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Phase I Study of Concurrent Whole Brain Radiotherapy and Erlotinib for Multiple Brain Metastases From Non–Small-Cell Lung Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 5, pp. 1391–1396, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.10.026
CLINICAL INVESTIGATION
Lung
PHASE I STUDY OF CONCURRENT WHOLE BRAIN RADIOTHERAPY AND ERLOTINIB FOR MULTIPLE BRAIN METASTASES FROM NON–SMALL-CELL LUNG CANCER JOLINE S. W. LIND, M.D.,* FRANK J. LAGERWAARD, M.D., PH.D.,y EGBERT F. SMIT, M.D., PH.D.,* y AND SURESH SENAN, M.R.C.P., F.R.C.R., PH.D. Departments of * Pulmonary Diseases and y Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands Purpose: Erlotinib has shown activity in patients with brain metastases from non–small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Methods and Materials: Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. Results: A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. Conclusion: WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non–smallcell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study. Ó 2009 Elsevier Inc. Brain metastases, Non–small-cell lung cancer, Erlotinib, Whole brain radiotherapy.
INTRODUCTION
in objective tumor response rates of 9–19% in patients with advanced NSCLC. In patients whose NSCLC progresses after previous chemotherapy, erlotinib can result in a 2-month survival benefit (6–8). In the first-line setting, the combination of erlotinib with other forms of chemotherapy has not shown a survival benefit (9–11). Epidermal growth factor receptor tyrosine kinase inhibitors show activity in patients with brain metastases from NSCLC, with two retrospective analyses of gefinitib reporting objective intracranial response rates of 43–60% (12, 13). A prospective trial of 40 East Asian patients treated with gefitinib for lung adenocarcinoma and brain metastases showed an 83% intracranial disease control rate and a 38% objective response rate, with symptom improvement in 40% (14). A prospective study in a Western population reported an overall disease control rate of 27% (15). A number of case reports of erlotinib have similarly demonstrated objective intracranial responses, with improvement of cerebral metastasis-related symptoms and little toxicity (16–20).
Approximately 20–40% of patients with non–small-cell lung cancer (NSCLC) will develop brain metastases at some point during the course of their disease (1, 2). Although patients with a single or limited number of brain metastases are candidates for neurosurgery or stereotactic radiosurgery, most patients have multiple brain metastases and/or extensive extracranial disease, rendering them ineligible for such treatment. The standard treatment for these patients consists of a short course of palliative whole brain radiotherapy (WBRT). The median survival after WBRT is 3–6 months, depending on the prognostic factors such as performance status, patient age, and the extent of extracranial disease, with almost one half of patients dying of intracranial disease progression (3, 4). Overexpression of the epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase protein, is common in NSCLC, and its presence is associated with a poor prognosis (5). The use of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has resulted
Conflict of interest: S. Senan and F. J. Lagerwaard have been involved with advisory boards for Roche. Received July 31, 2008, and in revised form Oct 1, 2008. Accepted for publication Oct 8, 2008.
Reprint requests to: Frank J. Lagerwaard, M.D., Ph.D., Department of Radiation Oncology, VU University Medical Center, de Boelelaan 1117, Amsterdam 1081 HV The Netherlands. Tel: (+31) 020-4444-0414; Fax: (+31) 020-4444-0410; E-mail: fj. [email protected] 1391
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Overexpression of EGFR in tumors is associated with reduced local control after RT (21). Preclinical data have shown that inhibition of EGFR increases local tumor control after RT, and a prospective Phase III trial of patients with head-and-neck tumors found combined RT with the antiEGFR antibody cetuximab to increase both local tumor control and survival (22). A retrospective analysis in patients with WBRT for brain metastases from lung adenocarcinoma reported greater response rates with concurrent gefitinib (23). Because of the response rates reported with EGFR inhibitors for brain metastases from NSCLC and the radiation-enhancement effect of EGFR inhibition, we hypothesized that combining EGFR inhibitors with WBRT might improve the dismal prognosis of these patients. Therefore, we performed a prospective, two-cohort, dose-escalation Phase I trial combining WBRT with concurrent and maintenance erlotinib to assess the safety and tolerability of this combination.
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Table 1. Eligibility criteria Age $18 y RPA class 1 or 2 Ability to take oral medication Granulocyte count $1.5 109/L Platelet count >100 109/L Serum bilirubin #1.5 ULN AST and/or ALT #2 ULN (or #5 ULN if clearly attributable to liver metastasis) Serum creatinine #1.5 ULN (or creatinine clearance $600 mL/min) Patients with reproductive potential: use of effective contraception Women with childbearing potential: negative pregnancy test within 72 h of starting therapy Abbreviations: RPA = recursive partitioning analysis; ULN = upper limit of normal; AST = aspartate aminotransferase; ALT = alanine aminotransferase. as the dose of erlotinib that could be safely administered with WBRT that resulted in tolerable, manageable, and reversible toxicity.
METHODS AND MATERIALS Patient selection Patients with pathologically confirmed NSCLC and evidence of cerebral metastases on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans were eligible for study enrollment if they were not candidates for neurosurgical excision or stereotactic radiosurgery. The full details of inclusion and exclusion criteria are listed in Tables 1 and 2.
