original contribution
`Single-Agent Gefitinib in Patients with Untreated
`Advanced Non–Small-Cell Lung Cancer and Poor
`Performance Status: A Minnie Pearl Cancer Research
`Network Phase II Trial
`
`David R. Spigel,1 John D. Hainsworth,1 Emily R. Burkett,1 Howard A. Burris,1
`Denise A. Yardley,1 Melodie Thomas,1 Suzanne F. Jones,1 Natalie R. Dickson,1
`Daniel C. Scullin,2 James E. Bradof,3 James R. Rubinsak,4 Joseph E. Brierre,5
`F. Anthony Greco1
`
`Abstract
`BACKGROUND: Patients with advanced non–small-cell lung cancer (NSCLC) and poor performance status
`(PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients.
`PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this
`study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible
`patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV
`NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional
`Assessment of Cancer–Lung questionnaire. Patient characteristics included a median age of 75 years; PS of
`2/3; and bronchoalveolar (n = 3), adenocarcinoma (n = 29), squamous cell (n = 21), large-cell (n = 11), and
`unspecified histology (n = 6). Mean treatment duration was 4 months (range, 3 days to 18 months), and medi-
`an duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70
`patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%),
`and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were
`3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50%
`and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and
`SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy
`in advanced NSCLC for patients with poor PS.
`
`Clinical Lung Cancer, Vol. 7, No. 2, 127-132, 2005
`
`Key words: First-line treatment, Multicenter trial,
`Quality of life, Stage IIIB/IV disease
`
`Introduction
`Combination chemotherapy is recommended as first-line treat-
`ment for patients with advanced non–small-cell lung cancer
`
`1Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville
`2Consultants in Blood Disorders and Cancer, Louisville, KY
`3Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC
`4Florida Cancer Specialists, Ft. Myers
`5Louisiana Oncology Associates, Lafayette
`Submitted: Jun 6, 2005; Revised: Aug 1, 2005; Accepted: Aug 9, 2005
`Address for correspondence: David R. Spigel, MD, Sarah Cannon Research
`Institute, 250 25th Ave N, Suite 110, Nashville, TN 37203
`Fax: 615-329-7374; e-mail: dspigel@tnonc.com
`
`(NSCLC) and good performance status (PS).1 Randomized studies
`have confirmed that combination chemotherapy improves overall
`survival, symptoms of advanced disease, and quality of life (QOL)
`compared with best supportive care alone.2-4 However, in patients
`with poor PS (Eastern Cooperative Oncology Group [ECOG]
`≥ 2), combination chemotherapy may result in substantial toxicity.
`Gefitinib is an oral epidermal growth factor receptor (EGFR)
`tyrosine kinase inhibitor (TKI) approved by the US Food and
`Drug Administration (FDA) as single-agent therapy for patients
`with advanced NSCLC who have progressive disease after plat-
`inum agent–based and docetaxel chemotherapies. In 2 large phase
`II monotherapy studies in patients with advanced NSCLC who
`
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`
`Clinical Lung Cancer September 2005
`
`127
`
`AVENTIS EXHIBIT 2088
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Gefitinib in Untreated Advanced NSCLC with Poor PS
`
`Table 1
`
`Visit Response Score
`
`Score
`
`Functional Assessment
`of Cancer—Lung
`
`Lung Cancer Scale
`
`Change from
`Baseline
`³ +6
`£ –6
`
`Otherwise
`³ +2
`£ –2
`
`Otherwise
`
`Visit Response
`
`Worsened
`
`Improved
`
`No change
`
`Worsened
`
`Improved
`
`No change
`
`had received previous chemotherapy, gefitinib was associated with
`symptom improvement and objective tumor responses.5,6
`Adverse events in these trials were minimal and generally limited
`to grade 1/2 rash and diarrhea. Gefitinib’s excellent safety profile
`and proven activity in refractory NSCLC make it an ideal agent
`to study in the first-line setting in patients with poor PS who are
`not candidates for combination chemotherapy.
`We conducted a phase II trial of gefitinib in patients with poor
`PS and untreated advanced NSCLC based on established antitu-
`mor activity with gefitinib and limited systemic toxicity. The dose
`and daily schedule were derived from randomized studies and
`consistent with FDA approval. The results of the phase II trial are
`reported here.
