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Phase II Randomized Trial of Erlotinib or Vinorelbine in Chemonaive, Advanced, Non-small Cell Lung Cancer Patients Aged 70 Years or Older
ORIGINAL ARTICLE
Phase II Randomized Trial of Erlotinib or Vinorelbine in Chemonaive, Advanced, Non-small Cell Lung Cancer Patients Aged 70 Years or Older Yuh-Min Chen, MD, PhD, FCCP,*†‡ Chun-Ming Tsai, MD,* Wen-Chien Fan, MD,§ Jen-Fu Shih, MD,* Shih-Hao Liu, MD,储 Chieh-Hung Wu, MD,* Teh-Ying Chou, MD, PhD,储 Yu-Chin Lee, MD,* Reury-Perng Perng, MD, PhD,* and Jacqueline Whang-Peng, MD‡
Introduction: The primary objective of this study was to compare the response rates of elderly, chemonaive patients with advanced non-small cell lung cancer (NSCLC) treated with daily oral erlotinib versus oral vinorelbine. Methods: Chemonaive Taiwanese patients aged 70 years or older who had advanced NSCLC were randomized to receive either oral erlotinib 150 mg (E) daily or oral vinorelbine 60 mg/m2 (V) on days 1 and 8 every 3 weeks. Results: From February 2007 to July 2008, 116 patients were enrolled and 113 were included in the intent-to-treat population: 57 patients in the E group and 56 patients in the V group. Objective response rates were 22.8% (13 of 57) in E and 8.9% (5 of 56) in V (p ⫽ 0.0388). Median progression-free survival (PFS) was 4.57 months in E and 2.53 months in V (p ⫽ 0.0287), with an 80.6% increase in median PFS for E compared with V. Median survival time was 11.67 months in E and 9.3 months in V (p ⫽ 0.6975). Toxicities were generally mild in both groups. Median PFS was longest for epidermal growth factor receptor gene (EGFR)-mutated patients in the E group, followed by EGFR-mutated patients in V, EGFR wild type in E, and EGFR wild type in V (p ⫽ 0.0034). Overall survival was longer for EGFR-mutated patients than for EGFR wild-type patients (p ⬍ 0.0001). Conclusions: Erlotinib is highly effective compared with oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. EGFR-mutated patients had better survival than those with EGFR wild-type disease, regardless of the treatment received. Key Words: Chemotherapy, Epidermal growth factor receptor, Nonsmall-cell lung cancer, Targeted therapy, Tyrosine-kinase inhibitor. (J Thorac Oncol. 2012;7: 412–418) *Chest Department, Taipei Veterans General Hospital; †Department of Medicine, School of Medicine, National Yang-Ming University; ‡Centre of Excellent Cancer Research (CECR), School of Medicine, Taipei Medical University; §Chest Department, Chutung Veterans General Hospital; and 储Koo Foundation Sun Yat-Sen Cancer Centre, Taipei, Taiwan. Diclosure: The authors have no conflicts of interest. Address for correspondence: Dr. Yuh-Min Chen, Chest Department, Taipei Veterans General Hospital, 201, Sec. 2, Shih-pai Road, Taipei 112, Taiwan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0702-0412
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ung cancer is typically a disease of elderly patients, with incidence peaking in the 70- to 80-year age group.1 An analysis of the Surveillance, Epidemiology, and End Results Database revealed that patients aged 70 years or older accounted for 47% of all lung cancers.2 Despite the fact that elderly patients account for the majority of the lung cancer population, they are less likely to receive treatment than younger patients.3,4 There is also an underrepresentation of elderly patients (those aged 70 years or older) in clinical trials of chemotherapy in non-small cell lung cancer (NSCLC).5 Thus, clinical trials specifically designed to investigate treatments for elderly patients with NSCLC are important and should be prioritized.6 Single-agent chemotherapy, with agents such as gemcitabine or vinorelbine, is the typical option for advanced NSCLC in treatment-naive elderly patients.6 – 8 Data analysis suggests that outcomes in the fit elderly mirror results observed in younger patients, although treatment-related toxicity is generally worse.6,9,10 We recently published data showing that combining vinorelbine with cisplatin produced a better response rate and longer median time to disease progression versus vinorelbine alone in elderly patients with NSCLC. This improvement in some efficacy endpoints, however, came with significantly increased toxicity and no survival advantage for the doublet.11 The efficacy of oral vinorelbine is similar to that of the intravenous form, but the oral form is more convenient and does not necessitate central venous access as required with a Port-A implantation.12 Considering that all third-generation agents (vinorelbine, gemcitabine, and taxanes) have similar activity and efficacy in NSCLC, and single-agent vinorelbine is considered a standard regimen for elderly patients with NSCLC, oral vinorelbine may be more attractive and convenient for many elderly patients and their healthcare providers, because it is easy to use with no need for intravenous injection. Epidermal growth factor receptor (EGFR) tyrosinekinase inhibitors (TKIs), such as erlotinib and gefitinib, are active agents against advanced NSCLC when given as second- or third-line therapy, compared with best supportive care or standard chemotherapy.6,13,14 Several trials have been conducted with these agents in selected groups of chemona-
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ive patients with advanced NSCLC, such as elderly and poor performance status (PS) patients, to address the concern about treatment-related toxicities (TRTs) with conventional chemotherapy.15–19 EGFR TKIs have also been investigated in highly selected groups of chemonaive NSCLC patients with the intention of selecting patients most likely to respond to EGFR TKI therapy, such as those whose tumors harbor activating EGFR mutations.20 –22 EGFR TKIs are usually more effective in Asian NSCLC patients, most likely due to the higher percentage of activating EGFR mutations in this population, with favorable objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS). Furthermore, the efficacy of erlotinib is less influenced by histologic subtype, gender, and smoking status, compared with gefitinib.13,23 On the basis of these findings, we hypothesized that in elderly Taiwanese patients with NSCLC, first-line therapy with erlotinib would be at least as effective as chemotherapy with oral vinorelbine. In this study, the primary end point was to compare the ORR of erlotinib versus oral vinorelbine as first-line treatment in elderly Taiwanese patients with NSCLC. We also examined the role of activating EGFR mutations as a predictor of the efficacy of erlotinib or vinorelbine.
