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Phase II Study of Erlotinib in Advanced Non–Small-Cell Lung Cancer After Failure of Gefitinib

Byoung Chul Cho, Chong-Kun Im, Moo-Suk Park, Se Kyu Kim, Joon Chang, Jong Pil Park, Hye Jin Choi, Yu Jin Kim, Sang-Joon Shin, Joo Hyuk Sohn, Hoguen Kim, Joo Hang Kim

From the Yonsei Cancer Center; Department of Internal Medicine; Lung Cancer Clinic Severance Hospital; and the Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

Address reprint requests to Joo Hang Kim, MD, PhD, Yonsei University College of Medicine, Seodaemun-gu shinchon-dong 134, Seoul, Korea; e-mail: kjhang{at}yumc.yonsei.ac.kr

	ABSTRACT

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Purpose This study was designed to evaluate the efficacy and toxicity of erlotinib in patients with advanced non–small-cell lung cancer (NSCLC) who experienced disease progression after treatment with gefitinib.

Patients and Methods The study included stage IIIB/IV recurrent or metastatic NSCLC patients who received two or three prior chemotherapy regimens and showed progressive disease within 4 months of gefitinib therapy discontinuation. Patients received erlotinib 150 mg/d until disease progression or unacceptable toxicity. Epidermal growth factor receptor (EGFR) mutations and other genetic abnormalities were analyzed from available tumor samples.

Results Patient and disease characteristics (N = 21) included median age 56 years; number of prior chemotherapy regimens (three; n = 11); female sex (n = 11); adenocarcinoma (n = 15); and never-smoker status (n = 11). Among the 17 patients with tumor samples available, EGFR mutations were detected in five. The disease control rate (DCR) and response rate (RR) for all patients were 28.6% and 9.5%, respectively. The median duration of disease control was 125 days. The median time to progression and overall survival were 60 days and 158 days, respectively. Patients who had stable disease (SD) while receiving gefitinib showed significantly higher DCR (75% v 17.6% in non-SD patients; P = .050) and RR (50.0% v 0% in non-SD patients; P = .029). Among 17 patients with biomarker results available, those lacking EGFR mutations who had SD while receiving gefitinib showed significantly higher DCR and RR.

Conclusion Erlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) is a promising target for the therapy of non–small-cell lung cancer (NSCLC). Strategies for EGFR-targeted cancer therapies include inhibition of the intracellular tyrosine domain of the receptor by small molecules such as gefitinib or erlotinib. Both agents are orally active, reversible EGFR tyrosine kinase inhibitors (TKIs) that block signal transduction pathways implicated in the proliferation and survival of cancer cells.^1-3

Gefitinib was the first oral EGFR TKI to become commercially available. Modest response rates were observed from the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) phase II trials of gefitinib.^4,5 Asians, patients with adenocarcinoma, and those who had never smoked were more likely than were other patients to have a response to gefitinib. Mutations in the EGFR tyrosine kinase domain have recently been reported to be associated with dramatic responses to gefitinib.^6-12 In the Iressa Survival Evaluation in Lung Cancer (ISEL) study, however, gefitinib failed to prolong survival in patients with advanced NSCLC after the failure of at least one prior chemotherapy regimen.¹³ Based on the results of the ISEL study, gefitinib was removed from the market in the US and European Union.^14,15 However, because Asian patients derived benefits from gefitinib treatment in a subgroup analysis of the ISEL, gefitinib is currently being used as a second- or third-line option for the treatment of refractory NSCLC in East Asia.^16-18

Erlotinib is the only EGFR TKI shown to provide a survival benefit for advanced NSCLC patients.¹⁹ Use of erlotinib for the treatment of advanced NSCLC after the failure of at least one prior chemotherapy regimen was approved by the US Food and Drug Administration on the basis of data from a phase III study (BR.21).^19,20 This study revealed a survival advantage of 6.67 months for erlotinib versus 4.70 months for the placebo.

In contrast to the ISEL results, erlotinib appears to prolong survival for most of the patients subsets.^19,20 Indeed, erlotinib demonstrated a survival benefit even in several subsets in which gefitinib does not appear to be active, such as patients with squamous cell carcinoma histology, smokers, and male patients. The clinical results suggest that erlotinib may be a more efficacious agent than gefitinib. It is also conceivable that there might be significant differences in the mechanisms of sensitivity between these two agents.

Currently, there are many patients with no further treatment options who have progressed while receiving gefitinib. With the demonstrated survival advantages of erlotinib,¹⁹ there is a potential rationale to use erlotinib after the failure of gefitinib.

We conducted a phase II study to evaluate erlotinib as a potential therapeutic option in heavily pretreated NSCLC patients with progressive disease after treatment with gefitinib. We analyzed tumor biopsy samples to examine the relationship between biomarkers and clinical outcomes.

