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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
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 median 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
(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 platinum agent–based and docetaxel chemotherapies. In 2 large phase II monotherapy studies in patients with advanced NSCLC who
Combination chemotherapy is recommended as first-line treatment 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: [email protected]
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Gefitinib in Untreated Advanced NSCLC with Poor PS Table 1
Table 2
Visit Response Score Score
Change from Baseline
Visit Response
³ +6
Worsened
£ –6
Improved
Otherwise
No change
³ +2
Worsened
£ –2
Improved
Otherwise
No change
Functional Assessment of Cancer—Lung
Lung Cancer Scale
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 antitumor 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 trials group (see Appendix A). Eligibilty criteria included no previous 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 included 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 morning. 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
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Quality of Life and Symptom Response Best Overall Response Scoring
Best Overall Response Score
Criteria
Improved
Two visit responses of “improved” a minimum of 28 days apart with no interim visit response of “worsened.”
No Change
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.”
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 inducers (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 measurements (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 4week cycles. Patients with stable disease or better response received further treatment until disease progression or unacceptable 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 progression 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 emotional 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 listed in Table 2 were used for each score, based on the individual 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 calculated as the percentage of all analyzed patients with a best over-
David R. Spigel et al Table 3
Table 4
Patient Characteristics
Characteristic Median Age, Years (Range)
Number of Patients (%) 75 (55-88)
Sex Female
29 (41)
Male
41 (59)
Patient Outcome (N = 70) Response
Number of Patients (%) 0
Complete Response
3 (4)
Partial Response Stable Disease
32 (46)
Progressive Disease
18 (26)
Unevaluable*
17 (24)
Performance Status 2
58 (83)
3
12 (17)
Histologic Subtype Adenocarcinoma
29 (41)
Squamous cell
21 (30)
Large cell
11 (16)
Bronchoalveolar
3 (4)
Unspecified
6 (9)
History of Smoking Yes
54 (96)*
No
2 (4)
History of Radiation Therapy Yes
12 (17)
No
58 (83)
History of Cerebral Metastases at Enrollment
*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%), bronchoalveolar (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 7 (10)
No
63 (90)
*Smoking histories not available on all patients.
all response score of “improved.” A score “control rate” was calculated 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 baseline 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.
Seventy patients were enrolled on study and treated with gefitinib. Seventeen patients did not complete ≥ 8 weeks (2 cycles) of treatment or undergo restaging studies (because of intercurrent 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
100 Progression-Free Survival (%)
Yes
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)
80 60 40 20
0
3
6
9
12
15
18
Time (Months)
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Gefitinib in Untreated Advanced NSCLC with Poor PS Figure 2 Overall Survival with Gefitinib in Patients with Advanced NSCLC and Poor Performance Status 100 Median Survival: 6.3 months (95%CI, 4.2-7.9 months)
Survival (%)
80
Overall Survival: 6 Months = 50% (28 patients at risk) 1 Year = 24% (6 patients at risk)
60 40 20
0
3
6
9
12
15
18
Time (Months)
Table 5
Treatment-Related Nonhematologic Toxicity (n = 66)
Toxicity Fatigue
20 (30.3)
11 (16.7)
0
Weakness
7 (10.6)
8 (12)
0
Infection (including pneumonia, cellulites, and sinus infection)
4 (6.1)
1 (1.5)
1 (1.5)
Nausea
4 (6.1)
1 (1.5)
0
Vomiting
0
2 (3)
0
Diarrhea
10 (15.2)
2 (3)
0
Dyspnea/SOB
9 (13.6)
5 (7.6)
1 (1.5)
Arthralgia
1 (1.5)
0
0
Myalgia
3 (4.5)
1 (1.5)
0
Rash
8 (12)
2 (3)
0
14 (21.2)
3 (4.5)
0
4 (6.1)
0
0
3 (4.5)
0
0
2 (3)
0
0
Hypotension
0
2 (3)
0
Hypertension
0
0
1 (1.5)
Dizziness
0
1 (1.5)
0
Dry Mouth
1 (1.5)
0
0
0
1 (1.5)
0
1 (1.5)
1 (1.5)
0
1 (1.5)
0
0
0
1 (1.5)
2 (3)
Anorexia
and 83 years, with tumor histologies of adenocarcinoma (n = 2) and large cell (n = 2) and histories of smoking in all cases. Thirtytwo 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%, respectively. 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 attributed 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 toxicities 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 completed by 70% and 67% of enrolled patients, respectively, at baseline; 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
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Grade 2 (%) Grade 3 (%) Grade 4 (%)