METHODS This study was an open-label, randomized, phase II trial conducted according to guidelines for good clinical practice. The study protocol was approved by the institutional review board (NCT01196078). Patients with NSCLC who had never received chemotherapy, targeted therapy, or hormonal therapy were entered into the study after giving informed consent. Eligibility criteria were a histologic or cytologic diagnosis of inoperable NSCLC; an Eastern Cooperative Oncology Group (ECOG) PS of 0 –3; measurable lesion(s); no previous radiotherapy on measurable lesion(s); adequate bone marrow reserve with a granulocyte count more than or equal to 1500/mm3, platelets more than or equal to 100,000/ mm3, and hemoglobin more than or equal to 10 g/dL. Patients with symptomatic or unstable brain metastases, inadequate liver or renal function, or uncontrolled systemic disease were excluded from the study. The primary objective of the study was to compare response rate between the two treatment arms. Secondary objectives were to compare disease control rate (DCR), PFS, OS, tolerability, and quality of life (QoL), as assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) QoL instrument, between the two treatment arms. Baseline evaluations included documentation of the patient’s history and a physical examination. A complete blood cell count, serum biochemistry profile, electrocardiogram, and computed tomography (CT) scan of the chest (including the liver and adrenal glands) were also performed. A whole-body bone scan and brain CT or magnetic resonance imaging scan were performed as routine pretreatment evaluations. Subsequent complete blood cell count and serum biochemistry studies were performed every 3 weeks until patients went off the study or completed treatment. An additional complete blood cell count was performed on day 8
Phase II Randomized Trial
for the vinorelbine group (i.e. before the patients took oral vinorelbine). Eligible patients were randomized (stratified by histology, smoking status [no, ⬍100 lifetime cigarettes; yes, more than or equal to 100 lifetime cigarettes regardless of current smoking status], ECOG PS, and gender) to receive either oral erlotinib 150 mg/d (E arm) or oral vinorelbine 60 mg/m2 on days 1 and 8 of every 3-weekly cycle (V arm). The vinorelbine dose could increase to 80 mg/m2 beginning from cycle 2 provided the patient did not suffer from any more than or equal to grade 2 toxicity. Drug-related adverse events and toxicities were recorded, according to the Common Toxicity Criteria of the National Cancer Institute version 3.0. Evaluation of response was performed after two cycles of treatment, and every two cycles thereafter until completion of six cycles. Best response was assessed according to the RECIST version 1.0.24 Responding patients and those with stable disease continued treatment until disease progression or completion of six cycles. Patients could continue treatment beyond six cycles provided their disease was controlled, and subsequent treatment response evaluation was performed every four cycles. This study was designed to enroll at least 53 eligible patients in each arm. This calculation assumed that the true ORR for the more effective treatment would be 10% higher than for the other treatment. Assuming that the lower response rate was 15% and the higher one was 25%, with a power of 0.9 and a p value of 0.05, each treatment group required 53 eligible patients (Simon phase II randomized trial design).25 ORR and survival outcomes were analyzed using an intent-to-treat (ITT) principle. The p value of the comparison of differences in tumor response rates between the two patient groups was determined by using logistic regression analysis with consideration for multiple factors including gender, ECOG PS, histology, and smoking status. PFS and OS were analyzed using the Kaplan-Meier estimation method with the log-rank test. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. PFS was calculated from the date of randomization to the date of first documented progression or death from any cause. OS was measured from the date of randomization until the date of death or last follow-up. SAS v.8.2 software was used for statistical analysis. EGFR mutation analysis was performed with nucleotide sequence analysis. The VarientSEQr Resequencing Primer Set (Applied Biosystems, Foster City, CA) was selected for mutational analysis of the tyrosine-kinase domain, specifically exons 18 –21 of the EGFR gene. DNA was extracted, exons 18 –21 were amplified, and uncloned polymerase chain reaction fragments were sequenced and analyzed in both sense and antisense directions for the presence of heterozygous mutations. All sequence variants were confirmed by multiple independent polymerase chain reaction amplifications, and forward and reverse sequencing reactions were done. Chromatograms were analyzed using SeqScape v2.1 Software (Applied Biosystems). Genomic DNA was derived from formalin-fixed paraffin blocks for mutational analysis of the EGFR coding sequence. Normal control DNA
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Chen et al.
FIGURE 1. Disposition status of 116 enrolled elderly patients with non-small cell lung cancer.
provided by the ABI company was used for wild-type control. Classical activating EGFR mutation was defined as having an exon 19 deletion or exon 21 L858R point mutation.
TABLE 1. Baseline Clinical Characteristics of the ITT Population (n ⫽ 113) Characteristic
RESULTS Patient Characteristics From February 2007 to July 2008, 116 patients were enrolled in this study, comprising 58 patients in the E arm and 58 patients in the V arm. Two patients, one in each arm, withdrew consent, did not receive any study medication and were excluded from the ITT population. One patient in the V arm had symptomatic brain metastases at baseline and was also excluded from the ITT population; he was kept in the safety analysis, however, because he had received one dose of the study medication. Thus, the ITT population consisted of 113 patients: 57 in the E arm and 56 in the V arm. Figure 1 summarizes the subject disposition status (CONSORT diagram). The clinical characteristics of the ITT population are shown in Table 1. Males and smokers each accounted for nearly 80% of the patients, and almost two-thirds of the patients had adenocarcinoma. There was no statistical difference in the clinical characteristics of the two treatment groups. Sixty patients (53.1%) had tumor tissue samples available for EGFR mutation analysis.
Efficacy Analyses The median number of cycles received was 5 in the E arm and 3.5 in the V arm. After two cycles of treatment, 13 patients (22.8%) in the E arm and 5 (8.9%) in the V arm had a partial response to treatment, which represented a statistically significant difference in ORR in favor of the E arm (p ⫽ 0.0388). There was, however, no significant difference in the response rates of the two treatment groups when performing subgroup analyses, including gender, smoking status, PS, histology, and EGFR mutation status. The DCR was 71.93%
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Age, yr Mean Median (range) Sex, n (%) Male Female Smoking status, n (%) Yes No Histology, n (%) Squamous-cell carcinoma Adenocarcinoma Other Staging, n (%) Unresectable stage IIIB Stage IV ECOG PS, n (%) 0 1 2 3
Erlotinib (n ⴝ 57)
Vinorelbine (n ⴝ 56)
78.1 77 (70–90)
77.8 77 (70–90)
0.7191
47 (82.5) 10 (17.5)
45 (80.4) 11 (19.6)
0.7743
45 (79) 12 (21)
44 (78.6) 12 (21.4)
0.961
19 (33.3) 36 (63.2) 2 (3.5)
13 (23.2) 37 (66.1) 6 (10.7)
0.2625
14 (24.6) 43 (75.4)
10 (17.9) 46 (82.1)
0.3836
2 (3.5) 44 (77.2) 9 (15.8) 2 (3.5)
2 (3.6) 39 (69.6) 12 (21.4) 3 (5.4)
0.8537
pa
a The p value comparing difference between groups is computed using the t test, Wilcoxon test, 2, or Fisher exact test. ECOG, Eastern Cooperative Oncology Group; ITT, intent-to-treat; PS, performance status.