Patient monitoring The baseline assessments included medical history, physical examination, neurologic examination, routine laboratory tests, CT scans of the chest and abdomen, and CT or MRI scans of the brain. Patients were assessed for toxicity and clinical response by the radiation oncologist and/or pulmonologist at weeks 1 and 2 of WBRT and at 2 weeks, 4 weeks, and 2 months and then every 2 months thereafter until disease progression and/or death. MRI scans of the brain and CT scans of the chest were performed at 3-month intervals.
Study design The study (Protocol No. NCT00536861) was approved by the hospital medical ethics committee and was conducted in accordance with ethical principles as set out in the Declaration of Helsinki and International Conference on Harmonization/Good Clinical Practice. All patients provided written informed consent before study entry.
Radiotherapy Whole brain RT was delivered to a total dose of 30 Gy in 10 oncedaily fractions, and the overall treatment time was 2 weeks. Patients were placed in the supine position with customized immobilization masks. The treatment was delivered to the brain using lateral-opposing portals with 6-MV photons. Steroids were administered at the discretion of the treating physician, as indicated by the clinical signs and symptoms.
Erlotinib Erlotinib was initiated 1 week before the start of WBRT with a two-cohort erlotinib dose-escalating scheme. In the first cohort, 4 patients were treated with oral erlotinib at a dose of 100 mg/d. In the absence of any Grade 3 or greater toxicity at a minimum of 4 weeks after WBRT completion, the erlotinib dose was increased to 150 mg/d. In both cohorts, maintenance erlotinib after WBRT was 150 mg/d until severe or intolerable toxicity, disease progression, or death. The maximal erlotinib dose evaluated for concurrent treatment was 150 mg, the standard recommended dose for systemic therapy. Dose-limiting toxicity was defined as Grade 4 skin toxicity, Grade 3 or 4 diarrhea not improving with the addition of loperamide at a maximal dose during 48 h, any other Grade 3 or 4 clinically significant, nonhematologic toxicity (excluding Grade 3 nausea and any grade of alopecia), and any toxicity that resulted in a delay in treatment and a dose reduction. The maximal tolerated dose was defined
Endpoints and statistical analysis The primary endpoint toxicity was scored according to the National Cancer Institute Common Toxic Criteria for Adverse Events, version 3.0. Nonhematologic adverse events of all grades and hematological adverse events of Grade 3 or greater were recorded. The secondary endpoints of overall survival and interval to progression were determined using the Kaplan-Meier method and calculated from the start of erlotinib treatment. Intracranial and extracranial tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors.
RESULTS Patient characteristics Between May 2006 and December 2007, 13 patients were enrolled: 4 patients in Cohort 1 and 9 patients in Cohort 2. Two patients from Cohort 2 withdrew from the study before WBRT because of rapid clinical deterioration after 3 and 4 days of erlotinib therapy, respectively. Neither experienced treatment-related adverse events. Both were excluded from the data analysis. The 11 evaluable patients consisted of 5 women and 6 men, with a median age of 65 years (range, 57–89). The patient and tumor characteristics are summarized in Table 3. In the 6 patients with newly diagnosed NSCLC, erlotinib maintenance was substituted for standard chemotherapy. Of the 11 patients, 9 required treatment with dexamethasone before RT for symptoms caused by the intracranial metastases. All 11 patients completed WBRT. The median treatment duration with erlotinib was 83 days (range, 38–523). The median
WBRT and erlotinib for brain metastases from NSCLC d J. S. W. LIND et al.
Table 2. Exclusion criteria Signs and symptoms or MRI findings consistent with leptomeningeal metastases Presence of unstable systemic disease except for lung cancer Concomitant use of phenytoin Previous use of systemic Her1/EGFR inhibitors Any other malignancies in preceding 5 y Any significant ophthalmologic abnormality Abbreviations: MRI = magnetic resonance imaging; EGFR = epidermal growth factor receptor.