`
`Patients and Methods
`Patients
`This multicenter phase II trial was conducted in the Minnie
`Pearl Cancer Research Network, a community-based clinical tri-
`als group (see Appendix A). Eligibilty criteria included no previ-
`ous chemotherapy or biologic therapy for advanced NSCLC;
`ECOG PS of 2/3; measurable disease; absolute neutrophil count
`≥ 1500 cells/mL, platelet counts ≥ 100,000 cells/μL, hemoglobin
`≥ 8.0 g/dL, normal liver function (bilirubin < 1.5 mg/dL and
`serum aspartate aminotransferase < 2 times the upper limit of
`normal); and signed informed consent. Exclusion criteria includ-
`ed parenchymal brain metastases, with the exception of patients
`with brain metastases previously treated with definitive resection
`and/or radiation therapy with no evidence of residual disease on
`imaging. The trial was approved by the institutional review boards
`at respective participating centers.
`
`Dose and Treatment Schedule
`Gefitinib was supplied by AstraZeneca Pharmaceuticals in
`250-mg tablets. Patients received 4-week (28-day) supplies of
`gefitinib and were instructed to take 250 mg orally each morn-
`ing. No routine premedications were required. Crushing tablets
`was not permitted. For patients unable to swallow whole tablets,
`gefitinib could be dissolved in water. Four weeks of therapy was
`considered 1 cycle of treatment. There were no dose reductions;
`however, treating physicians could hold gefitinib ≤ 14 days in
`the event of grade 3/4 toxicity. After toxicity resolved to grade
`≤ 1, gefitinib was restarted at the previous dose of 250 mg per
`day. Gefitinib was discontinued only for disease progression or
`
`Table 2
`
`Quality of Life and Symptom Response Best Overall
`Response Scoring
`
`Best Overall
`Response Score
`
`Criteria
`
`Improved
`
`No Change
`
`Worsened
`
`Two visit responses of “improved” a
`minimum of 28 days apart with no interim
`visit response of “worsened.”
`
`Does not qualify for overall score response
`of “improved”; 2 visit responses of “no change”
`or “improved” a minimum of 28 days apart
`with no interim visit response of “worsened.”
`
`Does not qualify for overall score response
`of “improved” or “no change”;
`2 consecutive visit responses of “worsened.”
`
`Other
`
`Does not qualify for any of the listed score responses.
`
`if unacceptable drug-related adverse events occurred. Because of
`potential drug interactions, concomitant use of CYP3A4 induc-
`ers (phenytoin, carbamazepine, rifampicin, phenobarbital, or St.
`John’s Wort) was not allowed.
`
`Outcomes Measured
`The primary endpoint of the trial was to assess the overall
`response rate (ORR, partial plus complete response proportion)
`associated with gefitinib in patients with advanced NSCLC.
`Response was assessed according to bidimensional measure-
`ments (World Health Organization Response Evaluation
`Criteria), and toxicity was assessed according to the National
`Cancer Institute Common Toxicity Criteria, version 2.0.
`Assessment of tumor size took place at the end of every two 4-
`week cycles. Patients with stable disease or better response
`received further treatment until disease progression or unac-
`ceptable toxicity. Patients were monitored with history, physical
`examination, PS, complete blood count, and comprehensive
`metabolic profiles every 4 weeks. Progression-free survival (PFS)
`was defined as the time from start of therapy to disease progres-
`sion or last follow-up date, and overall survival (OS) was defined
`as the time from start of therapy to death or last follow-up date.
`Quality of life was evaluated at baseline and every 4 weeks
`using version 3 of the Functional Assessment of Cancer—Lung
`(FACT-L) questionnaire.7 This questionnaire uses a 5-point
`scale and addresses physical, functional, social, and emotion-
`al well-being, as well as lung cancer symptoms and concerns
`and relationship with the health care provider (not at all = 0,
`a little bit = 1, somewhat = 2, quite a bit = 3, and very much
`= 4). In addition, symptomatic response (SR) to treatment
`was evaluated at baseline and every week using the Lung
`Cancer Scale (LCS, subscale of FACT-L) diary. At a given
`visit, the criteria listed in Table 1 were used to assign a visit
`response score. At the conclusion of the trial, the criteria list-
`ed in Table 2 were used for each score, based on the individ-
`ual visit responses, to assign a best overall response score. A
`best response for the FACT-L scores was calculated based on
`the absolute change from baseline.