in the E arm and 57.14% in the V arm (p ⫽ 0.1061). After the study treatment had failed, 29 patients in the E arm received chemotherapy (15, vinorelbine alone; 7, vinorelbine plus platinum; and 6, other chemotherapeutic agents) and 22
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patients in the V arm received EGFR TKIs (either erlotinib or gefitinib) (Figure 1). Median PFS was 4.57 months in the E arm (eight patients censored) and 2.53 months in the V arm (four patients censored) (p ⫽ 0.0287; Figure 2A). The HR was 0.6444 for E versus V (95% confidence interval 0.4325–
Phase II Randomized Trial
0.9601; p ⫽ 0.0308). The 1-year PFS rate was 19.0% in the E arm and 6.1% in the V arm. There was a trend toward longer median PFS in the E arm than in the V arm when performing subgroup analyses, including gender, histology, smoking status, PS, and EGFR mutation status (Table 2). Cox regression multivariate analysis for PFS, including treatment with E or V, smoking or not, male or female, EGFR mutated tumor or wild-type, adenocarcinoma or other NSCLC, and PS less than or equal to 1 or more than or equal to 2, provided an HR of 0.4633 for E treatment (p ⫽ 0.0159), 3.4686 for smoking (p ⫽ 0.0107), 2.188 for male (p ⫽ 0.1934), 0.39 for EGFR-mutated tumor (p ⫽ 0.0087), 0.8232 for adenocarcinoma (p ⫽ 0.5463), and 0.9219 for PS less than or equal to 1 (p ⫽ 0.8151). Median OS was 11.67 months in the E arm (14 patients censored) and 9.30 months in the V arm (14 patients censored) (p ⫽ 0.6975; Figure 2B). The 1-year survival rate was 48.8% in the E arm and 41.7% in the V arm. After the study treatment had failed, 22 patients in the E arm received cross-over vinorelbine-based salvage therapy with a median OS of 17.3 months (four patients censored) from the date of randomization into the study. Similarly, 22 patients in the V arm received EGFR TKI salvage therapy with a median OS from randomization of 22.6 months (8 patients censored) (p ⫽ 0.8925).
TABLE 2. Subgroup Analyses of PFS by Clinical Characteristics and EGFR Mutation Status Treatment Erlotinib
FIGURE 2. Survival status of intent-to-treat population treated with erlotinib (n ⫽ 57) or vinorelbine (n ⫽ 56). A, Progression-free survival (PFS): median PFS was 4.57 months in the erlotinib arm (eight censored) and 2.53 months in the vinorelbine arm (four censored) (p ⫽ 0.0287). Hazard ratio was 0.6444 for erlotinib treatment comparing vinorelbine treatment (95% confidence interval: 0.4325– 0.9601; p ⫽ 0.0308). The 1-year PFS was 19% in the erlotinib arm and 6.1% in the vinorelbine arm. B, Overall survival (OS): median OS was 11.67 months in the erlotinib arm (14 censored) and 9.3 months in the vinorelbine arm (14 censored) (p ⫽ 0.6975). The 1-year survival rate was 48.8% in the erlotinib arm and 41.7% in the vinorelbine arm.
Sex Male Female Histology Adenocarcinoma Squamous cell Other Smoking status No Yes ECOG PS 0 1 2 3 EGFR mutation status Mutateda Wild type Unknown
Vinorelbine
n
Median (mo)
n
Median (mo)
p
47 10
4.07 8.4
42 11
2.5 8.87
0.1323 0.1348
38 18
4.57 4.07
41 12
3 1.47
0.0464 0.1501
1
1.23
3
1.47
0.0833
15 42
8.4 3.83
15 41
4.13 2.47
0.0223 0.3528
2 44 9 2
9.63 4.57 1.37 1.03
2 40 11 3
1.53 2.8 1.87 7.03
0.4328 0.0152 0.6137 0.8864
9 21 27
8.4 3.83 5.07
15 15 26
3.97 1.47 2.17
0.2255 0.0436 0.073
a Included tumors with activating mutations of EGFR, specifically exon 19 deletions or exon 21 L858R point mutations. PFS, progression-free survival; EGFR, epidermal growth factor receptor gene; ECOG, Eastern Cooperative Oncology Group; PS, performance status.
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Biomarker Analyses Of the 60 patients whose tumors had known EGFR mutation status, 24 had an activating EGFR mutation (9 in the E arm and 15 in the V arm; 21 had exon 19 deletions and 3 had L858R mutations in exon 21), and 36 had wild-type EGFR. Median PFS was highest in the EGFR-mutated subgroup in the E arm (n ⫽ 9, one censored, median 8.4 months), followed by the EGFR-mutated subgroup in the V arm (n ⫽ 15, two censored, median 3.97 months), the EGFR wild-type subgroup in the E arm (n ⫽ 21, one censored, median 3.83 months), and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 1.47 months) (Figure 3A; p ⫽ 0.0034). In the unknown EGFR status group, median PFS was longer if patients received E (n ⫽ 27, six censored, median 5.07 months) instead of V (n ⫽ 26, two censored, median 2.17 months) (p ⫽ 0.073). When patients in both arms were considered together, median PFS was significantly prolonged in those whose tumors had activating EGFR mutations (n ⫽ 24, three censored, median 7.57 months), compared with EGFR wild type (n ⫽ 36, one censored, median 2.47 months) (p ⫽ 0.0119). OS was longer for the EGFR-mutated subgroup in both the E arm (n ⫽ 9, three censored, median 22.8 months) and the V arm (n ⫽ 15, nine censored, median 29.9 months), compared with EGFR wild-type subgroups in both the E arm (n ⫽ 21, two censored, median 6.9 months) and the V arm (n ⫽ 15, zero censored, median 4.43 months) (Figure 3B, p ⬍ 0.0001). When the patients in both arms were considered together, OS was significantly longer for patients whose tumors had activating EGFR mutations (n ⫽ 24, 12 censored, median 33.6 months) versus EGFR wild type (n ⫽36, two censored, median 5.3 months) (p ⬍ 0.0001).
Safety and Tolerability One hundred fourteen patients received at least one dose of study treatment. TRTs were generally mild, and the majority of patients did not need any dose adjustment; there was no toxicity-related death. The most frequent TRTs (incidence rate more than or equal to 10%) in the E arm were rash (64.91%), diarrhea (29.82%), and mouth ulceration (14.04%); in the V arm, decreased appetite (26.32%), diarrhea (12.28%), vomiting (10.53%), and anorexia (10.53%) were the most frequent TRTs. Skin rash, diarrhea, and mouth ulceration occurred more frequently with E than with V (p ⬍ 0.05), while decreased appetite occurred more frequently in the V arm than the E arm (p ⬍ 0.05).
QoL The FACT-L questionnaire contains four general subscales, including physical well-being, social/family well-being, emotional well-being, functional well-being, and one lung cancer symptom-specific subscale, the lung cancer subscale. The FACT-L questionnaires were given to patients at six assessment time points (cycles 1– 6) and at the end of treatment. Most FACT-L subscales showed no significant change at the end of treatment for both treatment arms, except that patients in the E arm had significantly better physical well-being than patients in the V arm. Most patients in both
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FIGURE 3. Survival status of patients with epidermal growth factor receptor gene (EGFR) mutation data available (n ⫽ 60). A, Progression-free survival (PFS): median PFS was higher in the EGFR-mutated subgroup in the E arm (n ⫽ 9, one censored, median 8.4 months), followed by the EGFRmutated subgroup in the V arm (n ⫽ 15, two censored, median 3.97 months), the EGFR wild-type subgroup in the E arm (n ⫽ 21, one censored, median 3.83 months), and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 1.47 months) (p ⫽ 0.0034). B, Overall survival (OS): median OS was longer in the EGFR-mutated subgroup in the E arm (n ⫽ 9, three censored, median 22.8 months) and the EGFR-mutated subgroup in the V arm (n ⫽ 15, nine censored, median 29.8 months), followed by the EGFR wild-type subgroup in the E arm (n ⫽ 21, two censored, median 6.9 months) and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 4.43 months) (p ⬍ 0.0001).
arms had stable pulmonary symptoms (lung cancer subscale) at the end of treatment.