	PATIENTS AND METHODS

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Patient Eligibility
This study included patients age 18 years or older with recurrent or metastatic NSCLC who received two or three prior chemotherapy regimens and who showed progressive disease within 4 months of gefitinib therapy discontinuation. The patients had at least one unidimensionally measurable lesion, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, life expectancy of at least 3 months, and adequate organ functions (WBC 3,000/µL, platelets 100,000/µL, hemoglobin 9.0 g/dL, serum creatinine 1.5x the upper limit of normal [ULN], bilirubin 1.25x ULN, and serum aminotransferases 2.5x ULN). Patients were excluded if they had unresolved chronic toxicity of prior therapy, other active malignancies, uncontrolled brain metastasis, or severe comorbid conditions. Paraffin-embedded tumor samples were obtained where possible for exploratory analysis of genomic profiles. The institutional review board of the hospital approved this study and the genetic analysis of the tumors, and written informed consent was obtained from all enrolled patients.

Treatment
Patients received erlotinib doses at 150 mg/d. One dose reduction per patient from 150 mg to 100 mg was permitted. Erlotinib administration could be interrupted for a maximum of 21 days. Therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent.

Evaluation of Response and Adverse Events
Baseline evaluations included a complete medical history, physical and radiologic examinations, CBC, and biochemistries. Evaluation of treatment response by computed tomography scan was repeated every 4 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.²¹ If a patient was documented as having a complete response (CR) or a partial response (PR), a confirmatory evaluation was performed after 4 weeks. Disease control was defined as the best tumor response of CR, PR, or stable disease (SD) that was confirmed and sustained for 60 days or longer. Time to progression (TTP) was defined as the period from the start of treatment to the date when disease progression or death was observed. Overall survival (OS) was defined as the period from the start of treatment to the date of death. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).

Biomarker Analysis
Nucleotide sequencing of the kinase domain of EGFR (exons 18 to 21) was performed using nested polymerase chain reaction (PCR) amplification of individual exons. Details of sequencing have been described previously.¹² An additional primer pair was used for EGFR exon 20; forward: 5'-CCCTGTGCTAGGTCTTTTGC; reverse: 5'-CACACTGAGCACTCAATAAAGAGAA. Specific mutations in K-ras exon 2 (codon 12/13) and p53 exon 5 to 8 were identified as published.^35,40

Statistical Analysis
The primary objective was to assess the disease control rate (DCR; CR + PR + SD 90 days) of erlotinib therapy. The secondary objectives were to evaluate the response rate (RR) and survival, and to perform exploratory evaluations of tumor tissue for genomic profiles.

Simon's two-stage MiniMax design was used to determine the sample size. A DCR of 40% in eligible patients would indicate potential usefulness, whereas a rate of 15% would be the lower limit of interest. With = 0.05 and ß = 0.2, the estimated accrual number was 19 patients. Allowing for a 10% loss to follow-up rate, a total of 21 patients were planned to enroll.

DCRs and RRs were compared between demographic factors using Fisher's exact test. The survival distribution was estimated by the Kaplan-Meier method. TTP and OS were compared between demographic factors using the log-rank test.

	RESULTS

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Patient Characteristics
Baseline characteristics of all patients are as described in Table 1. The median age of patients on entering this study was 56 years. Approximately half of the patients were female, and adenocarcinoma was the major histologic type. Patients who had never smoked made up 52.4%.

Four of six gefitinib responders showed progressive disease on erlotinib despite favorable characteristics (five female patients with adenocarcinoma histology, four never-smokers, and three patients with EGFR mutations). The remaining two patients showed SD for relatively short duration of 111 and 101 days, respectively.

Ten of 11 patients who initially showed progressive disease while receiving gefitinib were also refractory to erlotinib. Most of these patients had unfavorable characteristics (eight male smokers, four with histologies other than adenocarcinoma, two with p53 mutation). Time from initial diagnosis to erlotinib therapy was almost half in these patients (33.6 v 15.8 months in patients refractory to treatment with TKIs), suggesting that this subset of tumors has more aggressive biology.

With a median follow-up duration of 120 days (range, 13 to 240 days), the median TTP and OS were 60 days (95% CI, 43 to 77 days) and 158 days (95% CI, 141 to 175 days), respectively (Fig 1). Response to prior gefitinib therapy was also a predictor of survival. Patients who had SD while receiving gefitinib showed longer median TTP (140 v 37 days in non-SD patients; P = .005; Fig 2) and OS (not reached v 150 days in non-SD patients; P = .043), respectively.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curve of time to progression and overall survival.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Time to progression (TTP) according to response to prior gefitinib therapy. Patients who had stable disease (SD) while receiving gefitinib showed longer median TTP (140 v 37 days in non-SD patients; P = .005).

