Abstract

Objective

There are few standard therapeutic options beyond second-line treatment. We aimed to evaluate the efficacy and safety of erlotinib monotherapy as third-line chemotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations.

Methods

In this phase II trial, patients who did not have epidermal growth factor receptor mutations and who had previously received two cytotoxic chemotherapy regimens containing platinum were treated with erlotinib (150 mg, per os) until disease progression or unacceptable toxicity.

Results

Twenty patients were eligible for the assessment of efficacy and safety. Three cases showed a partial response, and eight cases showed stable disease with an overall response rate of 15.0% (95% confidence interval: 5.2–36.0%) and a disease control rate of 55.0% (95% confidence interval: 34.2–74.2%). Median progression-free survival and overall survival time were 2.1 and 6.7 months, respectively. Although dose reduction was required in one patient because of skin toxicity, grade 3/4 toxicity or pulmonary disease was not observed.

Conclusions

Erlotinib as third-line therapy showed an acceptable response rate, survival time and toxicity. It could be a potential third-line therapy for patients without epidermal growth factor receptor mutations.

INTRODUCTION

Lung cancer is a leading cause of cancer mortality in many countries (1,2). Although platinum-based chemotherapy with third-generation antitumor agents is currently used as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) (3–5), the outcomes are far from acceptable (3). Most patients eventually become refractory to chemotherapy or experience disease progression, and require salvage chemotherapy.

Recently, more effective and less toxic first- and second-line chemotherapy offer increasing opportunities for further lines of chemotherapy. However, standard therapeutic options beyond second-line treatment are insufficient (6). There is a paucity of clinical-trial data that have addressed the role of third-line treatment by restricting study subjects to those who have already received ≥2 prior regimens and, if data are available, most are retrospective analyses (5). This is because the efficacy of chemotherapy is attenuated as the number of treatment options increases and because the number of eligible patients for further therapy is limited (7,8). Many authors have evaluated the efficacy of third-line chemotherapy together with second-line treatment.

Recent clinical trials showed the superiority of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in cytotoxic chemotherapy for patients with EGFR mutations (9–11). Another type of EGFR tyrosine kinase inhibitor, erlotinib (Tarceva®; Chugai Pharmaceutical Company Limited, Tokyo, Japan) has been reported to have benefits in a wider range of patients. In a BR.21 trial that investigated the survival benefit of erlotinib in relapsed patients, erlotinib prolonged overall survival compared with placebo, and the survival advantage of erlotinib was unaffected by EGFR gene mutations (12). In that study, 49% of patients had already received ≥2 prior regimens, and erlotinib was thought to be as efficacious as third-line therapy.

Currently, if an EGFR mutation is known to exist, EGFR tyrosine kinase inhibitors are used (5,13). Cytotoxic platinum-containing chemotherapy is recommended as first-line treatment in patients without EGFR mutations. As second-line treatment, erlotinib as well as the cytotoxic agents docetaxel and pemetrexed are used. In particular, second-line treatment with pemetrexed has been increasingly used because of its equivalent efficacy and lower toxicity compared with docetaxel (14). In the case of erlotinib-naïve subjects, erlotinib is recommended as third-line therapy. However, the efficacy of erlotinib as third-line chemotherapy for Japanese patients without EGFR mutations beyond two cytotoxic chemotherapy regimens remains unclear. We conducted a phase II study with oral administration of erlotinib in patients with advanced NSCLC who had already received two chemotherapy regimens and had wild-type EGFR. We aimed to determine the efficacy and safety of third-line erlotinib for patients without EGFR mutations.

PATIENTS AND METHODS

Ethical Approval of the Study Protocol

The study protocol was approved by the Institutional Review Board of each participating center. Each patient gave written informed consent to be included in the study.