DISCUSSION Kudoh et al.26 reported from Japan that intravenous vinorelbine treatment (25 mg/m2 days 1 and 8, every 3 weeks,
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TABLE 3.
Trials of First-Line EGFR TKIs in Chemonaive Elderly Patients (70 yr or Older) with NSCLC
First Author Jackman15 Swinson16 Crinò (INVITE)17 Ebi19 Chen
Phase II Randomized Trial
Regimen
n
ORR (%)
Median PFS (mo)
Median OS (mo)
1-yr Survival (%)
Erlotinib Gefitinib Gefitinib Vinorelbine IV Gefitinib Erlotinib Vinorelbine PO
80 41 97 99 50a 57 56
10 10 3 5 25 22.8 8.9
3.5 1 2.7 2.9 4 4.57 2.53
10.9 2.7 5.9 8.0 10 13.47 10.53
46 NR 33.9 33.2 50 51.7 47.3
a Aged 75 yr or older. EGFR, epidermal growth factor receptor; TKIs, tyrosine-kinase inhibitors; IV, intravenous; NR, not reported; NSCLC, non-small-cell lung cancer; ORR, objective response rates; OS, overall survival; PFS, progression-free survival; PO, oral.
the recommended dose in Japan) yielded a 3.1-month median PFS, 9.9% response rate, and 36.7% 1-year survival rate in a randomized phase III trial of treatment-naive elderly Japanese patients with NSCLC. The starting dose of oral vinorelbine at 60 mg/m2 in this study was the equivalent of the 25 mg/m2 intravenous dose used in the Japanese study.12 In our study, median PFS was longer in patients who received erlotinib treatment than vinorelbine; this difference existed regardless of the patient’s EGFR mutation status (mutated, wild type, or unknown). In addition, male patients, current or former smokers, and those with squamous-cell carcinoma also had numerically longer (although not statistically significant) PFS with erlotinib versus vinorelbine (Table 2). These results imply that erlotinib could be considered as an effective first-line treatment for elderly patients with NSCLC, irrespective of clinical or EGFR mutation status. The treatment results in patients whose tumors had EGFR mutations were similar to those of the IRESSA PanAsia study, but the results in patients whose tumors were EGFR wild-type differed between the two studies.22 Patients with EGFR wild-type tumors had better PFS with erlotinib than vinorelbine in our study, whereas in the IRESSA PanAsia study, PFS was superior with paclitaxel plus carboplatin versus gefitinib in the EGFR wild-type subgroup.22 Possible reasons for this difference include superior efficacy of doublet chemotherapy versus single-agent chemotherapy,27 greater potency of erlotinib compared with gefitinib, and the different EGFR mutation detection methods used in the studies. In the study by Jackman et al.,15 in which 80 elderly NSCLC patients were treated with erlotinib, a partial response was noted in 10% of patients and the DCR was 51% (Table 3). The 1-year survival rate of 46% for these erlotinibtreated elderly patients was relatively similar to, or better than, that of elderly patients treated with first-line chemotherapy.7,11 In the study by Crino` et al.,17 elderly treatment-naive NSCLC patients were treated with gefitinib or intravenous vinorelbine. The ORR and DCR were 3.1 and 43.3%, respectively, for patients receiving gefitinib. Median survival was 5.9 months, and the 1-year survival rate was 33.9% in gefitinib-treated elderly patients. The ORR, median PFS, and median OS in both the gefitinib and intravenous vinorelbine arms were poorer than in our erlotinib and oral vinorelbine arms, respectively (Table 3).
The better response of Asian patients to EGFR TKIs and their longer survival has been documented repeatedly. Median OS was shorter in Swinson et al.,16 in which elderly NSCLC patients were treated with gefitinib. By contrast, in a Japanese study of treatment-naive elderly NSCLC patients, in which the majority were female (65%), had adenocarcinoma (82%), and had never smoked (61%), treatment with gefitinib produced a response rate of 25% and median OS of 10 months.19 The clinical characteristics of this Japanese study are quite different from ours: our patients had higher proportions of poor clinical characteristics, which is consistent with the condition of general geriatric lung cancer patients. Of course, it is difficult to compare these different studies, because they had different patient populations with different clinical characteristics and different EGFR mutation profiles. However, based on limited small studies, it seems that erlotinib had a similar or better effect in both White and Asian unselected elderly NSCLC patients who received a first-line EGFR TKI, in terms of PFS and OS, compared with gefitinib (Table 3). In addition, oral vinorelbine had better results than intravenous vinorelbine, when comparing our study with that of Crino` et al.17 In conclusion, both oral agents are appropriate treatment, but erlotinib is more highly effective than oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. Patients with activating EGFR mutation-positive disease had better survival than those with EGFR wild-type disease, irrespective of whether they received erlotinib or vinorelbine.
ACKNOWLEDGMENTS Supported by F. Hoffmann-La Roche, Ltd (protocol number ML20322) and grants from the National Science Council of the Republic of China (grant no. NSC99 –2314B-075– 035-MY3) and the Taipei Veterans General Hospital (grant no. V99-C1– 050). Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche, Ltd. REFERENCES 1. Schottenfeld D. Etiology and epidemiology of lung cancer. In HI Pass, JB Mitchell, DH Johnson, et al. (Eds)., Lung Cancer—Principles and Practice. Philadelphia, PA: Lippincott Williams & Wilkins, 2000. Pp. 367–388.
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2. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the Surveillance, Epidemiology, and End Results Database. J Clin Oncol 2007;25:5570 –5577. 3. Kuo CW, Chen YM, Chao JY, et al. Non-small cell lung cancer in very young and very old patients. Chest 2000;117:354 –357. 4. Chen YM, Perng RP, Shih JF, et al. Chemotherapy for non-small-cell lung cancer in elderly patients. Chest 2005;128:132–139. 5. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:173–181. 6. Azzoli CG, Baker Jr S, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009;27:6251– 6266. 7. The elderly lung cancer vinorelbine Italian study group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999;91:66 –72. 8. 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. 9. Gridelli C, Langer C, Maione P, et al. Lung cancer in the elderly. J Clin Oncol 2007;25:1898 –1907. 10. Gridelli C, Maionea P, Rossia A, et al. Treatment of advanced nonsmall-cell lung cancer in the elderly. Lung Cancer 2009;66:282–286. 11. Chen YM, Perng RP, Shih JF, et al. A phase II randomized study of vinorelbine alone or with cisplatin against chemo-naïve inoperable non-small cell lung cancer in the elderly. Lung Cancer 2008;61:214 – 219. 12. Chen YM, Yu CJ, Yang CH, et al. A phase II study of oral vinorelbine in combination with cisplatin conducted in Taiwan in patients with unresectable localized or metastatic non-small cell lung carcinoma. Lung Cancer 2007;56:89 –95. 13. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 2005;353:123–132. 14. Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809 –1818. 15. Jackman DM, Yeap BY, Lindeman NI, et al. Phase II clinical trial of chemotherapy-naïve patients ⱖ 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol 2007;25:760 –766.