Constipation Mucositits Cough
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 improvements 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 wellbeing, respectively (Table 7). Symptom response improvement, control, and worsened rates were 32%, 48%, and 47%, respectively; 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 represented 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
David R. Spigel et al Table 6
Grade 2 Treatment-Related Hematologic Toxicity (n = 66)* Toxicity
Anemia
Number of Patients (%) 13 (19.7)
Leukopenia
0
Thrombocytopenia
0
Neutropenic Fever
0
Platelet Transfusion
0
RBC Transfusion
3 (4.5)
Epoetin Alfa or Exemestane
9 (13.6)
*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, relatively 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 benefit 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 chemotherapy, cautioning selection of patients with a PS of 2.1 In a large randomized trial comparing 4 chemotherapy regimens in the first-line treatment of advanced NSCLC, a subset of patients with a PS of 2 experienced significant treatmentrelated 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 gemcitabine/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 single-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-
Table 7
Quality of Life Improvement, Control, and Worsened Rates
Improvement FACT-L Rate (%) (Well-Being)
Control Rate (%)
Worsened Rate (%) 8
Physical
12
86
Social/Family
3
82
7
Emotional
5
87
14
Functional
14
73
9
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 chemotherapy regimen for patients with a poor PS. A European Experts Panel recently concluded that several single-agent and combination regimens 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 administered 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-related symptoms and QOL as reported by 48% and 82% of patients, respectively. These results are consistent with those from other phase II trials 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 disease control rates for each trial were 54% and 42%, respectively, 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 program.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 compassionate 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
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Gefitinib in Untreated Advanced NSCLC with Poor PS Appendix A Minnie Pearl Cancer Research Network Participating Sites Site Name Tennessee Oncology, PLLC
City, State Nashville, TN
Wellstar Health System Cancer Research
Marietta, GA
Consultants in Blood Disorders and Cancer
Louisville, KY
Mary Bird Perkins Cancer Center Louisiana Oncology Associates Grand Rapids Community Clinical Oncology Program
Baton Rouge, LA Lafayette, LA 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
Jonesboro, AR Macon, GA
Florida Cancer Specialists
Ft. Myers, FL
Enoch Callaway Cancer Clinic
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 efficacy 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 firstline 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 benefit from TKI treatment.22,23 As well, improvements in survival associated with TKI-related skin toxicity provide rationale for trials 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
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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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Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92-98. 14. Lilenbaum RC, Herndon JE, II, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 2005; 23:190-196. 15. Perrone F, Di Maio M, Gallo C, et al. Outcome of patients with a performance status of 2 in the Multicenter Italian Lung Cancer in the Elderly Study (MILES). J Clin Oncol 2004; 22:5018-5020. 16. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95:362-372. 17. Gridelli C, Ardizzoni A, Le Chevalier T, et al. Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Ann Oncol 2004; 15:419-426. 18. Le Chevalier T, Brisgand D, Douillard J, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12:360-367. 19. Soria JC, Brisgand D, and Le Chevalier T. Do all patients with advanced non-small-cell lung cancer benefit from cisplatin-based combination therapy? Ann Oncol 2001; 12: 1667-1670. 20. Kommareddy A, Coplin MA, Gao F, et al. Single-agent gefitinib as first-line therapy in patients with advanced non-small cell lung cancer: Washington University experience. Lung Cancer 2004; 45:221-225. 21. Johnson BE, Lucca J, Rabin MS, et al. Preliminary results from a phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in patients > 70 years of age with previously untreated advanced non-small cell lung carcinoma. Proc Am Soc Clin Oncol 2004; 23:633 (Abstract #7080). 22. Kaneda H, Tamura K, Kurata T, et al. Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced nonsmall-cell lung cancer. Lung Cancer 2004; 46:247-254. 23. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar Pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004; 22:1103-1109. 24. Paez JG, Janne PA, Lee JC, et al. EGFR Mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497-1500. 25. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129-2139.
