
`0
`1
`Stage
`IIIB
`IV
`Recurrence after surgery
`Histologic type
`Adenocarcinoma
`Squamous cell carcinoma
`Large cell carcinoma
`Smoking history
`Current
`Former
`Never
`
`No. of
`Patients
`
`42
`40
`
`24
`16
`
`61
`44-74
`
`14
`26
`
`3
`34
`3
`
`30
`3
`7
`
`27
`5
`8
`
`patient from this subgroup achieved PR within 4 weeks, with the
`remaining patient achieving PR within 8 weeks. The background of
`the 12 responding patients was as follows: nine females, three males; 11
`adenocarcinomas, one large-cell carcinoma; six individuals who never
`smoked, five current smokers, and one former smoker. Response rates
`based on patient characteristics were as follows: three of 24 (13%)
`males, nine of 16 (56%) females (P ⫽ .0050); 11 of 30 (37%) individ-
`uals with adenocarcinoma, one of 10 (10%) individuals with squa-
`mous or large-cell carcinoma (P ⫽ .0048); six of 32 (19%) current or
`former smokers, and six of eight (75%) individuals who never smoked
`(P ⫽ .0048).
`The median follow-up time was 23 months, and nine patients
`were still alive at the most recent follow-up. The median survival time
`was 13.9 months (95% CI, 9.1 to 18.7 months), and the 1-year survival
`rate was 55% (Fig 1).
`Safety and Toxicity
`Toxicity was evaluated in all eligible patients. The most common
`toxicity was rash (Table 3). Thirty-eight percent and 13% of patients
`
`Table 2. Efficacy of Single Agent Treatment With Gefitinib in Patients With
`Stage IIIb or IV Non–Small-Cell Lung Cancer
`
`Type of
`Response
`
`Complete
`Partial
`CR ⫹ PR
`95% CI
`Stable disease
`Progression
`
`No. of
`Patients
`
`% of
`Patients
`
`0
`12
`12
`
`16
`12
`
`17 to 47
`
`0
`30
`30
`
`40
`30
`
`Fig 1. Overall survival of all eligible patients (n ⫽ 40) was calculated according
`to the Kaplan-Meier method. The median survival time was 13.9 months (95%
`CI, 9.1 to 18.7 months), and the 1-year survival rate was 55%.
`
`experienced grade 1 or 2 rash, respectively. One patient experienced
`grade 3 nausea and vomiting, leading to gefitinib treatment being
`terminated. Grade 3 hepatic toxicity was observed in one patient, also
`causing termination of gefitinib treatment.
`The most problematic toxicity was ILD. We reviewed the medical
`records, chest x-rays, and CT films of all the cases, which were sus-
`pected as ILD by the physician in charge. ILD was diagnosed on the
`basis of standard or high-resolution CT findings of the chest (diffuse
`ground-glass opacity, consolidation, or infiltrate) and no response to
`antibiotics. We diagnosed that four patients experienced grade 5 ILD
`during or after first-line treatment with gefitinib. The first patient was
`a 61-year-old man. He developed dyspnea and fever elevation
`(38.1°C) on day 23 of the treatment with gefitinib and administration
`of gefitinib was terminated. Chest CT demonstrated bilateral diffuse
`ground-glass opacity, and PaO2 was 43.7mmHg in the room air. KL-6
`antigen, a serum marker of interstitial pneumonia, was not elevated
`
`Table 3. Maximum Toxicity Grades Associated With Single Agent Treatment
`With Gefitinib in 40 Patients With Non–Small-Cell Lung Cancer
`
`Toxicity Grade
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Toxicity
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`Rash
`Dry skin
`Diarrhea
`Nausea
`Mucositis
`Alopecia
`Hyponatremia
`Hypokalemia
`Hepatic
`Renal
`ILD
`
`15
`4
`7
`3
`6
`4
`24
`12
`11
`4
`0
`
`38
`10
`18
`8
`15
`10
`60
`30
`28
`10
`0
`
`5
`0
`0
`0
`0
`0
`0
`0
`2
`1
`0
`
`13
`0
`0
`0
`0
`0
`0
`0
`5
`3
`0
`
`0
`0
`0
`1
`0
`0
`3
`0
`1
`0
`0
`
`0
`0
`0
`3
`0
`0
`8
`0
`3
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`4
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`10
`
`Abbreviations: CR, complete response; PR, partial response.
`
`Abbreviation: ILD; interstitial lung disease.