`Quality of life and SR score “improvement rates” were calcu-
`lated as the percentage of all analyzed patients with a best over-
`
`128 Clinical Lung Cancer September 2005
`
`

`
`Table 3
`
`Patient Characteristics
`
`Table 4
`
`Patient Outcome (N = 70)
`
`David R. Spigel et al
`
`Response
`
`Number of Patients (%)
`
`Complete Response
`
`Partial Response
`
`Stable Disease
`
`Progressive Disease
`
`Unevaluable*
`
`0
`
`3 (4)
`
`32 (46)
`
`18 (26)
`
`17 (24)
`
`*Patients included in the response analysis who were unevaluable because of intercurrent
`illness (n = 2); patient compliance/request (n = 3); physician decision (n = 1); death (n = 4);
`rapid tumor progression (n = 2); and poor subjective response (n = 5).
`
`Results
`Patient Characteristics
`From March 2003 to March 2004, 72 patients were enrolled
`on study. Two patients were ineligible because of a PS of 1.
`Baseline characteristics for all eligible patients are described in
`Table 3. The median age was 75 years (range, 55-88 years).
`Twenty-nine patients (41%) had adenocarcinoma histology; the
`others were of squamous (30%), large cell (16%), bronchoalve-
`olar (4%), or unspecified subtype (9%). Fifty-eight patients
`(83%) had a PS of 2 and 12 patients (17%) had a PS of 3. The
`mean treatment duration was 4 months (range, 3 days to 18
`months), and median duration of follow-up was 12 months
`(range, 6-18 months).
`
`Response and Survival
`Seventy patients were enrolled on study and treated with gefi-
`tinib. Seventeen patients did not complete ≥ 8 weeks (2 cycles)
`of treatment or undergo restaging studies (because of intercur-
`rent illness, n = 2; patient compliance/request, n = 3; physician
`decision, n = 1; death, n = 4; rapid tumor progression, n = 2; or
`poor subjective response, n = 5) and were deemed unevaluable.
`However, all 70 patients are included in the response analysis
`(Table 4). Three patients (4%; 95% CI, 1%-11%) exhibited a
`partial response (PR) with response durations of 32, 45, and 51
`weeks, respectively; 2 of these patients remain on study. The 3
`responding patients included 2 women and 1 man, aged 66, 73,
`
`Figure 1
`
`Progression-Free Survival with Gefitinib in Patients with
`Advanced NSCLC and Poor Performance Status
`
`Median PFS: 3.7 months
`(95% CI, 3.2-4.7 months)
`Progression-Free Survival:
`6 Months = 35% (16 patients at risk)
`1 Year = 21% (3 patients at risk)
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`Time (Months)
`
`Clinical Lung Cancer September 2005
`
`129
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Progression-Free Survival (%)
`
`Characteristic
`
`Median Age, Years (Range)
`
`Number of
`Patients (%)
`75 (55-88)
`
`Sex
`
` Female
`
` Male
`
`Performance Status
`
` 2
`
` 3
`
`Histologic Subtype
`
` Adenocarcinoma
`
` Squamous cell
`
` Large cell
`
` Bronchoalveolar
`
` Unspecified
`
`History of Smoking
`
` Yes
`
` No
`
`History of Radiation Therapy
`
` Yes
`
` No
`
`History of Cerebral Metastases at Enrollment
`
` Yes
`
` No
`
`*Smoking histories not available on all patients.
`
`29 (41)
`
`41 (59)
`
`58 (83)
`
`12 (17)
`
`29 (41)
`
`21 (30)
`
`11 (16)
`
`3 (4)
`
`6 (9)
`
`54 (96)*
`
`2 (4)
`
`12 (17)
`
`58 (83)
`
`7 (10)
`
`63 (90)
`
`all response score of “improved.” A score “control rate” was cal-
`culated as the percentage of all analyzed patients with a best
`overall response score of “improved” or “no change.” A “score
`worsened” rate was calculated as the percentage of all analyzed
`patients with a best overall response score of “worsened.”