follow-up of all patients was 95 days (range, 42–557) from the start of erlotinib treatment. Toxicity Treatment-related toxicity is summarized in Table 4. No treatment-related neurotoxicity was observed, and escalation of the dose of dexamethasone was not required in any of the 9 patients receiving this agent during WBRT. Toxicity was generally Grade 1 or 2, with the most frequent toxicities being fatigue (64%), acneiform rash (45%), anorexia (45%), diarrhea (45%), taste alteration (45%), weight loss (45%), nausea (36%), and dyspnea (27%). No Grade 3 or greater hematologic toxicity was observed. In Cohort 1, no treatment-related Grade 3 or greater toxicity was observed. In Cohort 2, 2 patients developed Grade 3 treatment-related toxicity: 1 developed an acneiform rash that responded to 7 days of oral minocycline treatment, and 1 developed fatigue. Two patients had Grade 5 treatment-related interstitial lung disease (ILD), 43 and 46 days after starting erlotinib, respectively. In both cases, ILD was a contributing factor to death (at 52 and 59 days, respectively) and was confirmed at autopsy. Serious adverse events unrelated to study treatment occurred in 3 patients: one Grade 3 dehydration secondary to diuretic use and poor oral intake causing a 5-day interruption of erlotinib treatment; one primary tumor-related bilateral laryngeal nerve palsy requiring tracheostomy placement, and one gastric ulcer hemorrhage that was considered dexamethasone related and was treated with intralesional adrenaline and pantoprazol. Overall survival and pattern of progression The median overall survival time was 133 days (range, 42–557) from the start of protocol therapy. At the time of this analysis, 2 patients were alive, both no longer in the study because of disease progression after 51 and 204 days, respectively. Five patients survived >150 days, all of whom developed an erlotinib-induced acneiform rash. Four patients died without signs of disease progression during erlotinib therapy. The cause of death was histologically confirmed erlotinib-induced interstitial lung disease in 2 patients (1 with concurrent pneumonia and 1 with myocardial infarction), exacerbation of chronic obstructive pulmonary disease in 1 patient and postoperative congestive cardiac failure (after tracheotomy placement for laryngeal nerve palsy) in 1 patient with a history of cardiac disease. Disease progression during erlotinib treatment was observed in 7 patients (64%) during follow-up, and in 6 of these
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Table 3. Patient (n = 11) and tumor characteristics Characteristic Gender Female Male Age (y) Median Range WHO performance status 0 1 RPA class 1 2 Smoking history Current/previous Never Tumor histologic type Adenocarcinoma Squamous Large cell Previous therapy Surgery only Chemoradiotherapy only Chemoradiotherapy + surgery Surgery + chemotherapy None Brain metastases 0–5 6–10 >10 Size of largest brain metastasis (cm) Median Range Dexamethasone use Yes No
Value 5 (45) 6 (55) 65 57–84 2 (18) 9 (82) 1 (9) 10 (91) 10 (91) 1 (9) 5 (45) 2 (18) 4 (36) 2 (18) 1 (9) 1 (9) 1 (9) 6 (45) 5 (45) 5 (45) 1 (9) 1.9 0.6–3.6 9 (82) 2 (18)
Abbreviations: WHO = World Health Organization; RPA = recursive partitioning analysis. Data presented as number of patients, with percentages in parentheses, unless otherwise noted.
patients, the progression was extracranial. Clinical intracranial progression was seen in 1 patient only at 204 days. The median time to any progression was 141 days (range, 38–523).
Radiographic response Imaging of the brain was performed after WBRT in only 7 patients because the other 4 patients had died before the planned follow-up scan. Although not a formal endpoint of the study, the objective intracranial response at 3 months after WBRT was a partial response in 5 patients and stable disease in 2, corresponding to an intracranial disease control rate of 100% at 3 months. Intracranial progression was confirmed on follow-up imaging in the single patient with clinical progression on MRI imaging at 204 days. DISCUSSION This is the first prospective trial to combine WBRT and concurrent erlotinib for the treatment of brain metastases
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Table 4. All treatment-related toxicity Grade NCI-CTC adverse event Constitutional symptoms Fatigue Weight loss Dermatology Cheilitis Dry skin Nail changes Pruritus/itching Rash acne/acneiform Radiation dermatitis Gastrointestinal Anorexia Constipation Diarrhea Dyspepsia Mucositis Nausea Taste alteration Vomiting Hemorrhage (pulmonary/upper respiratory: respiratory tract NOS) Ocular/visual (dry eye syndrome) Pain (neurology headache) Pulmonary/upper respiratory Cough Dyspnea Pneumonitis/pulmonary infiltrates
Any
1
2
3
4
5
7 (64) 1 (9) 5 (45) 1 (9) 5 (45) 2 (18) 3 (27) 1 (9) 2 (18) 1 (9) 1 (9) 5 (45) 1 (9)
1 (9) 2 (18) 1 (9) 1 (9) 3 (27) 1 (9) 1 (9) 1 (9)
5 (45) 1 (9) 5 (45) 1 (9) 1 (9) 4 (36) 5 (45) 3 (27) 1 (9)
3 (27) 2 (18) 1 (9) 5 (45) 1 (9) 1 (9) 2 (18) 2 (18) 3 (27) 2 (18) 2 (18) 1 (9) 1 (9)
2 (18) 2 (18) 1 (9) 1 (9) 2 (18) 1 (9) 1 (9) 3 (27) 2 (18) 1 (9) 2 (18)
2 (18)
Abbreviations: NCI-CTC = National Cancer Institute Common Toxicity Criteria; NOS = not otherwise specified. Data presented as number of patients, with percentages in parentheses.