`
`66
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`
`

`
`First-Line Single Agent Gefitinib in NSCLC
`
`(351 U/mL) on day 24, but elevated on day 31 (1,400 U/mL). Beta-D-
`glucan, a serum marker of fungal infection and Pneumocystis carinii
`pneumonia, was also negative. Methylprednisolone and antibiotics
`were administered, with temporal improvement of ILD. However,
`subsequently, pulmonary function gradually deteriorated, leading to
`death. Autopsy revealed alveolar damage with organization around
`the bronchus and vessels in both neoplastic and non-neoplastic le-
`sions, compatible with drug-induced ILD. The second patient was a
`64-year-old man. Chest CT on day 27 showed stable disease, but
`administration of gefitinib was continued (protocol violation). Peri-
`odic chest x-ray film on day 45 showed abnormal shadow in the left
`lung field. High-resolution CT of the chest on the same day revealed
`reticular shadow on bilateral upper lobe. The treatment with gefitinib
`was terminated on day 45. KL-6 antigen was not elevated on day 49
`(276 U/mL). Methylprednisolone and antibiotics were administered,
`but were not effective, leading to death. The third patient was a 67-
`year-old man. Chest CT on day 30 demonstrated enlargement of
`primary lesion and bilateral reticular shadow in subpleural lesions.
`Gefitinib was terminated on day 30. The patient developed dyspnea
`without fever elevation on day 37. Pao2 in the room air fell to 61.0
`mmHg from 82.4 mmHg at pretreatment. Chest x-ray showed that
`the bilateral diffuse reticular shadow deteriorated. Methylpred-
`nisolone and antibiotics were administered, but were not effective,
`leading to death. Autopsy revealed severe fibrotic thickness of alveolar
`septum, compatible with severe interstitial pneumonia. There was no
`pathological evidence of carcinomatous lymphangiosis. The fourth
`patient was a 59-year-old woman. Chest x-ray showed consolidation
`in the left lung on day 21. Slight fever (37.9°C) developed on day 22.
`Blood culture was negative. Antibiotics were administered, but con-
`solidation deteriorated and spread to both lungs on day 25. Gefitinib
`was terminated on day 25. KL-6 antigen was elevated to 3,590 U/mL.
`Methylprednisolone was administered, but was not effective, leading
`to death (Table 4). Four other patients experienced ILD after second-
`line or third-line chemotherapy. Two patients received second-line
`treatment with cisplatin plus vinorelbine (one and four courses), one
`patient received treatment with cisplatin plus gemcitabine (one
`course), and one patient received third-line treatment with docetaxel
`(four courses). Three of four patients received steroids, with temporal
`
`improvement of ILD being observed in two patients. However, ILD
`deteriorated during tapering of steroid treatment, with three patients
`subsequently dying. One patient stopped the third-line treatment with
`docetaxel, with the associated ILD showing improvement in this case
`without steroid treatment (Table 4).
`We retrospectively reviewed the pretreatment chest x-rays and
`CT films of all patients. Interstitial shadow was not detected on pre-
`treatment chest x-ray films in any patients. However, six patients
`showed evidence of interstitial shadow on pretreatment chest CT
`films. Three of the six patients with interstitial shadow, as determined
`by pretreatment chest CT, experienced ILD either during or following
`administration of gefitinib or second-line chemotherapy. None of the
`six patients responded to gefitinib treatment. On the other hand, four
`of 34 patients who showed no interstitial shadow on pretreatment
`chest CT films experienced ILD. Interstitial shadow as determined by
`pretreatment chest CT was not a statistically significant risk factor of
`ILD (P ⫽ .0819; Table 5).
`
`Second-Line Chemotherapy
`A total of 30 patients received second-line chemotherapy.
`Twenty-seven patients received platinum-based chemotherapy (cis-
`platin plus vinorelbine; n ⫽ 17), carboplatin plus paclitaxel (n ⫽ 5),
`cisplatin plus gemcitabine (n ⫽ 3), cisplatin plus docetaxel (n ⫽ 1),
`and cisplatin plus irinotecan (n ⫽ 1). The remaining three patients
`received vinorelbine plus gemcitabine or vinorelbine alone. Nine of 30
`patients achieved PR with these second-line chemotherapies. The
`objective response rate of second-line chemotherapy was 30% (95%
`CI, 15% to 50%).
`
`Mutation Status of the EGFR Gene
`Out of 42 enrolled patients, 16 patients were diagnosed patholog-
`ically, 22 were diagnosed cytologically, and four patients recurred after
`surgical resection. Biopsied specimens were available in nine patients.
`Therefore, tissue samples were available in a total of 13 patients. These
`13 patients included four PRs, six with stable disease, and three PDs.