`Demographic data and summary statistics describing the study
`population (eg, ranges and medians of age, description of base-
`line PS, tabulation of tumors, and histologies) were measured.
`Safety data, which included laboratory parameters and adverse
`events, were tabulated for all patients.
`With standard chemotherapy programs, response rates are
`approximately 10%-20%, with median survival of 3-5 months
`in patients with a PS of 2. It was hypothesized that the outcome
`of the treated patient group in this trial would be inferior to
`these reported statistics, because patients with a PS of 3 were
`included. The null hypothesis for this trial was that the overall
`response rate would be 5%. Therefore, an objective response
`rate ≥ 15%, QOL or symptom improvement rate of > 25%, or
`median survival ≥ 5 months would be study results that would
`merit further investigation of single-agent gefitinib in this
`patient population. The α level of the trial design was 0.05 and
`the power was 0.8.
`
`

`
`Gefitinib in Untreated Advanced NSCLC with Poor PS
`
`Figure 2
`
`Overall Survival with Gefitinib in Patients with Advanced
`NSCLC and Poor Performance Status
`
`Table 5
`
`Treatment-Related Nonhematologic Toxicity (n = 66)
`
`Toxicity
`
`Grade 2 (%)
`
`Grade 3 (%)
`
`Grade 4 (%)
`
`0 0
`
`1 (1.5)
`
`0 0 0
`
`1 (1.5)
`
`Fatigue
`
`Weakness
`
`Infection (including
`pneumonia, cellulites,
`and sinus infection)
`
`Nausea
`
`Vomiting
`
`Diarrhea
`
`Dyspnea/SOB
`
`Arthralgia
`
`20 (30.3)
`
`7 (10.6)
`
`4 (6.1)
`
`4 (6.1)
`
`0
`
`10 (15.2)
`
`9 (13.6)
`
`1 (1.5)
`
`11 (16.7)
`
`8 (12)
`
`1 (1.5)
`
`1 (1.5)
`
`2 (3)
`
`2 (3)
`
`5 (7.6)
`
`0
`
`Median Survival: 6.3 months
`(95%CI, 4.2-7.9 months)
`
`Overall Survival:
`6 Months = 50% (28 patients at risk)
`1 Year = 24% (6 patients at risk)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Survival (%)
`
`0
`
`3
`
`9
`
`12
`
`15
`
`18
`
`0 0 0 0 0 0 0 0
`
`1 (1.5)
`
`0 0 0 0 0
`
`2 (3)
`
`1 (1.5)
`
`2 (3)
`
`3 (4.5)
`
`0 0 0
`
`2 (3)
`
`0
`
`1 (1.5)
`
`0
`
`1 (1.5)
`
`1 (1.5)
`
`0
`
`1 (1.5)
`
`3 (4.5)
`
`8 (12)
`
`14 (21.2)
`
`4 (6.1)
`
`3 (4.5)
`
`2 (3)
`
`0 0 0
`
`1 (1.5)
`
`0
`
`1 (1.5)
`
`1 (1.5)
`
`0
`
`Myalgia
`
`Rash
`
`Anorexia
`
`Constipation
`
`Mucositits
`
`Cough
`
`Hypotension
`
`Hypertension
`
`Dizziness
`
`Dry Mouth
`
`Eye Irritation
`
`Headache
`
`Taste Change
`
`DVT/PE
`
`Abbreviations: DVT = deep vein thrombosis; PE = pulmonary embolus; SOB = shortness of breath
`
`patients completed QOL or SR surveys beyond 2 cycles: 11
`patients after 4 cycles; 6 patients after 6 cycles; and 3 patients after
`8 cycles. On average, 82% of evaluable patients reported improve-
`ments or no change in QOL from baseline. Eighty-six percent,
`82%, 87%, and 73% of patients reported improvements or no
`change in physical, social/family, emotional, and functional well-
`being, respectively (Table 7). Symptom response improvement,
`control, and worsened rates were 32%, 48%, and 47%, respec-
`tively; SR improvement and worsened rates were similar among
`patients with SD. Male patients accounted for 89% of patients
`with SD reporting worsening SR, whereas female patients repre-
`sented 67% of patients with SD reporting SR improvement.
`There were too few responses to correlate with QOL or SR rates.