from NSCLC. The combination was well tolerated, with no deterioration in neurologic symptoms, and all patients were able to complete the 2 weeks of WBRT. Treatment-related toxicity was mainly limited to Grade 1 or 2 and was consistent with the previously documented toxicity profile of erlotinib. The most common treatment-related toxicities were fatigue, acneiform rash, anorexia, diarrhea, taste alteration, weight loss, nausea, and dyspnea. During maintenance erlotinib therapy, however, 2 patients developed fatal erlotinib-induced ILD, of whom 1 had concurrent pneumonia and 1 concurrent multiple pulmonary emboli and myocardial infarction. ILD is only a recently recognized complication of EGFR-TKI therapy and remains poorly understood. It has been reported by the Food and Drug Administration to occur in 0.8% of erlotinib-treated patients with NSCLC, with a median time to onset of 47 days (24). The occurrence of 2 cases of erlotinib-induced ILD during maintenance erlotinib therapy in this study was unanticipated. Although it is unlikely that a correlation exists between this relatively high incidence of erlotinib-induced ILD and the combination of WBRT with concurrent
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erlotinib, the safety of maintenance erlotinib monotherapy in this patient population requires additional investigation. Approximately 50% of patients with brain metastases who are treated with WBRT die of neurologic progression (3, 4). In our study, only 1 patient (9%) developed neurologic progression after 204 days. In addition, the objective intracranial disease control rate observed in 7 patients who underwent imaging 3 months after WBRT completion was encouraging, because 5 patients had a partial response and 2 stable disease. Our small sample size is inherent to any Phase I trial and larger Phase II studies are thus needed to further assess the efficacy of this combination treatment. To our knowledge, no data exist regarding the permeability of the intact blood–brain barrier to erlotinib. However, tumor samples in glioblastoma patients have reported concentrations of erlotinib and the active metabolite OSI-420 comparable to those shown to be active against cancer cell lines in preclinical studies (25, 26), which might be a reflection of the locally disrupted blood–brain barrier in primary and secondary brain tumors (27). Erlotinib was not used in our study as a single modality but in combination with WBRT. Therefore, our study design did not evaluate erlotinib doses that were >150 mg, because this was the dose registered for systemic therapy. The high intracranial response rates observed in the present study at a dose of 150 mg suggest that greater doses might not be needed for the treatment of brain metastases. Our findings are consistent with the recent data reporting efficacy of EGFR-TKIs against brain metastases from NSCLC. The data for erlotinib are limited to a number of case reports, including 2 cases of complete intracranial responses (16–20). More data are available for gefitinib (12– 14). Additional evidence that improved local tumor control can be achieved by combing EGFR inhibitors with RT has come from a retrospective analysis of 63 patients treated with WBRT for brain metastases from lung adenocarcinoma, in which a greater response was seen for concurrent gefitinib than with WBRT alone (23). Potential mechanisms of RT outcome enhancement by EGFR inhibitors include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization, reduced cell repopulation, inhibition of radiation-induced DNA damage repair, and improved reoxygenation (28, 29). In contrast, the relatively high proportion of extracranial progression suggests that maintenance erlotinib monotherapy after WBRT has limited efficacy in an unselected Western population. The median survival observed in our study was 133 days (range, 42–557). The 5 patients with survival >150 days all had had an erlotinib-induced rash. This is consistent with published data showing rash to be a biomarker for an extracranial response and survival in patients with NSCLC treated with EGRF-TKIs (30). Whether the rash correlates with an intracranial response has yet to be established. Other predictors of a response to EGFR-TKIs are female gender, Asian origin, absence of a smoking history, adenocarcinoma histologic features, and EGFR mutations; however,
WBRT and erlotinib for brain metastases from NSCLC d J. S. W. LIND et al.
K-ras mutations appear to be associated with resistance (31, 32). A retrospective study of 8 Japanese patients with brain metastases from NSCLC found gefitinib to be effective in all patients with EGFR mutations within the tyrosine kinase domain and ineffective in those with wild-type EGFR (33). A mutational analysis could be performed in 3 of our patients, all of whom had wild-type EGFR. One of the latter died of intrathoracic disease progression after 58 days and the other 2, of whom 1 had a K-ras mutation, died of erlotinib associated-ILD as described in the ‘‘Results’’ section. Future studies are needed to evaluate the predictors and biomarkers of efficacy to optimize patient selection and monitoring.
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CONCLUSION The combination of WBRT with concurrent erlotinib appears to be safe and well tolerated. The absence of neurotoxicity, and the suggestion of high intracranial response rates, justifies additional study of this combination in a larger, randomized Phase II study assessing the efficacy and predictors of response. This combination treatment might improve the current dismal prognosis of patients with brain metastases from NSCLC. However, the efficacy and safety of maintenance erlotinib monotherapy is unclear. Other maintenance strategies must be investigated. This will also minimize the risk of developing erlotinib-induced ILD.
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15. Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non–small-cell lung cancer: A prospective trial. Ann Oncol 2004;15:1042–1047. 16. Popat S, Hughes S, Papadopoulos P, et al. Recurrent responses to non-small cell lung cancer brain metastases with erlotinib. Lung Cancer 2007;56:135–137. 17. Lai CS, Boshoff C, Falzon M, et al. Complete response to erlotinib treatment in brain metastases from recurrent NSCLC. Thorax 2006;61:91. 18. Pan M, Santamaria M, Wollman DB. CNS response after erlotinib therapy in a patient with metastatic NSCLC with an EGFR mutation. Nat Clin Pract Oncol 2007;4:603–607. 19. Gridelli C, Maione P, Galetta D, et al. Three cases of long-lasting tumor control with erlotinib after progression with gefitinib in advanced non-small cell lung cancer. J Thorac Oncol 2007;2: 758–761. 20. Fekrazad MH, Ravindranathan M, Jones DV Jr. Response of intracranial metastases to erlotinib therapy. J Clin Oncol 2007;25: 5024–5026. 21. Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 1999;5: 2884–2890. 22. Baumann M, Krause M. Targeting the epidermal growth factor receptor in radiotherapy: Radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 2004;72:257–266. 23. Gow CH, Chien CR, Chang YL, et al. Radiotherapy in lung adenocarcinoma with brain metastases: Effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res 2008;14:162–168. 24. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: Erlotinib (Tarceva) tablets. Oncologist 2005;10:461–466. 25. Lassman AB, Rossi MR, Raizer JJ, et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res 2005;11:7841–7850. 26. Broniscer A, Panetta JC, O’Shaughnessy M, et al. Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420. Clin Cancer Res 2007;13: 1511–1515. 27. van den Bent MJ. The role of chemotherapy in brain metastases. Eur J Cancer 2003;39:2114–2120. 28. Baumann M, Krause M, Dikomey E, et al. EGFR-targeted anticancer drugs in radiotherapy: Preclinical evaluation of mechanisms. Radiother Oncol 2007;83:238–248. 29. Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005;65:3328–3335.