Key words: First-line treatment, Multicenter trial, Quality of life, Stage IIIB/IV disease
Introduction
(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 platinum agent–based and docetaxel chemotherapies. In 2 large phase II monotherapy studies in patients with advanced NSCLC who
Combination chemotherapy is recommended as first-line treatment 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: [email protected]
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Gefitinib in Untreated Advanced NSCLC with Poor PS Table 1
Table 2
Visit Response Score Score
Change from Baseline
Visit Response
³ +6
Worsened
£ –6
Improved
Otherwise
No change
³ +2
Worsened
£ –2
Improved
Otherwise
No change
Functional Assessment of Cancer—Lung
Lung Cancer Scale
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 antitumor 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 trials group (see Appendix A). Eligibilty criteria included no previous 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 included 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 morning. 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
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Quality of Life and Symptom Response Best Overall Response Scoring
Best Overall Response Score
Criteria
Improved
Two visit responses of “improved” a minimum of 28 days apart with no interim visit response of “worsened.”
No Change
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.”
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 inducers (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 measurements (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 4week cycles. Patients with stable disease or better response received further treatment until disease progression or unacceptable 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 progression 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 emotional 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 listed in Table 2 were used for each score, based on the individual 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 calculated as the percentage of all analyzed patients with a best over-
David R. Spigel et al Table 3
Table 4
Patient Characteristics
Characteristic Median Age, Years (Range)
Number of Patients (%) 75 (55-88)
Sex Female
29 (41)
Male
41 (59)
Patient Outcome (N = 70) Response
Number of Patients (%) 0
Complete Response
3 (4)
Partial Response Stable Disease
32 (46)
Progressive Disease
18 (26)
Unevaluable*
17 (24)
Performance Status 2
58 (83)
3
12 (17)
Histologic Subtype Adenocarcinoma
29 (41)
Squamous cell
21 (30)
Large cell
11 (16)
Bronchoalveolar
3 (4)
Unspecified
6 (9)
History of Smoking Yes
54 (96)*
No
2 (4)
History of Radiation Therapy Yes
12 (17)
No
58 (83)
History of Cerebral Metastases at Enrollment
*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%), bronchoalveolar (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 7 (10)
No
63 (90)
*Smoking histories not available on all patients.
all response score of “improved.” A score “control rate” was calculated 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 baseline 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.