`EGFR mutations were detected in four tumor tissues, including the
`in-frame nucleotide deletions in exon 19 (n ⫽ 3) and an L858R
`mutation in exon 21 (n ⫽ 1). One tumor had an in-frame deletion and
`
`Table 4. Four Patients Developed Interstitial Lung Disease During First-Line Chemotherapy With Gefitinib, With Another Four Patients Showing ILD During
`Either Second- or Third-Line Chemotherapy
`
`Age
`(years)
`
`61
`64
`67
`59
`61
`68
`68
`59
`
`Sex
`
`M
`M
`M
`F
`M
`M
`M
`M
`
`Smoking
`Index
`
`1,520
`880
`1,880
`0
`820
`2,000
`705
`1,170
`
`Pathology
`
`Onset of ILD
`
`Response to
`Gefitinib
`
`Death From
`Chemotherapy
`
`AD
`AD
`SQ
`AD
`AD
`LA
`AD
`AD
`
`Day 23ⴱ
`Day 45ⴱ
`Day 37†
`Day 21ⴱ
`Day 131‡
`Day 37‡
`Day 22§
`Day 108储
`
`PD
`SD
`PD
`PD
`SD
`PD
`PR
`SD
`
`Day 74
`Day 51
`Day 45
`Day 35
`Day 154
`Day 106
`Day 87
`Alive
`
`Abbreviations: ILD, interstitial lung disease; M, male; F, female; AD, adenocarcinoma; SQ, squamous cell carcinoma; LA, large-cell carcinoma; PD, progressive
`disease; SD, stable disease; PR, partial response.
`ⴱDuring gefitinib administration.
`†One week after discontinuation of gefitinib.
`‡ After 2nd-line chemotherapy of cisplatin and vinorelbine.
`§ After 2nd-line chemotherapy of cisplatin and gemcitabine.
`储 After 3rd-line chemotherapy of docetaxel.
`
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`

`
`Niho et al
`
`Table 5. Interstitial Shadow on Pretreatment Chest Computed Tomography
`Films and ILD
`
`Interstitial Shadow on Pretreatment
`Chest Computed Tomography Scans
`
`No existence
`Existence
`
`NOTE. P ⫽ .0819.
`Abbreviation: ILD interstitial lung disease.
`
`No ILD
`
`29
`3
`
`ILD
`
`5
`3
`
`an E746V mutation in exon 19. All four PR patients had EGFR muta-
`tions (Table 6).
`
`DISCUSSION
`
`This phase II study was designed to evaluate the efficacy and safety of
`first-line single agent treatment with gefitinib in patients with ad-
`vanced NSCLC. There is no other paper that evaluates single agent
`treatment with gefitinib prospectively in patients with advanced
`NSCLC. The observed response rate of 30% (95% CI, 17% to 47%),
`median survival of 13.9 months and 1-year survival of 55% are prom-
`ising. However, grade 5 ILD occurred in 10% (95% CI, 3% to 24%) of
`patients. This high rate of ILD was not acceptable. The incidence of
`ILD was seen to be less than 1% in two randomized controlled studies
`comparing gefitinib with placebo in combination with gemcitabine
`and cisplatin or paclitaxel and carboplatin.12,13 The reason for the high
`incidence of ILD observed in our study is unknown. The West Japan
`Thoracic Oncology Group analyzed 1,976 patients receiving gefitinib
`retrospectively. In this case, the incidence of ILD was 3.2% (95% CI,
`2.5% to 4.6%) and the death rate due to ILD was 1.3% (95% CI,
`0.8% to1.9%). Multivariate analyses found that risk factors in-
`
`cluded being male, individuals who smoked, and complication of
`interstitial pneumonia.14 Our retrospective analyses revealed that
`three of six patients with interstitial shadow on pretreatment chest
`CT films, but not detected on chest x-ray films developed ILD; on
`the other hand, five of 34 patients without interstitial shadow
`developed ILD. Interstitial shadow on pretreatment chest CT was a
`marginally significant risk factor of ILD (P ⫽ .0819). It might be
`suggested that patients with interstitial shadow on pretreatment
`chest CT films be excluded from administration of gefitinib; how-
`ever, our analyses were biased because we analyzed retrospectively
`and did not blind patient clinical information. Prospective analysis
`is needed to evaluate interstitial shadow by chest CT before treat-
`ment with gefitinib.
`The Southwest Oncology Group conducted a phase II trial to
`evaluate gefitinib in patients with advanced bronchioloalveolar
`carcinoma (SWOG 0126). Previously untreated (n ⫽ 102) and
`treated (n ⫽ 36) patients were entered and eligible in SWOG 0126.