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30. Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913–3921. 31. Sequist LV, Bell DW, Lynch TJ, et al. Molecular predictors of response to epidermal growth factor receptor antagonists in non–small-cell lung cancer. J Clin Oncol 2007;25:587–595.
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32. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer— Molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144. 33. Shimato S, Mitsudomi T, Kosaka T, et al. EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib. Neuro Oncol 2006;8: 137–144.
doi:10.1016/j.ijrobp.2008.10.026
CLINICAL INVESTIGATION
Lung
PHASE I STUDY OF CONCURRENT WHOLE BRAIN RADIOTHERAPY AND ERLOTINIB FOR MULTIPLE BRAIN METASTASES FROM NON–SMALL-CELL LUNG CANCER JOLINE S. W. LIND, M.D.,* FRANK J. LAGERWAARD, M.D., PH.D.,y EGBERT F. SMIT, M.D., PH.D.,* y AND SURESH SENAN, M.R.C.P., F.R.C.R., PH.D. Departments of * Pulmonary Diseases and y Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands Purpose: Erlotinib has shown activity in patients with brain metastases from non–small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Methods and Materials: Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. Results: A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. Conclusion: WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non–smallcell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study. Ó 2009 Elsevier Inc. Brain metastases, Non–small-cell lung cancer, Erlotinib, Whole brain radiotherapy.
INTRODUCTION
in objective tumor response rates of 9–19% in patients with advanced NSCLC. In patients whose NSCLC progresses after previous chemotherapy, erlotinib can result in a 2-month survival benefit (6–8). In the first-line setting, the combination of erlotinib with other forms of chemotherapy has not shown a survival benefit (9–11). Epidermal growth factor receptor tyrosine kinase inhibitors show activity in patients with brain metastases from NSCLC, with two retrospective analyses of gefinitib reporting objective intracranial response rates of 43–60% (12, 13). A prospective trial of 40 East Asian patients treated with gefitinib for lung adenocarcinoma and brain metastases showed an 83% intracranial disease control rate and a 38% objective response rate, with symptom improvement in 40% (14). A prospective study in a Western population reported an overall disease control rate of 27% (15). A number of case reports of erlotinib have similarly demonstrated objective intracranial responses, with improvement of cerebral metastasis-related symptoms and little toxicity (16–20).
Approximately 20–40% of patients with non–small-cell lung cancer (NSCLC) will develop brain metastases at some point during the course of their disease (1, 2). Although patients with a single or limited number of brain metastases are candidates for neurosurgery or stereotactic radiosurgery, most patients have multiple brain metastases and/or extensive extracranial disease, rendering them ineligible for such treatment. The standard treatment for these patients consists of a short course of palliative whole brain radiotherapy (WBRT). The median survival after WBRT is 3–6 months, depending on the prognostic factors such as performance status, patient age, and the extent of extracranial disease, with almost one half of patients dying of intracranial disease progression (3, 4). Overexpression of the epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase protein, is common in NSCLC, and its presence is associated with a poor prognosis (5). The use of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has resulted
Conflict of interest: S. Senan and F. J. Lagerwaard have been involved with advisory boards for Roche. Received July 31, 2008, and in revised form Oct 1, 2008. Accepted for publication Oct 8, 2008.
Reprint requests to: Frank J. Lagerwaard, M.D., Ph.D., Department of Radiation Oncology, VU University Medical Center, de Boelelaan 1117, Amsterdam 1081 HV The Netherlands. Tel: (+31) 020-4444-0414; Fax: (+31) 020-4444-0410; E-mail: fj. [email protected] 1391
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Overexpression of EGFR in tumors is associated with reduced local control after RT (21). Preclinical data have shown that inhibition of EGFR increases local tumor control after RT, and a prospective Phase III trial of patients with head-and-neck tumors found combined RT with the antiEGFR antibody cetuximab to increase both local tumor control and survival (22). A retrospective analysis in patients with WBRT for brain metastases from lung adenocarcinoma reported greater response rates with concurrent gefitinib (23). Because of the response rates reported with EGFR inhibitors for brain metastases from NSCLC and the radiation-enhancement effect of EGFR inhibition, we hypothesized that combining EGFR inhibitors with WBRT might improve the dismal prognosis of these patients. Therefore, we performed a prospective, two-cohort, dose-escalation Phase I trial combining WBRT with concurrent and maintenance erlotinib to assess the safety and tolerability of this combination.