Seventy patients were enrolled on study and treated with gefitinib. Seventeen patients did not complete ≥ 8 weeks (2 cycles) of treatment or undergo restaging studies (because of intercurrent 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
100 Progression-Free Survival (%)
Yes
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)
80 60 40 20
0
3
6
9
12
15
18
Time (Months)
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Gefitinib in Untreated Advanced NSCLC with Poor PS Figure 2 Overall Survival with Gefitinib in Patients with Advanced NSCLC and Poor Performance Status 100 Median Survival: 6.3 months (95%CI, 4.2-7.9 months)
Survival (%)
80
Overall Survival: 6 Months = 50% (28 patients at risk) 1 Year = 24% (6 patients at risk)
60 40 20
0
3
6
9
12
15
18
Time (Months)
Table 5
Treatment-Related Nonhematologic Toxicity (n = 66)
Toxicity Fatigue
20 (30.3)
11 (16.7)
0
Weakness
7 (10.6)
8 (12)
0
Infection (including pneumonia, cellulites, and sinus infection)
4 (6.1)
1 (1.5)
1 (1.5)
Nausea
4 (6.1)
1 (1.5)
0
Vomiting
0
2 (3)
0
Diarrhea
10 (15.2)
2 (3)
0
Dyspnea/SOB
9 (13.6)
5 (7.6)
1 (1.5)
Arthralgia
1 (1.5)
0
0
Myalgia
3 (4.5)
1 (1.5)
0
Rash
8 (12)
2 (3)
0
14 (21.2)
3 (4.5)
0
4 (6.1)
0
0
3 (4.5)
0
0
2 (3)
0
0
Hypotension
0
2 (3)
0
Hypertension
0
0
1 (1.5)
Dizziness
0
1 (1.5)
0
Dry Mouth
1 (1.5)
0
0
0
1 (1.5)
0
1 (1.5)
1 (1.5)
0
1 (1.5)
0
0
0
1 (1.5)
2 (3)
Anorexia
and 83 years, with tumor histologies of adenocarcinoma (n = 2) and large cell (n = 2) and histories of smoking in all cases. Thirtytwo 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%, respectively. 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 attributed 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 toxicities 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 completed by 70% and 67% of enrolled patients, respectively, at baseline; 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
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Grade 2 (%) Grade 3 (%) Grade 4 (%)
Constipation Mucositits Cough
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 improvements 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 wellbeing, respectively (Table 7). Symptom response improvement, control, and worsened rates were 32%, 48%, and 47%, respectively; 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 represented 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
David R. Spigel et al Table 6
Grade 2 Treatment-Related Hematologic Toxicity (n = 66)* Toxicity
Anemia
Number of Patients (%) 13 (19.7)
Leukopenia
0
Thrombocytopenia
0
Neutropenic Fever
0
Platelet Transfusion
0
RBC Transfusion
3 (4.5)
Epoetin Alfa or Exemestane
9 (13.6)
*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, relatively 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 benefit 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 chemotherapy, cautioning selection of patients with a PS of 2.1 In a large randomized trial comparing 4 chemotherapy regimens in the first-line treatment of advanced NSCLC, a subset of patients with a PS of 2 experienced significant treatmentrelated 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 gemcitabine/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 single-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-
Table 7
Quality of Life Improvement, Control, and Worsened Rates
Improvement FACT-L Rate (%) (Well-Being)
Control Rate (%)
Worsened Rate (%) 8
Physical
12
86
Social/Family
3
82
7
Emotional
5
87
14
Functional
14
73
9
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 chemotherapy regimen for patients with a poor PS. A European Experts Panel recently concluded that several single-agent and combination regimens 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 administered 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-related symptoms and QOL as reported by 48% and 82% of patients, respectively. These results are consistent with those from other phase II trials 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 disease control rates for each trial were 54% and 42%, respectively, 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 program.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 compassionate 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
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Gefitinib in Untreated Advanced NSCLC with Poor PS Appendix A Minnie Pearl Cancer Research Network Participating Sites Site Name Tennessee Oncology, PLLC
City, State Nashville, TN
Wellstar Health System Cancer Research
Marietta, GA
Consultants in Blood Disorders and Cancer
Louisville, KY
Mary Bird Perkins Cancer Center Louisiana Oncology Associates Grand Rapids Community Clinical Oncology Program
Baton Rouge, LA Lafayette, LA 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
Jonesboro, AR Macon, GA
Florida Cancer Specialists
Ft. Myers, FL
Enoch Callaway Cancer Clinic
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 efficacy 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 firstline 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 benefit from TKI treatment.22,23 As well, improvements in survival associated with TKI-related skin toxicity provide rationale for trials 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
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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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