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16. Swinson D, Williams S, Beddard K, et al. Phase II trial of first-line gefitinib in patients unsuitable for chemotherapy with stage III/IV non-small-cell lung cancer. J Clin Oncol 2005 ASCO Annual Meeting Proceedings Part I;23:(Abstract 7256). 17. Crino` L, Cappuzzo F, Zatloukal P, et al. Gefitinib versus vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol 2008;26: 4253– 4260. 18. Lilenbaum R, Axelrod R, Thomas S, et al. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-smallcell lung cancer and a performance status of 2. J Clin Oncol 2008;26: 863– 869. 19. Ebi N, Semba H, Tokunaga S, et al. A phase II trial of gefitinib monotherapy in chemotherapy-naïve patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol 2008;3:1166 – 1171. 20. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442–2449. 21. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958 – 967. 22. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947– 957. 23. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521–529. 24. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. 25. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375–1381. 26. Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-smallcell lung cancer: results of the West Japan Thoracic Oncology Group trial (WJTOG 9904). J Clin Oncol 2006;24:3657–3663. 27. Quoix EA, Oster J, Westeel V, et al. Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2010 ASCO Annual Meeting Proceedings Part I;28:(Abstract 2).
Copyright © 2012 by the International Association for the Study of Lung Cancer
Phase II Randomized Trial of Erlotinib or Vinorelbine in Chemonaive, Advanced, Non-small Cell Lung Cancer Patients Aged 70 Years or Older Yuh-Min Chen, MD, PhD, FCCP,*†‡ Chun-Ming Tsai, MD,* Wen-Chien Fan, MD,§ Jen-Fu Shih, MD,* Shih-Hao Liu, MD,储 Chieh-Hung Wu, MD,* Teh-Ying Chou, MD, PhD,储 Yu-Chin Lee, MD,* Reury-Perng Perng, MD, PhD,* and Jacqueline Whang-Peng, MD‡
Introduction: The primary objective of this study was to compare the response rates of elderly, chemonaive patients with advanced non-small cell lung cancer (NSCLC) treated with daily oral erlotinib versus oral vinorelbine. Methods: Chemonaive Taiwanese patients aged 70 years or older who had advanced NSCLC were randomized to receive either oral erlotinib 150 mg (E) daily or oral vinorelbine 60 mg/m2 (V) on days 1 and 8 every 3 weeks. Results: From February 2007 to July 2008, 116 patients were enrolled and 113 were included in the intent-to-treat population: 57 patients in the E group and 56 patients in the V group. Objective response rates were 22.8% (13 of 57) in E and 8.9% (5 of 56) in V (p ⫽ 0.0388). Median progression-free survival (PFS) was 4.57 months in E and 2.53 months in V (p ⫽ 0.0287), with an 80.6% increase in median PFS for E compared with V. Median survival time was 11.67 months in E and 9.3 months in V (p ⫽ 0.6975). Toxicities were generally mild in both groups. Median PFS was longest for epidermal growth factor receptor gene (EGFR)-mutated patients in the E group, followed by EGFR-mutated patients in V, EGFR wild type in E, and EGFR wild type in V (p ⫽ 0.0034). Overall survival was longer for EGFR-mutated patients than for EGFR wild-type patients (p ⬍ 0.0001). Conclusions: Erlotinib is highly effective compared with oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. EGFR-mutated patients had better survival than those with EGFR wild-type disease, regardless of the treatment received. Key Words: Chemotherapy, Epidermal growth factor receptor, Nonsmall-cell lung cancer, Targeted therapy, Tyrosine-kinase inhibitor. (J Thorac Oncol. 2012;7: 412–418) *Chest Department, Taipei Veterans General Hospital; †Department of Medicine, School of Medicine, National Yang-Ming University; ‡Centre of Excellent Cancer Research (CECR), School of Medicine, Taipei Medical University; §Chest Department, Chutung Veterans General Hospital; and 储Koo Foundation Sun Yat-Sen Cancer Centre, Taipei, Taiwan. Diclosure: The authors have no conflicts of interest. Address for correspondence: Dr. Yuh-Min Chen, Chest Department, Taipei Veterans General Hospital, 201, Sec. 2, Shih-pai Road, Taipei 112, Taiwan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0702-0412
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L
ung cancer is typically a disease of elderly patients, with incidence peaking in the 70- to 80-year age group.1 An analysis of the Surveillance, Epidemiology, and End Results Database revealed that patients aged 70 years or older accounted for 47% of all lung cancers.2 Despite the fact that elderly patients account for the majority of the lung cancer population, they are less likely to receive treatment than younger patients.3,4 There is also an underrepresentation of elderly patients (those aged 70 years or older) in clinical trials of chemotherapy in non-small cell lung cancer (NSCLC).5 Thus, clinical trials specifically designed to investigate treatments for elderly patients with NSCLC are important and should be prioritized.6 Single-agent chemotherapy, with agents such as gemcitabine or vinorelbine, is the typical option for advanced NSCLC in treatment-naive elderly patients.6 – 8 Data analysis suggests that outcomes in the fit elderly mirror results observed in younger patients, although treatment-related toxicity is generally worse.6,9,10 We recently published data showing that combining vinorelbine with cisplatin produced a better response rate and longer median time to disease progression versus vinorelbine alone in elderly patients with NSCLC. This improvement in some efficacy endpoints, however, came with significantly increased toxicity and no survival advantage for the doublet.11 The efficacy of oral vinorelbine is similar to that of the intravenous form, but the oral form is more convenient and does not necessitate central venous access as required with a Port-A implantation.12 Considering that all third-generation agents (vinorelbine, gemcitabine, and taxanes) have similar activity and efficacy in NSCLC, and single-agent vinorelbine is considered a standard regimen for elderly patients with NSCLC, oral vinorelbine may be more attractive and convenient for many elderly patients and their healthcare providers, because it is easy to use with no need for intravenous injection. Epidermal growth factor receptor (EGFR) tyrosinekinase inhibitors (TKIs), such as erlotinib and gefitinib, are active agents against advanced NSCLC when given as second- or third-line therapy, compared with best supportive care or standard chemotherapy.6,13,14 Several trials have been conducted with these agents in selected groups of chemona-
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ive patients with advanced NSCLC, such as elderly and poor performance status (PS) patients, to address the concern about treatment-related toxicities (TRTs) with conventional chemotherapy.15–19 EGFR TKIs have also been investigated in highly selected groups of chemonaive NSCLC patients with the intention of selecting patients most likely to respond to EGFR TKI therapy, such as those whose tumors harbor activating EGFR mutations.20 –22 EGFR TKIs are usually more effective in Asian NSCLC patients, most likely due to the higher percentage of activating EGFR mutations in this population, with favorable objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS). Furthermore, the efficacy of erlotinib is less influenced by histologic subtype, gender, and smoking status, compared with gefitinib.13,23 On the basis of these findings, we hypothesized that in elderly Taiwanese patients with NSCLC, first-line therapy with erlotinib would be at least as effective as chemotherapy with oral vinorelbine. In this study, the primary end point was to compare the ORR of erlotinib versus oral vinorelbine as first-line treatment in elderly Taiwanese patients with NSCLC. We also examined the role of activating EGFR mutations as a predictor of the efficacy of erlotinib or vinorelbine.