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Table 1. Eligibility criteria Age $18 y RPA class 1 or 2 Ability to take oral medication Granulocyte count $1.5 109/L Platelet count >100 109/L Serum bilirubin #1.5 ULN AST and/or ALT #2 ULN (or #5 ULN if clearly attributable to liver metastasis) Serum creatinine #1.5 ULN (or creatinine clearance $600 mL/min) Patients with reproductive potential: use of effective contraception Women with childbearing potential: negative pregnancy test within 72 h of starting therapy Abbreviations: RPA = recursive partitioning analysis; ULN = upper limit of normal; AST = aspartate aminotransferase; ALT = alanine aminotransferase. as the dose of erlotinib that could be safely administered with WBRT that resulted in tolerable, manageable, and reversible toxicity.
METHODS AND MATERIALS Patient selection Patients with pathologically confirmed NSCLC and evidence of cerebral metastases on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans were eligible for study enrollment if they were not candidates for neurosurgical excision or stereotactic radiosurgery. The full details of inclusion and exclusion criteria are listed in Tables 1 and 2.
Patient monitoring The baseline assessments included medical history, physical examination, neurologic examination, routine laboratory tests, CT scans of the chest and abdomen, and CT or MRI scans of the brain. Patients were assessed for toxicity and clinical response by the radiation oncologist and/or pulmonologist at weeks 1 and 2 of WBRT and at 2 weeks, 4 weeks, and 2 months and then every 2 months thereafter until disease progression and/or death. MRI scans of the brain and CT scans of the chest were performed at 3-month intervals.
Study design The study (Protocol No. NCT00536861) was approved by the hospital medical ethics committee and was conducted in accordance with ethical principles as set out in the Declaration of Helsinki and International Conference on Harmonization/Good Clinical Practice. All patients provided written informed consent before study entry.
Radiotherapy Whole brain RT was delivered to a total dose of 30 Gy in 10 oncedaily fractions, and the overall treatment time was 2 weeks. Patients were placed in the supine position with customized immobilization masks. The treatment was delivered to the brain using lateral-opposing portals with 6-MV photons. Steroids were administered at the discretion of the treating physician, as indicated by the clinical signs and symptoms.
Erlotinib Erlotinib was initiated 1 week before the start of WBRT with a two-cohort erlotinib dose-escalating scheme. In the first cohort, 4 patients were treated with oral erlotinib at a dose of 100 mg/d. In the absence of any Grade 3 or greater toxicity at a minimum of 4 weeks after WBRT completion, the erlotinib dose was increased to 150 mg/d. In both cohorts, maintenance erlotinib after WBRT was 150 mg/d until severe or intolerable toxicity, disease progression, or death. The maximal erlotinib dose evaluated for concurrent treatment was 150 mg, the standard recommended dose for systemic therapy. Dose-limiting toxicity was defined as Grade 4 skin toxicity, Grade 3 or 4 diarrhea not improving with the addition of loperamide at a maximal dose during 48 h, any other Grade 3 or 4 clinically significant, nonhematologic toxicity (excluding Grade 3 nausea and any grade of alopecia), and any toxicity that resulted in a delay in treatment and a dose reduction. The maximal tolerated dose was defined
Endpoints and statistical analysis The primary endpoint toxicity was scored according to the National Cancer Institute Common Toxic Criteria for Adverse Events, version 3.0. Nonhematologic adverse events of all grades and hematological adverse events of Grade 3 or greater were recorded. The secondary endpoints of overall survival and interval to progression were determined using the Kaplan-Meier method and calculated from the start of erlotinib treatment. Intracranial and extracranial tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors.
RESULTS Patient characteristics Between May 2006 and December 2007, 13 patients were enrolled: 4 patients in Cohort 1 and 9 patients in Cohort 2. Two patients from Cohort 2 withdrew from the study before WBRT because of rapid clinical deterioration after 3 and 4 days of erlotinib therapy, respectively. Neither experienced treatment-related adverse events. Both were excluded from the data analysis. The 11 evaluable patients consisted of 5 women and 6 men, with a median age of 65 years (range, 57–89). The patient and tumor characteristics are summarized in Table 3. In the 6 patients with newly diagnosed NSCLC, erlotinib maintenance was substituted for standard chemotherapy. Of the 11 patients, 9 required treatment with dexamethasone before RT for symptoms caused by the intracranial metastases. All 11 patients completed WBRT. The median treatment duration with erlotinib was 83 days (range, 38–523). The median
WBRT and erlotinib for brain metastases from NSCLC d J. S. W. LIND et al.