`Also, the limited number of patients completing surveys prevents
`the finding of any consistent correlation between the FACT-L
`and SR rates, or between these rates and survival. Finally, too few
`patients reported histories of nonsmoking (n = 2) for correlative
`studies in terms of QOL and SR. Reasons for noncompliance
`included patient preference, illness/death, or coming off study.
`
`Discussion
`In this multicenter phase II trial, we evaluated the efficacy of
`the EGFR TKI gefitinib in the first-line treatment of advanced
`
`6
`
`Time (Months)
`
`and 83 years, with tumor histologies of adenocarcinoma (n = 2)
`and large cell (n = 2) and histories of smoking in all cases. Thirty-
`two patients (46%; 95% CI, 35%-58%) had stable disease (SD),
`and 18 patients (26%) had disease progression. The median
`PFS was 3.7 months (95% CI, 3.2-4.7 months, Figure 1). The
`6-month and 1-year PFS rates were 35% and 21%, respective-
`ly. Twenty-one of 70 patients (30%) remain alive. The median
`OS was 6.3 months (95% CI, 4.2-7.9 months; Figure 2).
`Overall survival rates at 6 months and 1 year were 50% and
`24%, respectively. Among patients with a PS of 3 (n = 12), there
`was 1 PR (8%) and 7 patients who had SD (58%), resulting in
`a disease control rate of 67%. Data on second-line therapy were
`limited to 17 patients (24% of total enrolled) and therefore are
`not available for analysis.
`
`Treatment-Related Toxicity
`Sixty-six patients were assessable for toxicity. Toxicities attrib-
`uted to gefitinib included fatigue/weakness, nausea/vomiting,
`dyspnea, diarrhea, rash, myalgias, anorexia, and anemia (Tables
`5 and 6). Grades 2 and 3 fatigue/weakness occurred in 27
`patients (41%) and 19 patients (29%), respectively. Grades 2
`and 3 nausea/vomiting occurred in 4 patients (6%) and 3
`patients (5%), respectively. Grades 2 and 3 dyspnea occurred in
`9 patients (14%) and 5 patients (8%), respectively. Grade 2/3
`anorexia was seen in 21% and 5% of patients, respectively. All
`remaining grade 3/4 toxicities, including rash and diarrhea,
`were seen in ≤ 3% of patients. Few grade 4 nonhematologic tox-
`icities were observed (infection, dyspnea, and hypertension in 1
`patient each; and deep vein thrombosis or pulmonary embolus
`in 2 patients). No grade 3/4 hematologic toxicities were seen;
`however, 13 patients (20%) had grade 2 anemia.
`
`Quality of Life and Symptom Response Analysis
`The FACT-L (QOL) and LCS (SR) questionnaires were com-
`pleted by 70% and 67% of enrolled patients, respectively, at base-
`line; and by 39% and 53% of patients included in the response
`analysis, respectively (with sufficient entries to permit best overall
`response scoring, as outlined in Table 2). A small number of
`
`130 Clinical Lung Cancer September 2005
`
`

`
`David R. Spigel et al
`
`Table 6
`
`Grade 2 Treatment-Related Hematologic Toxicity (n = 66)*
`
`Table 7
`
`Quality of Life Improvement, Control, and Worsened Rates
`
`Worsened
`Rate (%)
`
`8 7 1
`
`4 9
`
`Improvement
`Rate (%)
`12
`
`Control
`Rate (%)
`86
`
`82
`
`87
`
`73
`
`3 5 1
`
`4
`
`FACT-L
`(Well-Being)
`
`Physical
`
`Social/Family
`
`Emotional
`
`Functional
`
`inum agent–based doublet regimens have defined enrollment by
`age rather than PS. In these trials, patients with a PS of 2 account
`for a minority of patients, and patients with a PS of 3 are often
`excluded altogether. Currently, there is no standard chemothera-
`py regimen for patients with a poor PS. A European Experts Panel
`recently concluded that several single-agent and combination reg-
`imens may be appropriate in patients with a PS of 2.17 Available
`evidence for patients with a of PS 2 suggests chemotherapy results
`in a median survival of 3-5 months and a 1-year survival rate of
`18%-20%.14,15,18,19 Our study demonstrated similar efficacy
`with single-agent gefitinib as first-line therapy.