After disease progression while receiving erlotinib, two patient subsequently received cetuximab, a recombinant monoclonal antibody that blocks the same EGFR signaling pathway. One of these patients showed partial response after 4 weeks of cetuximab therapy, with response duration of 100+ days. This patient (Case 4, Table 4), who harbored deletion mutation in EGFR, showed SD on erlotinib for 111 days.

Biomarker Analysis and Clinical Outcome
EGFR mutation were detected in five (29.4%) of 17 patients with paraffin-embedded tumor samples available. All mutations were overlapping in-frame deletions within exon 19.

In our study, 10 (47.6%) of 21 patients were refractory to both TKIs. To further explore underlying mechanisms of primary resistance to TKIs, we also looked for mutations in K-ras (exon 2) and p53 (exon 5 to 8). Two patients harbored mutations in p53. One patient carried a mutation in exon 5 (IVS5+2 T>A), together with the deletion mutation in EGFR exon 19, and another with a mutation in exon 7 (Arg248Gln [CGG>CAG]). None of the patients in our study had K-ras mutation.

EGFR mutations did not predict better DCR (one [20.0%] of five in EGFR mutants v four [33.3%] of 12 in nonmutants) or RR (zero [0%] of five in EGFR mutants v two [16.7%] of 12 in nonmutants) to erlotinib. Among 17 patients with biomarker results available, EGFR nonmutants who had SD while receiving gefitinib showed significantly higher DCR (three [100%] of three v two [21.4%] of 14 in non-SD and/or EGFR mutants; P = .029) and RR (2/3 [66.7%] v zero [0%] of 14 in non-SD and/or EGFR mutants; P = .022). In addition, these patients also showed longer median TTP (150 v 34 days; P = .004) and OS (not reached v 120 days, P = .112).

Among 21 patients, only one patient, who had responded to gefitinib and harbored EGFR mutation, underwent rebiopsy of tumor tissue after disease progression to look for secondary mutations. Mutation analysis of metastatic tumor tissue from her liver revealed a secondary threonine-to-methionine mutation at codon 790 (T790M), in addition to an exon19 deletion mutation. She showed progressive disease on subsequent erlotinib therapy.

Adverse Events
All 21 patients received at least one dose of erlotinib and were assessable for toxicity. The most common adverse event was grade 1/2 skin rash, which affected 28.5% of patients. Grade 3 skin rash occurred in one patient, whereas grade 1 diarrhea occurred in two patients. One patient (4.8%) discontinued erlotinib as a result of grade 3 vomiting. Dose reduction was required in one patient because of grade 3 skin rash.

	DISCUSSION

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To our knowledge, this is the first phase II study to assess whether erlotinib confers clinical benefit in patients with advanced NSCLC progressing while receiving gefitinib. Our study was designed to set a DCR at 90 days as a primary end point, which is considered reasonable in view of the palliative goal of treatment in this setting. The 28.6% overall DCR suggests that a meaningful percentage of patients in our study benefited from treatment with erlotinib. We can not rule out the possibility that the observed efficacy of erlotinib in our study may reflect natural history of disease rather than drug efficacy. However, the duration of disease control (median, 125 days) was substantial. Furthermore, we observed objective tumor responses in two patients (9.5%).

Our results are surprising because both EGFR TKIs share the same mechanism of EGFR blockade and may be cross resistant.^1-3 Our results suggests that some gefitinib-resistant tumors remain dependent on an active EGFR pathway for their proliferation, clearly implying that there must be qualitative differences between the two agents.

Interestingly, erlotinib produced higher clinical benefits in patients who had shown stable disease with prior gefitinib therapy in our study. It is difficult to clarify the mechanisms behind the effectiveness of erlotinib in this patient population. One potential explanation is that the standard doses of 250 mg gefitinib and 150 mg erlotinib are not biologically equivalent.^2,3,13,22,23 Erlotinib was administered at its maximum-tolerated dose, whereas gefitinib was administered at approximately one third of its maximum-tolerated dose. However, we are reluctant to attribute the activity of erlotinib to the difference in dose because of the lack of benefit from higher doses in previous IDEAL phase II studies.^4,5

Given the observation that four of six patients who benefited from erlotinib in our study were EGFR nonmutants, the second, non–mutually exclusive, possibility is that erlotinib may be more efficacious than gefitinib on wild-type EGFR by higher-affinity binding to the EGFR kinase domain. Erlotinib inhibits the activity of wild-type EGFR tyrosine kinase in tumor cells with 50% inhibitory concentration values of 2 to 20 nmol/L, whereas several-fold higher drug concentrations are required for gefitinib to block wild-type EGFR signaling.^6,7,24,25 This higher affinity binding might be partly attributed to water-mediated hydrogen bonding with the hydroxyl group of T790 in the binding pocket.²⁶ Of note, the steady-state plasma levels of gefitinib (250 mg/d) are much lower than those of erlotinib.^22,23 Therefore, a 250-mg dose of gefitinib might have been insufficient to completely inhibit the activated wild-type EGFR. Regardless of the underlying mechanism, our results suggest that tumor response to prior gefitinib therapy can be used as predictive marker for subsequent erlotinib therapy, and this observation needs to be validated in future studies.