Table 2. Exclusion criteria Signs and symptoms or MRI findings consistent with leptomeningeal metastases Presence of unstable systemic disease except for lung cancer Concomitant use of phenytoin Previous use of systemic Her1/EGFR inhibitors Any other malignancies in preceding 5 y Any significant ophthalmologic abnormality Abbreviations: MRI = magnetic resonance imaging; EGFR = epidermal growth factor receptor.
follow-up of all patients was 95 days (range, 42–557) from the start of erlotinib treatment. Toxicity Treatment-related toxicity is summarized in Table 4. No treatment-related neurotoxicity was observed, and escalation of the dose of dexamethasone was not required in any of the 9 patients receiving this agent during WBRT. Toxicity was generally Grade 1 or 2, with the most frequent toxicities being fatigue (64%), acneiform rash (45%), anorexia (45%), diarrhea (45%), taste alteration (45%), weight loss (45%), nausea (36%), and dyspnea (27%). No Grade 3 or greater hematologic toxicity was observed. In Cohort 1, no treatment-related Grade 3 or greater toxicity was observed. In Cohort 2, 2 patients developed Grade 3 treatment-related toxicity: 1 developed an acneiform rash that responded to 7 days of oral minocycline treatment, and 1 developed fatigue. Two patients had Grade 5 treatment-related interstitial lung disease (ILD), 43 and 46 days after starting erlotinib, respectively. In both cases, ILD was a contributing factor to death (at 52 and 59 days, respectively) and was confirmed at autopsy. Serious adverse events unrelated to study treatment occurred in 3 patients: one Grade 3 dehydration secondary to diuretic use and poor oral intake causing a 5-day interruption of erlotinib treatment; one primary tumor-related bilateral laryngeal nerve palsy requiring tracheostomy placement, and one gastric ulcer hemorrhage that was considered dexamethasone related and was treated with intralesional adrenaline and pantoprazol. Overall survival and pattern of progression The median overall survival time was 133 days (range, 42–557) from the start of protocol therapy. At the time of this analysis, 2 patients were alive, both no longer in the study because of disease progression after 51 and 204 days, respectively. Five patients survived >150 days, all of whom developed an erlotinib-induced acneiform rash. Four patients died without signs of disease progression during erlotinib therapy. The cause of death was histologically confirmed erlotinib-induced interstitial lung disease in 2 patients (1 with concurrent pneumonia and 1 with myocardial infarction), exacerbation of chronic obstructive pulmonary disease in 1 patient and postoperative congestive cardiac failure (after tracheotomy placement for laryngeal nerve palsy) in 1 patient with a history of cardiac disease. Disease progression during erlotinib treatment was observed in 7 patients (64%) during follow-up, and in 6 of these
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Table 3. Patient (n = 11) and tumor characteristics Characteristic Gender Female Male Age (y) Median Range WHO performance status 0 1 RPA class 1 2 Smoking history Current/previous Never Tumor histologic type Adenocarcinoma Squamous Large cell Previous therapy Surgery only Chemoradiotherapy only Chemoradiotherapy + surgery Surgery + chemotherapy None Brain metastases 0–5 6–10 >10 Size of largest brain metastasis (cm) Median Range Dexamethasone use Yes No
Value 5 (45) 6 (55) 65 57–84 2 (18) 9 (82) 1 (9) 10 (91) 10 (91) 1 (9) 5 (45) 2 (18) 4 (36) 2 (18) 1 (9) 1 (9) 1 (9) 6 (45) 5 (45) 5 (45) 1 (9) 1.9 0.6–3.6 9 (82) 2 (18)
Abbreviations: WHO = World Health Organization; RPA = recursive partitioning analysis. Data presented as number of patients, with percentages in parentheses, unless otherwise noted.
patients, the progression was extracranial. Clinical intracranial progression was seen in 1 patient only at 204 days. The median time to any progression was 141 days (range, 38–523).
Radiographic response Imaging of the brain was performed after WBRT in only 7 patients because the other 4 patients had died before the planned follow-up scan. Although not a formal endpoint of the study, the objective intracranial response at 3 months after WBRT was a partial response in 5 patients and stable disease in 2, corresponding to an intracranial disease control rate of 100% at 3 months. Intracranial progression was confirmed on follow-up imaging in the single patient with clinical progression on MRI imaging at 204 days. DISCUSSION This is the first prospective trial to combine WBRT and concurrent erlotinib for the treatment of brain metastases
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Table 4. All treatment-related toxicity Grade NCI-CTC adverse event Constitutional symptoms Fatigue Weight loss Dermatology Cheilitis Dry skin Nail changes Pruritus/itching Rash acne/acneiform Radiation dermatitis Gastrointestinal Anorexia Constipation Diarrhea Dyspepsia Mucositis Nausea Taste alteration Vomiting Hemorrhage (pulmonary/upper respiratory: respiratory tract NOS) Ocular/visual (dry eye syndrome) Pain (neurology headache) Pulmonary/upper respiratory Cough Dyspnea Pneumonitis/pulmonary infiltrates
Any
1
2
3
4
5
7 (64) 1 (9) 5 (45) 1 (9) 5 (45) 2 (18) 3 (27) 1 (9) 2 (18) 1 (9) 1 (9) 5 (45) 1 (9)
1 (9) 2 (18) 1 (9) 1 (9) 3 (27) 1 (9) 1 (9) 1 (9)
5 (45) 1 (9) 5 (45) 1 (9) 1 (9) 4 (36) 5 (45) 3 (27) 1 (9)
3 (27) 2 (18) 1 (9) 5 (45) 1 (9) 1 (9) 2 (18) 2 (18) 3 (27) 2 (18) 2 (18) 1 (9) 1 (9)
2 (18) 2 (18) 1 (9) 1 (9) 2 (18) 1 (9) 1 (9) 3 (27) 2 (18) 1 (9) 2 (18)
2 (18)
Abbreviations: NCI-CTC = National Cancer Institute Common Toxicity Criteria; NOS = not otherwise specified. Data presented as number of patients, with percentages in parentheses.