`The response rate was 19% and the median survival time was 12
`months in the untreated population.19 These subset analyses were
`comparable to our results.
`Recently, mutations in the tyrosine kinase domain of EGFR were
`found to be associated with gefitinib sensitivity in patients with
`NSCLC.16,20,21 Our retrospective analyses demonstrated that EGFR
`mutations were detected in four of 13 patients, and those four patients
`achieved PR in the single agent treatment of gefitinib. These results
`were compatible with previous reports.16,20,21
`Thirty patients received second-line chemotherapy, including
`platinum-based (n ⫽ 27) and nonplatinum-based (n ⫽ 3) regi-
`mens; the response rate was 30%. Pretreatment with gefitinib does
`not seem to adversely affect the response of second-line chemo-
`therapy. However, our small-scale study does not suggest the best
`second-line regimen. Platinum combined with any third-
`generation agents including paclitaxel, docetaxel, vinorelbine,
`
`Sex
`
`M
`
`F
`
`F
`
`F
`
`M
`M
`M
`M
`M
`M
`M
`F
`F
`
`Age
`(years)
`
`Pathologic
`Type
`
`68
`
`67
`
`54
`
`57
`
`61
`54
`45
`59
`67
`59
`61
`61
`61
`
`AD
`
`AD
`
`AD
`
`AD
`
`AD
`AD
`AD
`AD
`SQ
`AD
`AD
`SQ
`AD
`
`Smoking
`Status
`
`Current
`
`Current
`
`Current
`
`Never
`
`Current
`Current
`Current
`Current
`Current
`Current
`Current
`Current
`Current
`
`Overall
`Survival
`(months)
`
`14.9
`
`16.2
`
`5.6
`
`25.4
`
`7.5
`9.7
`16.2
`14.7
`2.4
`24.9
`2.4
`3.4
`16.3
`
`Table 6. Mutation Status of the EGFR Gene
`
`EGFR Gene
`
`Effect of Mutation
`
`Response to
`Gefitinib
`
`Response to
`Second Line
`Chemotherapy
`
`Deletion of 15 nucleotides
`(2236-2250)
`Deletion of 15 nucleotides
`(2236-2250)
`Deletion of 18 nucleotides
`(2238-2255) and
`substitution of T for A
`at nucleotides 2237
`Substitution of G for T at
`nucleotide 2573
`Wild
`Wild
`Wild
`Wild
`Wild
`Wild
`Wild
`Wild
`Wild
`
`In-frame deletion (E746-A750)
`
`In-frame deletion (E746-A750)
`
`In-frame deletion (L747-S752)
`and amino acid substitution
`(F746V)
`
`Amino acid substitution
`(L858R)
`
`—
`—
`—
`—
`—
`—
`—
`—
`—
`
`PR
`
`PR
`
`PR
`
`PR
`
`SD
`SD
`SD
`SD
`SD
`SD
`PD
`PD
`PD
`
`PD
`
`PD
`
`NR
`
`SD
`
`SD
`SD
`PR
`PR
`NR
`PR
`NR
`PD
`PR
`
`Abbreviations: EGFR, epidermal growth factor receptor; M, male; F, female; AD, adenocarcinoma; SQ, squamous cell carcinoma; PR, partial response; SD, stable
`disease; PD, progressive disease; NR, not received.
`
`68
`
`JOURNAL OF CLINICAL ONCOLOGY
`Downloaded from jco.ascopubs.org on June 17, 2016. For personal use only. No other uses without permission.
`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`First-Line Single Agent Gefitinib in NSCLC
`
`gemcitabine, or irinotecan is probably acceptable as the current
`standard first-line chemotherapy.
`First-line single agent with gefitinib is active, but produces unac-
`ceptably frequent ILD in the Japanese population. Being female, as
`well as adenocarcinoma, those who never smoked, and EGFR muta-
`tion were associated with response to gefitinib. Patients who re-
`sponded to gefitinib did not experience ILD during gefitinib
`chemotherapy. Further research via genetics and image analysis is
`
`needed to avoid ILD and identify a subgroup of patients that benefit
`from gefitinib treatment. If this is realized, single agent treatment with
`gefitinib could be an option as first-line chemotherapy in selected
`patients with advanced NSCLC. Furthermore, randomized trials are
`warranted to compare first-line single agent treatment with gefitinib
`followed by second-line platinum-based chemotherapy with first-line
`platinum-based chemotherapy followed by second- or third-line ge-
`fitinib treatment.
`
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