METHODS This study was an open-label, randomized, phase II trial conducted according to guidelines for good clinical practice. The study protocol was approved by the institutional review board (NCT01196078). Patients with NSCLC who had never received chemotherapy, targeted therapy, or hormonal therapy were entered into the study after giving informed consent. Eligibility criteria were a histologic or cytologic diagnosis of inoperable NSCLC; an Eastern Cooperative Oncology Group (ECOG) PS of 0 –3; measurable lesion(s); no previous radiotherapy on measurable lesion(s); adequate bone marrow reserve with a granulocyte count more than or equal to 1500/mm3, platelets more than or equal to 100,000/ mm3, and hemoglobin more than or equal to 10 g/dL. Patients with symptomatic or unstable brain metastases, inadequate liver or renal function, or uncontrolled systemic disease were excluded from the study. The primary objective of the study was to compare response rate between the two treatment arms. Secondary objectives were to compare disease control rate (DCR), PFS, OS, tolerability, and quality of life (QoL), as assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) QoL instrument, between the two treatment arms. Baseline evaluations included documentation of the patient’s history and a physical examination. A complete blood cell count, serum biochemistry profile, electrocardiogram, and computed tomography (CT) scan of the chest (including the liver and adrenal glands) were also performed. A whole-body bone scan and brain CT or magnetic resonance imaging scan were performed as routine pretreatment evaluations. Subsequent complete blood cell count and serum biochemistry studies were performed every 3 weeks until patients went off the study or completed treatment. An additional complete blood cell count was performed on day 8
Phase II Randomized Trial
for the vinorelbine group (i.e. before the patients took oral vinorelbine). Eligible patients were randomized (stratified by histology, smoking status [no, ⬍100 lifetime cigarettes; yes, more than or equal to 100 lifetime cigarettes regardless of current smoking status], ECOG PS, and gender) to receive either oral erlotinib 150 mg/d (E arm) or oral vinorelbine 60 mg/m2 on days 1 and 8 of every 3-weekly cycle (V arm). The vinorelbine dose could increase to 80 mg/m2 beginning from cycle 2 provided the patient did not suffer from any more than or equal to grade 2 toxicity. Drug-related adverse events and toxicities were recorded, according to the Common Toxicity Criteria of the National Cancer Institute version 3.0. Evaluation of response was performed after two cycles of treatment, and every two cycles thereafter until completion of six cycles. Best response was assessed according to the RECIST version 1.0.24 Responding patients and those with stable disease continued treatment until disease progression or completion of six cycles. Patients could continue treatment beyond six cycles provided their disease was controlled, and subsequent treatment response evaluation was performed every four cycles. This study was designed to enroll at least 53 eligible patients in each arm. This calculation assumed that the true ORR for the more effective treatment would be 10% higher than for the other treatment. Assuming that the lower response rate was 15% and the higher one was 25%, with a power of 0.9 and a p value of 0.05, each treatment group required 53 eligible patients (Simon phase II randomized trial design).25 ORR and survival outcomes were analyzed using an intent-to-treat (ITT) principle. The p value of the comparison of differences in tumor response rates between the two patient groups was determined by using logistic regression analysis with consideration for multiple factors including gender, ECOG PS, histology, and smoking status. PFS and OS were analyzed using the Kaplan-Meier estimation method with the log-rank test. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. PFS was calculated from the date of randomization to the date of first documented progression or death from any cause. OS was measured from the date of randomization until the date of death or last follow-up. SAS v.8.2 software was used for statistical analysis. EGFR mutation analysis was performed with nucleotide sequence analysis. The VarientSEQr Resequencing Primer Set (Applied Biosystems, Foster City, CA) was selected for mutational analysis of the tyrosine-kinase domain, specifically exons 18 –21 of the EGFR gene. DNA was extracted, exons 18 –21 were amplified, and uncloned polymerase chain reaction fragments were sequenced and analyzed in both sense and antisense directions for the presence of heterozygous mutations. All sequence variants were confirmed by multiple independent polymerase chain reaction amplifications, and forward and reverse sequencing reactions were done. Chromatograms were analyzed using SeqScape v2.1 Software (Applied Biosystems). Genomic DNA was derived from formalin-fixed paraffin blocks for mutational analysis of the EGFR coding sequence. Normal control DNA
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Chen et al.
FIGURE 1. Disposition status of 116 enrolled elderly patients with non-small cell lung cancer.
provided by the ABI company was used for wild-type control. Classical activating EGFR mutation was defined as having an exon 19 deletion or exon 21 L858R point mutation.
TABLE 1. Baseline Clinical Characteristics of the ITT Population (n ⫽ 113) Characteristic
RESULTS Patient Characteristics From February 2007 to July 2008, 116 patients were enrolled in this study, comprising 58 patients in the E arm and 58 patients in the V arm. Two patients, one in each arm, withdrew consent, did not receive any study medication and were excluded from the ITT population. One patient in the V arm had symptomatic brain metastases at baseline and was also excluded from the ITT population; he was kept in the safety analysis, however, because he had received one dose of the study medication. Thus, the ITT population consisted of 113 patients: 57 in the E arm and 56 in the V arm. Figure 1 summarizes the subject disposition status (CONSORT diagram). The clinical characteristics of the ITT population are shown in Table 1. Males and smokers each accounted for nearly 80% of the patients, and almost two-thirds of the patients had adenocarcinoma. There was no statistical difference in the clinical characteristics of the two treatment groups. Sixty patients (53.1%) had tumor tissue samples available for EGFR mutation analysis.
Efficacy Analyses The median number of cycles received was 5 in the E arm and 3.5 in the V arm. After two cycles of treatment, 13 patients (22.8%) in the E arm and 5 (8.9%) in the V arm had a partial response to treatment, which represented a statistically significant difference in ORR in favor of the E arm (p ⫽ 0.0388). There was, however, no significant difference in the response rates of the two treatment groups when performing subgroup analyses, including gender, smoking status, PS, histology, and EGFR mutation status. The DCR was 71.93%
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Age, yr Mean Median (range) Sex, n (%) Male Female Smoking status, n (%) Yes No Histology, n (%) Squamous-cell carcinoma Adenocarcinoma Other Staging, n (%) Unresectable stage IIIB Stage IV ECOG PS, n (%) 0 1 2 3
Erlotinib (n ⴝ 57)
Vinorelbine (n ⴝ 56)
78.1 77 (70–90)
77.8 77 (70–90)
0.7191
47 (82.5) 10 (17.5)
45 (80.4) 11 (19.6)
0.7743
45 (79) 12 (21)
44 (78.6) 12 (21.4)
0.961
19 (33.3) 36 (63.2) 2 (3.5)
13 (23.2) 37 (66.1) 6 (10.7)
0.2625
14 (24.6) 43 (75.4)
10 (17.9) 46 (82.1)
0.3836
2 (3.5) 44 (77.2) 9 (15.8) 2 (3.5)
2 (3.6) 39 (69.6) 12 (21.4) 3 (5.4)
0.8537
pa
a The p value comparing difference between groups is computed using the t test, Wilcoxon test, 2, or Fisher exact test. ECOG, Eastern Cooperative Oncology Group; ITT, intent-to-treat; PS, performance status.