from NSCLC. The combination was well tolerated, with no deterioration in neurologic symptoms, and all patients were able to complete the 2 weeks of WBRT. Treatment-related toxicity was mainly limited to Grade 1 or 2 and was consistent with the previously documented toxicity profile of erlotinib. The most common treatment-related toxicities were fatigue, acneiform rash, anorexia, diarrhea, taste alteration, weight loss, nausea, and dyspnea. During maintenance erlotinib therapy, however, 2 patients developed fatal erlotinib-induced ILD, of whom 1 had concurrent pneumonia and 1 concurrent multiple pulmonary emboli and myocardial infarction. ILD is only a recently recognized complication of EGFR-TKI therapy and remains poorly understood. It has been reported by the Food and Drug Administration to occur in 0.8% of erlotinib-treated patients with NSCLC, with a median time to onset of 47 days (24). The occurrence of 2 cases of erlotinib-induced ILD during maintenance erlotinib therapy in this study was unanticipated. Although it is unlikely that a correlation exists between this relatively high incidence of erlotinib-induced ILD and the combination of WBRT with concurrent
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erlotinib, the safety of maintenance erlotinib monotherapy in this patient population requires additional investigation. Approximately 50% of patients with brain metastases who are treated with WBRT die of neurologic progression (3, 4). In our study, only 1 patient (9%) developed neurologic progression after 204 days. In addition, the objective intracranial disease control rate observed in 7 patients who underwent imaging 3 months after WBRT completion was encouraging, because 5 patients had a partial response and 2 stable disease. Our small sample size is inherent to any Phase I trial and larger Phase II studies are thus needed to further assess the efficacy of this combination treatment. To our knowledge, no data exist regarding the permeability of the intact blood–brain barrier to erlotinib. However, tumor samples in glioblastoma patients have reported concentrations of erlotinib and the active metabolite OSI-420 comparable to those shown to be active against cancer cell lines in preclinical studies (25, 26), which might be a reflection of the locally disrupted blood–brain barrier in primary and secondary brain tumors (27). Erlotinib was not used in our study as a single modality but in combination with WBRT. Therefore, our study design did not evaluate erlotinib doses that were >150 mg, because this was the dose registered for systemic therapy. The high intracranial response rates observed in the present study at a dose of 150 mg suggest that greater doses might not be needed for the treatment of brain metastases. Our findings are consistent with the recent data reporting efficacy of EGFR-TKIs against brain metastases from NSCLC. The data for erlotinib are limited to a number of case reports, including 2 cases of complete intracranial responses (16–20). More data are available for gefitinib (12– 14). Additional evidence that improved local tumor control can be achieved by combing EGFR inhibitors with RT has come from a retrospective analysis of 63 patients treated with WBRT for brain metastases from lung adenocarcinoma, in which a greater response was seen for concurrent gefitinib than with WBRT alone (23). Potential mechanisms of RT outcome enhancement by EGFR inhibitors include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization, reduced cell repopulation, inhibition of radiation-induced DNA damage repair, and improved reoxygenation (28, 29). In contrast, the relatively high proportion of extracranial progression suggests that maintenance erlotinib monotherapy after WBRT has limited efficacy in an unselected Western population. The median survival observed in our study was 133 days (range, 42–557). The 5 patients with survival >150 days all had had an erlotinib-induced rash. This is consistent with published data showing rash to be a biomarker for an extracranial response and survival in patients with NSCLC treated with EGRF-TKIs (30). Whether the rash correlates with an intracranial response has yet to be established. Other predictors of a response to EGFR-TKIs are female gender, Asian origin, absence of a smoking history, adenocarcinoma histologic features, and EGFR mutations; however,
WBRT and erlotinib for brain metastases from NSCLC d J. S. W. LIND et al.
K-ras mutations appear to be associated with resistance (31, 32). A retrospective study of 8 Japanese patients with brain metastases from NSCLC found gefitinib to be effective in all patients with EGFR mutations within the tyrosine kinase domain and ineffective in those with wild-type EGFR (33). A mutational analysis could be performed in 3 of our patients, all of whom had wild-type EGFR. One of the latter died of intrathoracic disease progression after 58 days and the other 2, of whom 1 had a K-ras mutation, died of erlotinib associated-ILD as described in the ‘‘Results’’ section. Future studies are needed to evaluate the predictors and biomarkers of efficacy to optimize patient selection and monitoring.
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CONCLUSION The combination of WBRT with concurrent erlotinib appears to be safe and well tolerated. The absence of neurotoxicity, and the suggestion of high intracranial response rates, justifies additional study of this combination in a larger, randomized Phase II study assessing the efficacy and predictors of response. This combination treatment might improve the current dismal prognosis of patients with brain metastases from NSCLC. However, the efficacy and safety of maintenance erlotinib monotherapy is unclear. Other maintenance strategies must be investigated. This will also minimize the risk of developing erlotinib-induced ILD.
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