Patient Eligibility

Patients with pathologically confirmed inoperable stage-IIIB NSCLC (without an indication for radiotherapy) or stage-IV NSCLC who were aged ≥20 years, who showed Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and who were naïve for EGFR tyrosine kinase inhibitors, were eligible for the present study. Patients harboring activating EGFR mutations were excluded. Patients had to have received two prior systemic chemotherapy regimens (one of which was a platinum-containing regimen). Additional eligibility criteria included adequate function of the bone marrow, liver and kidney. Erlotinib was in tablet form; so patients had to be able to swallow. For staging, computed tomography (CT) of the thorax and abdomen, either CT or MRI of the brain, and radioisotopic bone imaging were carried out. Patients were excluded if they had severe complications or active interstitial lung disease.

Treatment Schedule

Patients started to receive erlotinib (150 mg, p.o.) every day after experiencing recurrence or progression of disease after second-line treatment. Treatment was continued until disease progression, unacceptable toxicity, interstitial lung disease or withdrawal of consent to participate in the study occurred. Doses were adjusted according to hematological and non-hematological toxicity. If > grade 3 rash or diarrhea occurred, treatment was withheld. After the rash or diarrhea resolved, erlotinib (100 mg per day) was restarted. If recovery of such toxicities could not be confirmed at a reduced dose, the patient was withdrawn from the study. If grade 4 non-hematological toxicity or ≥ grade 1 interstitial lung disease occurred, erlotinib treatment was discontinued.

Evaluation of Response and Toxicity

Imaging tests, complete blood count and blood chemistry analyses were conducted every 4 weeks. The response was assessed in reference to the CT findings that had initially been used to define tumor extent. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria version 3.0.

Status of EGFR Mutations

Mutation status was assessed by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, which is commercially available in Japan (15,16). This analysis can detect EGFR mutations in the presence of a 100-fold to 1000-fold background of wild-type alleles, and the sensitivity and specificity of this analysis is reported to be 97 and 100%, respectively (16). It can rapidly detect known alternations in a target region, deletions in exon 19 (E736-A750del, L747-A750delT751S, L747-S752delP753S, L747-E749delA750P, L747-S752delE746V and S752-I759del), mutations in exon 21 (L858R and L861Q) and in exon 18 (G719C, G719S and G719A) and a mutation in exon 20 (T790M).

Statistical Analyses

The primary endpoint was overall response rate. The minimum number of patients to be enrolled in this study was 19 assuming that the 95% confidence interval (CI) would be 10% below the conditions of an α error of 0.05 (one-sided) and a β error of 0.2, assuming an expected response rate of 20% and a threshold response rate of 3% (8) according to the one-arm binomial devised by the Southwest Oncology Group. Overall survival—which was defined as the time from the date when registration was carried out to the date of death from any cause, or when the subject was last known to have been alive—was estimated by the Kaplan–Meier method. Progression-free survival (PFS) was measured from the date of registration to the date of documented disease progression or death from any cause. All values were analyzed using JMP version 5.0.1J software (SAS Institute Japan; Tokyo, Japan). All statistical tests were two-sided, and P< 0.05 was considered significant.

RESULTS

Patient Characteristics

Twenty patients were enrolled and were assessable for the evaluation of efficacy and safety between July 2008 and August 2010. Patient characteristics are listed in Table 1. Most patients (95.0%) had a good performance status (ECOG 0 or 1). The predominant histological type was adenocarcinoma. All patients had received a platinum-based regimen as first-line treatment; 17 patients (85.0%) had received docetaxel monotherapy as second-line treatment. At the time of erlotinib treatment, five patients had stable brain metastases that had been treated. The median follow-up period was 6.6 months.

Table 1.