in the E arm and 57.14% in the V arm (p ⫽ 0.1061). After the study treatment had failed, 29 patients in the E arm received chemotherapy (15, vinorelbine alone; 7, vinorelbine plus platinum; and 6, other chemotherapeutic agents) and 22
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patients in the V arm received EGFR TKIs (either erlotinib or gefitinib) (Figure 1). Median PFS was 4.57 months in the E arm (eight patients censored) and 2.53 months in the V arm (four patients censored) (p ⫽ 0.0287; Figure 2A). The HR was 0.6444 for E versus V (95% confidence interval 0.4325–
Phase II Randomized Trial
0.9601; p ⫽ 0.0308). The 1-year PFS rate was 19.0% in the E arm and 6.1% in the V arm. There was a trend toward longer median PFS in the E arm than in the V arm when performing subgroup analyses, including gender, histology, smoking status, PS, and EGFR mutation status (Table 2). Cox regression multivariate analysis for PFS, including treatment with E or V, smoking or not, male or female, EGFR mutated tumor or wild-type, adenocarcinoma or other NSCLC, and PS less than or equal to 1 or more than or equal to 2, provided an HR of 0.4633 for E treatment (p ⫽ 0.0159), 3.4686 for smoking (p ⫽ 0.0107), 2.188 for male (p ⫽ 0.1934), 0.39 for EGFR-mutated tumor (p ⫽ 0.0087), 0.8232 for adenocarcinoma (p ⫽ 0.5463), and 0.9219 for PS less than or equal to 1 (p ⫽ 0.8151). Median OS was 11.67 months in the E arm (14 patients censored) and 9.30 months in the V arm (14 patients censored) (p ⫽ 0.6975; Figure 2B). The 1-year survival rate was 48.8% in the E arm and 41.7% in the V arm. After the study treatment had failed, 22 patients in the E arm received cross-over vinorelbine-based salvage therapy with a median OS of 17.3 months (four patients censored) from the date of randomization into the study. Similarly, 22 patients in the V arm received EGFR TKI salvage therapy with a median OS from randomization of 22.6 months (8 patients censored) (p ⫽ 0.8925).
TABLE 2. Subgroup Analyses of PFS by Clinical Characteristics and EGFR Mutation Status Treatment Erlotinib
FIGURE 2. Survival status of intent-to-treat population treated with erlotinib (n ⫽ 57) or vinorelbine (n ⫽ 56). A, Progression-free survival (PFS): median PFS was 4.57 months in the erlotinib arm (eight censored) and 2.53 months in the vinorelbine arm (four censored) (p ⫽ 0.0287). Hazard ratio was 0.6444 for erlotinib treatment comparing vinorelbine treatment (95% confidence interval: 0.4325– 0.9601; p ⫽ 0.0308). The 1-year PFS was 19% in the erlotinib arm and 6.1% in the vinorelbine arm. B, Overall survival (OS): median OS was 11.67 months in the erlotinib arm (14 censored) and 9.3 months in the vinorelbine arm (14 censored) (p ⫽ 0.6975). The 1-year survival rate was 48.8% in the erlotinib arm and 41.7% in the vinorelbine arm.
Sex Male Female Histology Adenocarcinoma Squamous cell Other Smoking status No Yes ECOG PS 0 1 2 3 EGFR mutation status Mutateda Wild type Unknown
Vinorelbine
n
Median (mo)
n
Median (mo)
p
47 10
4.07 8.4
42 11
2.5 8.87
0.1323 0.1348
38 18
4.57 4.07
41 12
3 1.47
0.0464 0.1501
1
1.23
3
1.47
0.0833
15 42
8.4 3.83
15 41
4.13 2.47
0.0223 0.3528
2 44 9 2
9.63 4.57 1.37 1.03
2 40 11 3
1.53 2.8 1.87 7.03
0.4328 0.0152 0.6137 0.8864
9 21 27
8.4 3.83 5.07
15 15 26
3.97 1.47 2.17
0.2255 0.0436 0.073
a Included tumors with activating mutations of EGFR, specifically exon 19 deletions or exon 21 L858R point mutations. PFS, progression-free survival; EGFR, epidermal growth factor receptor gene; ECOG, Eastern Cooperative Oncology Group; PS, performance status.
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Biomarker Analyses Of the 60 patients whose tumors had known EGFR mutation status, 24 had an activating EGFR mutation (9 in the E arm and 15 in the V arm; 21 had exon 19 deletions and 3 had L858R mutations in exon 21), and 36 had wild-type EGFR. Median PFS was highest in the EGFR-mutated subgroup in the E arm (n ⫽ 9, one censored, median 8.4 months), followed by the EGFR-mutated subgroup in the V arm (n ⫽ 15, two censored, median 3.97 months), the EGFR wild-type subgroup in the E arm (n ⫽ 21, one censored, median 3.83 months), and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 1.47 months) (Figure 3A; p ⫽ 0.0034). In the unknown EGFR status group, median PFS was longer if patients received E (n ⫽ 27, six censored, median 5.07 months) instead of V (n ⫽ 26, two censored, median 2.17 months) (p ⫽ 0.073). When patients in both arms were considered together, median PFS was significantly prolonged in those whose tumors had activating EGFR mutations (n ⫽ 24, three censored, median 7.57 months), compared with EGFR wild type (n ⫽ 36, one censored, median 2.47 months) (p ⫽ 0.0119). OS was longer for the EGFR-mutated subgroup in both the E arm (n ⫽ 9, three censored, median 22.8 months) and the V arm (n ⫽ 15, nine censored, median 29.9 months), compared with EGFR wild-type subgroups in both the E arm (n ⫽ 21, two censored, median 6.9 months) and the V arm (n ⫽ 15, zero censored, median 4.43 months) (Figure 3B, p ⬍ 0.0001). When the patients in both arms were considered together, OS was significantly longer for patients whose tumors had activating EGFR mutations (n ⫽ 24, 12 censored, median 33.6 months) versus EGFR wild type (n ⫽36, two censored, median 5.3 months) (p ⬍ 0.0001).
Safety and Tolerability One hundred fourteen patients received at least one dose of study treatment. TRTs were generally mild, and the majority of patients did not need any dose adjustment; there was no toxicity-related death. The most frequent TRTs (incidence rate more than or equal to 10%) in the E arm were rash (64.91%), diarrhea (29.82%), and mouth ulceration (14.04%); in the V arm, decreased appetite (26.32%), diarrhea (12.28%), vomiting (10.53%), and anorexia (10.53%) were the most frequent TRTs. Skin rash, diarrhea, and mouth ulceration occurred more frequently with E than with V (p ⬍ 0.05), while decreased appetite occurred more frequently in the V arm than the E arm (p ⬍ 0.05).