`Our study also demonstrated that gefitinib can be adminis-
`tered safely to patients who have a poor PS with advanced
`NSCLC. Grade 3/4 toxicity was primarily limited to fatigue and
`weakness, which more likely reflect patient PS. Consistent with
`the majority of gefitinib trials to date, rash and diarrhea were
`seen, but grade 3/4 toxicity was minimal. Importantly, gefitinib
`was associated with improvements or no change in disease-relat-
`ed symptoms and QOL as reported by 48% and 82% of
`patients, respectively.
`These results are consistent with those from other phase II tri-
`als in NSCLC with gefitinib.5,6 In 2 large monotherapy trials,
`gefitinib was given to patients with advanced NSCLC who had
`received ≥ 1 previous platinum agent–based regimen. The dis-
`ease control rates for each trial were 54% and 42%, respective-
`ly, with toxicities limited to grade 1/2 rash and diarrhea.
`Symptom improvement in these trials correlated with disease
`control, and median survival ranged from 7 to 8 months. The
`median ages of patients enrolled in these 2 trials were 61 and 62
`years, respectively; and the percentages of patients with a PS of
`0/1 were 87% and 80%, respectively.
`Two first-line monotherapy NSCLC studies with gefitinib
`have been reported. Twenty-five patients with advanced
`NSCLC received first-line gefitinb in an expanded access pro-
`gram.20 Patients were eligible if they had a poor PS or refused
`chemotherapy. Eighty-one percent of patients had a PS of 2 and
`the median age was 73 years old. The disease control rate was
`36% and toxicity was limited to diarrhea and rash. The median
`PFS and OS were 2.9 months and 14.1 months, respectively.
`Similarly, 22 patients deemed unfit (56%; PS > 2) or who
`refused chemotherapy received gefitinib as a part of a compas-
`sionate use program.21 The disease control rate in this small
`phase II study was 41%, and median PFS and OS were 2.2
`months and 12.6 months, respectively. Recently, preliminary
`results were reported from a phase II trial looking at the role of
`
`Toxicity
`
`Number of Patients (%)
`
`13 (19.7)
`
`0 0 0 0
`
`3 (4.5)
`
`9 (13.6)
`
`Anemia
`
`Leukopenia
`
`Thrombocytopenia
`
`Neutropenic Fever
`
`Platelet Transfusion
`
`RBC Transfusion
`
`Epoetin Alfa or Exemestane
`
`*There were no grade 3/4 toxicities.
`Abbreviation: RBC = red blood cell
`
`NSCLC in patients with poor PS (ECOG PS 2/3). The overall
`response rate was 4%, and 46% of patients had SD, resulting in
`an overall disease control rate of 50% (the proportion of patients
`with objective tumor responses combined with the proportion
`with stable disease). The median PFS and OS rates were 3.7
`months and 6.3 months, respectively.
`Our trial represents the largest prospective study of first-line
`single-agent treatment with an oral EGFR TKI in advanced
`NSCLC. The purpose of this trial was to evaluate a novel, rela-
`tively well-tolerated oral therapy in patients with poor PS (≥ 2),
`a group often underrepresented in NSCLC clinical trials.
`Patients with poor PS have largely been excluded from clinical
`trials because of the substantial risks and limited expected ben-
`efit of chemotherapy treatment.8-11 American Society of
`Clinical Oncology guidelines for the treatment of advanced
`NSCLC underscore the importance of patient selection and
`consideration of a good PS in treating patients with chemother-
`apy, cautioning selection of patients with a PS of 2.1
`In a large randomized trial comparing 4 chemotherapy regi-
`mens in the first-line treatment of advanced NSCLC, a subset
`of patients with a PS of 2 experienced significant treatment-
`related toxicity and limited 1-year survival (19%).12,13 This
`trial’s enrollment of patients with a PS of 2 was later amended
`to exclude these patients. In another recent large prospective
`study comparing paclitaxel versus carboplatin/paclitaxel in the
`first-line setting, randomization was stratified by stage (IIIB vs.