Patient characteristics

Characteristics Number of patients, n (%) 
Gender 
 Male 18 (90%) 
 Female 2 (10%) 
Age, years 
 Median 65.7 
 Range 44–83 
Performance statusa 
 0 14 (70.0%) 
 1 5 (25.0%) 
 2 1 (5.0%) 
Histologic type 
 Adenocarcinoma 11 (55.0%) 
 Squamous cell carcinoma 6 (30.0%) 
 Other 3 (15.0%) 
Smoking status 
 Current smoker 15 (75.0%) 
 Former smoker 3 (15.0%) 
 Never smoked 2 (10.0%) 
Stage 
 III B 6 (30.0%) 
 IV 14 (70.0%) 
Characteristics Number of patients, n (%) 
Gender 
 Male 18 (90%) 
 Female 2 (10%) 
Age, years 
 Median 65.7 
 Range 44–83 
Performance statusa 
 0 14 (70.0%) 
 1 5 (25.0%) 
 2 1 (5.0%) 
Histologic type 
 Adenocarcinoma 11 (55.0%) 
 Squamous cell carcinoma 6 (30.0%) 
 Other 3 (15.0%) 
Smoking status 
 Current smoker 15 (75.0%) 
 Former smoker 3 (15.0%) 
 Never smoked 2 (10.0%) 
Stage 
 III B 6 (30.0%) 
 IV 14 (70.0%) 

aPerformance status was according to the Eastern Cooperative Oncology Group Scale.

Efficacy

The median duration of third-line erlotinib treatment was 58 days (range, 26–181 days). Among 20 evaluable patients, 3 patients had a partial response (PR) and 8 had stable disease, yielding an overall response rate of 15.0% (95% CI: 5.2–36.0%) and a disease control rate of 55.0% (95% CI: 34.2–74.2%). Histologically, PR was observed in 2/11 (18.2%, 95% CI: 5.1–47.7%) patients with adenocarcinoma and 1/6 (16.7%, 95% CI: 3.0–56.4%) patient with squamous cell carcinoma. We found no significant difference in response rate and disease control rate between histological type, sex or smoking status. PFS and median survival time was 2.1 months (95% CI: 1.2–3.0 months, Figure 1) and 6.7 months (95% CI, 4.1–7.8 months, Figure 1), respectively. The 1-year survival rate was 13.5%.

Figure 1.

Progression-free survival (PFS) (dotted line) and overall survival (solid line) of the 20 treated patients were calculated using the Kaplan–Meier method.

Figure 1.

Progression-free survival (PFS) (dotted line) and overall survival (solid line) of the 20 treated patients were calculated using the Kaplan–Meier method.

Safety

The major adverse events are shown in Table 2. Common adverse events were skin rash (75.0%), anorexia (15.0%) and diarrhea (15.0%). The dose was reduced to 100 mg in one patient because of skin toxicity. All adverse events were tolerated and improved without treatment discontinuation. Grade 3/4 toxicity or interstitial lung disease, which is considered to be related to treatment, was not observed.

Table 2.

Maximum toxicity grades associated with erlotinib

Adverse events Number of patients, n (%)
 
 Grade
 
Grade 1–4 Grade 3–4 
   
Rash 15 (75) 
Oral mucositis 4 (20) 
Anorexia 3 (15) 
Diarrhea 3 (15) 
Pulmonary fibrosis 0 (0) 
Adverse events Number of patients, n (%)
 
 Grade
 
Grade 1–4 Grade 3–4 
   
Rash 15 (75) 
Oral mucositis 4 (20) 
Anorexia 3 (15) 
Diarrhea 3 (15) 
Pulmonary fibrosis 0 (0) 

DISCUSSION

This was the first study designed to explore the efficacy and safety of the EGFR tyrosine kinase inhibitor erlotinib as third-line chemotherapy for NSCLC patients without EGFR mutations. The response rate was 15.0% and the disease control rate was 55.0%. Most of the patients tolerated erlotinib treatment, even as third-line therapy. Erlotinib was therefore deemed suitable for third-line chemotherapy for patients without EGFR mutations.

Third-line chemotherapy has attracted special attention. Massarelli et al. reported that efficacy decreased with each subsequent line of treatment, and that the median survival with third-line therapy was 4 months. They claimed the need for a novel approach to patients who fail second-line therapy (8). Recently, advances in the treatment of lung cancer, including potent front-line chemotherapy, appropriate usage of molecular target drugs and supportive care, have permitted more patients to be considered eligible for third-line chemotherapy (17). In 2009, Girard et al. (18) reported that 28% of patients treated with first-line chemotherapy received third-line chemotherapy that was effective in improving symptoms and performance status. Many patients remain in good health even after the failure of second-line treatment and wish to receive third-line treatment. The importance of third-line chemotherapy for NSCLC is increasingly recognized. However, studies demonstrating suitable regimens and candidates, as well as efficacy and safety of chemotherapy beyond second-line therapy, are scarce (5,6).