QoL The FACT-L questionnaire contains four general subscales, including physical well-being, social/family well-being, emotional well-being, functional well-being, and one lung cancer symptom-specific subscale, the lung cancer subscale. The FACT-L questionnaires were given to patients at six assessment time points (cycles 1– 6) and at the end of treatment. Most FACT-L subscales showed no significant change at the end of treatment for both treatment arms, except that patients in the E arm had significantly better physical well-being than patients in the V arm. Most patients in both
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FIGURE 3. Survival status of patients with epidermal growth factor receptor gene (EGFR) mutation data available (n ⫽ 60). A, Progression-free survival (PFS): median PFS was higher in the EGFR-mutated subgroup in the E arm (n ⫽ 9, one censored, median 8.4 months), followed by the EGFRmutated subgroup in the V arm (n ⫽ 15, two censored, median 3.97 months), the EGFR wild-type subgroup in the E arm (n ⫽ 21, one censored, median 3.83 months), and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 1.47 months) (p ⫽ 0.0034). B, Overall survival (OS): median OS was longer in the EGFR-mutated subgroup in the E arm (n ⫽ 9, three censored, median 22.8 months) and the EGFR-mutated subgroup in the V arm (n ⫽ 15, nine censored, median 29.8 months), followed by the EGFR wild-type subgroup in the E arm (n ⫽ 21, two censored, median 6.9 months) and the EGFR wild-type subgroup in the V arm (n ⫽ 15, zero censored, median 4.43 months) (p ⬍ 0.0001).
arms had stable pulmonary symptoms (lung cancer subscale) at the end of treatment.
DISCUSSION Kudoh et al.26 reported from Japan that intravenous vinorelbine treatment (25 mg/m2 days 1 and 8, every 3 weeks,
Copyright © 2012 by the International Association for the Study of Lung Cancer
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TABLE 3.
Trials of First-Line EGFR TKIs in Chemonaive Elderly Patients (70 yr or Older) with NSCLC
First Author Jackman15 Swinson16 Crinò (INVITE)17 Ebi19 Chen
Phase II Randomized Trial
Regimen
n
ORR (%)
Median PFS (mo)
Median OS (mo)
1-yr Survival (%)
Erlotinib Gefitinib Gefitinib Vinorelbine IV Gefitinib Erlotinib Vinorelbine PO
80 41 97 99 50a 57 56
10 10 3 5 25 22.8 8.9
3.5 1 2.7 2.9 4 4.57 2.53
10.9 2.7 5.9 8.0 10 13.47 10.53
46 NR 33.9 33.2 50 51.7 47.3
a Aged 75 yr or older. EGFR, epidermal growth factor receptor; TKIs, tyrosine-kinase inhibitors; IV, intravenous; NR, not reported; NSCLC, non-small-cell lung cancer; ORR, objective response rates; OS, overall survival; PFS, progression-free survival; PO, oral.
the recommended dose in Japan) yielded a 3.1-month median PFS, 9.9% response rate, and 36.7% 1-year survival rate in a randomized phase III trial of treatment-naive elderly Japanese patients with NSCLC. The starting dose of oral vinorelbine at 60 mg/m2 in this study was the equivalent of the 25 mg/m2 intravenous dose used in the Japanese study.12 In our study, median PFS was longer in patients who received erlotinib treatment than vinorelbine; this difference existed regardless of the patient’s EGFR mutation status (mutated, wild type, or unknown). In addition, male patients, current or former smokers, and those with squamous-cell carcinoma also had numerically longer (although not statistically significant) PFS with erlotinib versus vinorelbine (Table 2). These results imply that erlotinib could be considered as an effective first-line treatment for elderly patients with NSCLC, irrespective of clinical or EGFR mutation status. The treatment results in patients whose tumors had EGFR mutations were similar to those of the IRESSA PanAsia study, but the results in patients whose tumors were EGFR wild-type differed between the two studies.22 Patients with EGFR wild-type tumors had better PFS with erlotinib than vinorelbine in our study, whereas in the IRESSA PanAsia study, PFS was superior with paclitaxel plus carboplatin versus gefitinib in the EGFR wild-type subgroup.22 Possible reasons for this difference include superior efficacy of doublet chemotherapy versus single-agent chemotherapy,27 greater potency of erlotinib compared with gefitinib, and the different EGFR mutation detection methods used in the studies. In the study by Jackman et al.,15 in which 80 elderly NSCLC patients were treated with erlotinib, a partial response was noted in 10% of patients and the DCR was 51% (Table 3). The 1-year survival rate of 46% for these erlotinibtreated elderly patients was relatively similar to, or better than, that of elderly patients treated with first-line chemotherapy.7,11 In the study by Crino` et al.,17 elderly treatment-naive NSCLC patients were treated with gefitinib or intravenous vinorelbine. The ORR and DCR were 3.1 and 43.3%, respectively, for patients receiving gefitinib. Median survival was 5.9 months, and the 1-year survival rate was 33.9% in gefitinib-treated elderly patients. The ORR, median PFS, and median OS in both the gefitinib and intravenous vinorelbine arms were poorer than in our erlotinib and oral vinorelbine arms, respectively (Table 3).
The better response of Asian patients to EGFR TKIs and their longer survival has been documented repeatedly. Median OS was shorter in Swinson et al.,16 in which elderly NSCLC patients were treated with gefitinib. By contrast, in a Japanese study of treatment-naive elderly NSCLC patients, in which the majority were female (65%), had adenocarcinoma (82%), and had never smoked (61%), treatment with gefitinib produced a response rate of 25% and median OS of 10 months.19 The clinical characteristics of this Japanese study are quite different from ours: our patients had higher proportions of poor clinical characteristics, which is consistent with the condition of general geriatric lung cancer patients. Of course, it is difficult to compare these different studies, because they had different patient populations with different clinical characteristics and different EGFR mutation profiles. However, based on limited small studies, it seems that erlotinib had a similar or better effect in both White and Asian unselected elderly NSCLC patients who received a first-line EGFR TKI, in terms of PFS and OS, compared with gefitinib (Table 3). In addition, oral vinorelbine had better results than intravenous vinorelbine, when comparing our study with that of Crino` et al.17 In conclusion, both oral agents are appropriate treatment, but erlotinib is more highly effective than oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. Patients with activating EGFR mutation-positive disease had better survival than those with EGFR wild-type disease, irrespective of whether they received erlotinib or vinorelbine.
ACKNOWLEDGMENTS Supported by F. Hoffmann-La Roche, Ltd (protocol number ML20322) and grants from the National Science Council of the Republic of China (grant no. NSC99 –2314B-075– 035-MY3) and the Taipei Veterans General Hospital (grant no. V99-C1– 050). Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche, Ltd. REFERENCES 1. Schottenfeld D. Etiology and epidemiology of lung cancer. In HI Pass, JB Mitchell, DH Johnson, et al. (Eds)., Lung Cancer—Principles and Practice. Philadelphia, PA: Lippincott Williams & Wilkins, 2000. Pp. 367–388.
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