Activating mutations in the gene for EGFR predicts the response to gefitinib or erlotinib in several studies.^6-12 However, a lack of correlation between EGFR mutations and response to erlotinib was observed in this study. A potential explanation for this lack of correlation exists. Acquired secondary mutations have now been demonstrated in patients who initially respond but later develop resistance to TKIs.^27-29 The novel mutation (T790M), where threonine is replaced by a bulkier methionine at codon 790, would result in steric hindrance to the binding of these two drugs. According to structural modeling, steric hindrance, resulting from acquired T790M mutation while receiving gefitinib therapy, may also interfere with the binding of erlotinib.^26,27 The T790M mutations occur more frequently in women who had never smoked and who had a deletion-type mutation.²⁸ Thus, when progression occurs in patients with gefitinib-responsive NSCLC with EGFR mutations, the tumor cell will have a high probability of containing secondary mutations in the EGFR gene that confer resistance to erlotinib as well as gefitinib.

Only minimal published data are available regarding the clinical activity of one EGFR TKI administered after the failure of another.^30,31 Govindan et al³¹ reported that erlotinib is not effective in patients progressing while receiving gefitinib. It should be noted, however, that all five cases in their report may have had an activating EGFR mutation because they had hallmarks associated with such mutations, such as female sex and/or never-smoker status.⁴¹ As the authors pointed out, they may have ceased responding because of the development of a resistance mutation, and therefore could not be expected to respond to erlotinib. Consistent with this assumption, none of the six patients who initially responded to gefitinib showed responses to erlotinib in our study.

The appropriate treatment of patients with progressive NSCLC that initially respond to EGFR TKIs remains unknown. It is encouraging that tumor cells with acquired resistance to gefitinib or erlotinib appear to be sensitive to irreversible EGFR inhibitors that covalently cross link the receptor.^32,33 The fact that we observed a case in which a response to cetuximab was seen after progression during treatment with two EGFR TKIs is noteworthy. Given that the mechanisms of action of the two drug classes do not completely overlap, and that cetuximab has documented single-agent activity in advanced NSCLC, this strategy certainly warrants further study.³⁴

In searching for additional genetic alterations modulating sensitivity to TKIs, we observed p53 mutations in two of 10 patients with primary resistance to TKIs. K-ras mutations, correlated with primary resistance to TKIs,^35,36 were not detected in our patients. It is also possible that overexpression of EGFR downstream molecules, such as p-AKT, might serve as a resistance mechanism to TKIs in our patients.^37-39 Ultimately, more comprehensive analysis of EGFR downstream signal molecules will be needed to fully understand the different genetic lesions driving primary resistance to TKIs.

In conclusion, erlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib. On the other hand, the prior gefitinib responders harboring EGFR mutation might be more appropriately considered for irreversible EGFR inhibitors, whereas those who showed PD while receiving gefitinib should be offered for clinical trials with novel agents.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Byoung Chul Cho, Joo Hang Kim

Financial support: Byoung Chul Cho, Joo Hang Kim

Administrative support: Moo-Suk Park, Se Kyu Kim, Joon Chang, Jong Pil Park, Joo Hyuk Sohn, Hoguen Kim, Joo Hang Kim

Provision of study materials or patients: Moo-Suk Park, Se Kyu Kim, Joon Chang, Jong Pil Park, Joo Hyuk Sohn, Hoguen Kim, Joo Hang Kim

Collection and assembly of data: Byoung Chul Cho, Chong-Kun Im

Data analysis and interpretation: Byoung Chul Cho, Chong-Kun Im, Joo Hang Kim

Manuscript writing: Byoung Chul Cho

Final approval of manuscript: Byoung Chul Cho, Chong-Kun Im, Moo-Suk Park, Se Kyu Kim, Joon Chang, Jong Pil Park, Hye Jin Choi, Yu Jin Kim, Sang-Joon Shin, Joo Hyuk Sohn, Hoguen Kim, Joo Hang Kim

	ACKNOWLEDGMENTS

 
We thank Sung Ho Choi for help for sequencing EGFR, K-ras, and p53 in tumor tissues.

	NOTES

 
B.C.C. and C.-K.I. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 19, 2006; accepted February 12, 2007.

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