There are a few retrospective studies on the efficacy and safety of third-line chemotherapy. Chang et al. (19) reported the efficacy of pemetrexed as third-line therapy. The response rate and the disease control rate was 13.8 and 55.4%, respectively. The median overall survival was 11.0 months. As one of the few prospective studies specifically designed to evaluate third-line treatment, a phase I combination study of vinorelbine and gemcitabine was conducted (20). Although this combination chemotherapy was feasible, showing a disease control rate of 73.6% and survival time of 6.8 months, it was not studied further. In the present study, we investigated the efficacy and safety of erlotinib restricted to third-line chemotherapy after receiving two systemic chemotherapy regimens according to recommendations (4,5). Furthermore, we limited study subjects to patients without EGFR mutations. The response rate was 15.0% in our third-line erlotinib treatment, which seems to be similar to that in sub-categorized third-line erlotinib therapy in the BR.21 study (12). Erlotinib could also be used safely as a third-line treatment. Although skin rash was the most common adverse event and the major cause for treatment interruption in the present study, this adverse event was, in general, well tolerated. Compared with the situations when first- and second-line treatments were selected, quality-of-life and convenience of treatment have been emphasized in third-line treatment. Taken together, erlotinib monotherapy is feasible as third-line chemotherapy for advanced NSCLC, even for patients without EGFR mutations.

In the IRESSA Pan-Asia study, which compared gefitinib with cytotoxic chemotherapy in East Asian patients with adenocarcinoma and a brief history of smoking, gefitinib showed superior PFS, especially in patients with EGFR mutations. Conversely, cytotoxic chemotherapy yielded longer PFS in patients without mutations (9). In therapy with gefitinib, the response rate and PFS were highly sensitive to EGFR mutations (10). However, in clinical trials, erlotinib yielded a survival benefit even in patients with squamous cell carcinoma histology, who were smokers or male, all of which are negative factors for gefitinib treatment (12,15,21). Although the presence of EGFR gene mutations is a predictive factor for responsiveness to erlotinib (22,23), patients with wild-type EGFR derived survival benefit from erlotinib (12,24–26). Yoshioka et al. conducted a phase II study to assess the efficacy of erlotinib in patients with wild-type EGFR, which involved almost half of the patients receiving erlotinib monotherapy as second-line chemotherapy (15). The response rate was 3.3% and PFS was 2.1 months, and erlotinib therapy for pretreated patients with wild-type EGFR was argued to have a modest activity. Also, in the present study, which was limited to patients harboring wild-type EGFR, erlotinib showed an acceptable response. Erlotinib can be used effectively as third-line chemotherapy across EGFR mutations, although the small sample size may affect the results. The fact that erlotinib is given at a higher biologically active dose than gefitinib may induce different efficacy in patients without EGFR mutations. Cho et al. (21) suggested that the higher-affinity binding potency of erlotinib to the EGFR kinase domain confers an advantage of erlotinib to patients without EGFR mutations.

In conclusion, erlotinib is useful as third-line chemotherapy for NSCLC patients without EGFR mutations. The comparatively favorable efficacy, survival time, tolerable toxicity and feasibility as outpatient care make erlotinib a good therapeutic option for third-line treatment. Further studies with a larger population are required to confirm our results and to define the adequate order of salvage treatments (especially if erlotinib is administered).

Conflict of interest statement

All authors declare no actual or potential conflicts of interest.

Acknowledgements

We thank Drs Asada, Matsui and Sagisaka for assistance in the collection of tissue samples for EGFR mutation status. No financial support was provided for this study.

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