`IV), age (≥ 70 vs. < 70 years), and PS (0/1 vs. 2).14 Eighteen
`percent of patients had a PS of 2. Overall, fewer patients with a
`PS of 2 were alive at 1 year compared with patients with PS 0/1
`(14% vs. 38%). These differences were seen in combination
`and single-agent treatment arms. Similarly, in a subset analysis
`(n = 130, 19%) of the Multicenter Italian Lung Cancer in the
`Elderly Study, which compared the combination of gemc-
`itabine/vinorelbine versus either agent alone in elderly patients,
`patients with a PS of 2 had worse outcomes (response rate, time
`to progression, and survival) compared with patients with a PS
`of 0/1.15,16 Combination therapy offered no advantage over sin-
`gle-agent treatment for this subset of patients.
`Consequently, few prospective studies in advanced NSCLC
`have focused enrollment on patients with poor PS. More often,
`studies of patients not considered candidates for standard plat-
`
`Clinical Lung Cancer September 2005
`
`131
`
`

`
`Gefitinib in Untreated Advanced NSCLC with Poor PS
`
`Appendix A
`
`Minnie Pearl Cancer Research Network Participating Sites
`
`Site Name
`
`Tennessee Oncology, PLLC
`
`Wellstar Health System Cancer Research
`
`Consultants in Blood Disorders and Cancer
`
`Mary Bird Perkins Cancer Center
`
`Louisiana Oncology Associates
`
`City, State
`Nashville, TN
`
`Marietta, GA
`
`Louisville, KY
`
`Baton Rouge, LA
`
`Lafayette, LA
`
`Grand Rapids Community Clinical Oncology Program
`
`Grand Rapids, MI
`
`Upstate Carolina Community Clinical Oncology Program
`
`Spartanburg, SC
`
`Associates in Oncology and Hematology
`
`Chattanooga, TN
`
`Northeast Arkansas Clinic
`
`Central Georgia Hematology Oncology
`
`Florida Cancer Specialists
`
`Enoch Callaway Cancer Clinic
`
`Jonesboro, AR
`
`Macon, GA
`
`Ft. Myers, FL
`
`LaGrange, GA
`
`the oral TKI erlotinib in the first-line treatment of elderly
`patients (> 70 years of age) with advanced NSCLC.21 Of note,
`2 of 36 patients had a PS of 2 and the remainder had a PS of 0
`or 1. The overall response rate was 13%, and 47% had stable
`disease, resulting in a disease control rate of 60%. The median
`durations of response and stable disease were 6.8 months and
`3.5 months, respectively. Direct comparisons with other TKI
`monotherapy trials in NSCLC are difficult because of varying
`study schemas, eligibility criteria, and patient selection.
`Nonetheless, the clinical efficacy of gefitinib in our study with a
`previously untreated population with poor PS rivals data from
`these trials of previously treated younger patients with good PS.
`Still, it is important to recognize this study’s limitations. First,
`this was a single-arm phase II trial, and so it is difficult to make
`generalizations about how effective and safe gefitinib is in all
`previously untreated patients with a poor PS—especially in
`patients with a PS of 3, who comprised only 17% of this patient
`sample. Second, the compliance rate for QOL assessment was
`poor, potentially biasing any conclusions from the analysis.
`Finally, too few patients never smoked to permit any further
`analysis of gefitinib’s role in this unique population of patients
`with a poor PS.
`Conclusion
`In summary, the oral EGFR TKI gefitinib shows modest effi-
`cacy and is well tolerated in the first-line treatment of patients
`with advanced NSCLC and poor PS. Prospective studies are in
`progress to best select patients most likely to benefit from first-
`line oral EGFR TKIs as single-agent therapies or in combination
`regimens with chemotherapy. Recent data from retrospective
`analyses suggest that female sex, a history of never smoking, and
`adenocarcimoa histology are important factors in predicting ben-
`efit from TKI treatment.22,23 As well, improvements in survival
`associated with TKI-related skin toxicity provide rationale for tri-
`als designed to escalate dosing to induce rash. Moreover, the
`recent elucidation of EGFR tyrosine kinase mutations may help
`predict TKI response and survival benefit, and prospective trials
`are under way.24,25
`
`Acknowledgements
`This study was supported in part by grants from AstraZeneca
`Pharmaceuticals LP, Wilmington, DE, and The Minnie Pearl
`Cancer Foundation, Nashville, TN.
`
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