Britta Weber

Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor

Introduction: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). Methods: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. Results: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. Conclusion: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.

Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib.

The feasibility of monitoring epidermal growth factor receptor (EGFR) mutations in plasma DNA from patients with advanced non–small cell lung cancer (NSCLC) during treatment with erlotinib and its relation to disease progression was investigated.

Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays

BackgroundLung cancer patients with mutations in the epidermal growth factor receptor (EGFR) are primary candidates for EGFR-targeted therapy. Reliable analyses of such mutations have previously been possible only in tumour tissue. Here, we demonstrate that mutations can be detected in plasma samples with allele-specific PCR assays.MethodsPairs of the diagnostic biopsy and plasma obtained just prior to start of erlotinib treatment were collected from 199 patients with adenocarcinoma of non-small-cell lung cancer. DNA from both sample types was isolated and examined for the presence of mutations in exons 18–21 of the EGFR gene, employing the cobas® EGFR Tissue Test and cobas® EGFR Blood Test (in development, Roche Molecular Systems, Inc., CA, USA).ResultsTest results were obtained in all 199 (100%) plasma samples and 196/199 (98%) of the biopsies. EGFR-activating mutations were identified in 24/199 (12%) plasma samples and 28/196 (14%) biopsy samples, and 17/196 (9%) matched pairs contained the same mutation. Six EGFR mutations were present only in plasma samples but not in the biopsy samples. The overall concordance of the EGFR gene mutations detected in plasma and biopsy tissue was 179/196 (91%) (kappa value: 0.621).ConclusionMutational analysis of the EGFR gene in plasma samples is feasible with allele-specific PCR assays and represents a non-invasive supplement to biopsy analysis.Trial registrationM-20080012 from March 10, 2008 and reported to ClinicalTrials.gov: NCT00815971.

PET imaging of patients with non-small cell lung cancer employing an EGF receptor targeting drug as tracer

Background:We have previously developed 11C-erlotinib as a new positron emission tomography (PET) tracer and shown that it accumulates in epidermal growth factor receptor (EGFR)-positive lung cancer xenografts in mice. Here, we present a study in patients with non-small cell lung cancer (NSCLC) investigating the feasibility of 11C-erlotinib PET as a potential method for the identification of lung tumours accumulating erlotinib.Methods:Thirteen patients with NSCLC destined for erlotinib treatment were examined by contrast-enhanced computed tomography (CT), 11C-erlotinib PET/low-dose CT and 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET/low-dose CT before start of the erlotinib treatment. After 12 weeks treatment, they were examined by 18F-FDG PET/contrast-enhanced CT for the assessment of clinical response.Results:Of the 13 patients included, 4 accumulated 11C-erlotinib in one or more of their lung tumours or lymph-node metastases. Moreover, 11C-erlotinib PET/CT identified lesions that were not visible on 18F-FDG PET/CT. Of the four patients with accumulation of 11C-erlotinib, one died before follow-up, whereas the other three showed a positive response to erlotinib treatment. Three of the nine patients with no accumulation died before follow-up, four showed progressive disease while two had stable disease after 12 weeks of treatment.Conclusion:Our data show a potential for 11C-erlotinib PET/CT for visualizing NSCLC lung tumours, including lymph nodes not identified by 18F-FDG PET/CT. Large clinical studies are now needed to explore to which extent pre-treatment 11C-erlotinib PET/CT can predict erlotinib treatment response.

EGFR mutation frequency and effectiveness of erlotinib: A prospective observational study in Danish patients with non-small cell lung cancer

OBJECTIVES In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line. MATERIALS AND METHODS Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response. RESULTS Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p<0.001 and 12.1 vs. 3.9 months, p<0.001. Performance status (0-1 vs. 2-3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients. CONCLUSION We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients.

Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib.

OBJECTIVES The central immune co-inhibitory programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway plays a key role in tumor immune evasion in non-small cell lung cancer (NSCLC). Soluble PD-1 (sPD-1) can be detected in the blood, and preclinical evidence suggests that sPD-1 blocks PD-1/-L1 interaction and improves anti-tumor immunity. The present study compares the concentration of sPD-1 in the serum of advanced NSCLC patients with Epidermal Growth Factor Receptor (EGFR) mutation prior to erlotinib treatment and at the time of progression and correlates these results to patient outcome. MATERIALS AND METHODS Blood samples from 38 patients with EGFR-mutated advanced NSCLC treated with erlotinib were analyzed for sPD-1 by sandwich ELISA. EGFR mutational status was assessed in circulating tumor DNA (ctDNA) and tumor biopsies. RESULTS sPD-1 could be detected in 21% of patients prior to erlotinib treatment, and at disease progression in 37% (p=0.015). An increase in sPD-1 during erlotinib therapy was found in 34%, a decrease in 8% and no change in 58% of patients. An increase in sPD-1 during treatment was associated with prolonged progression-free (adjusted HR 0.32, p=0.013) and overall survival (adjusted HR 0.33, p=0.006), but not associated with the emergence of EGFR T790M mutation in ctDNA at progression or any clinicopathological factors. CONCLUSION Patients with an increase in sPD-1 during erlotinib treatment have a more favorable outcome. Our results emphasize the vast clinical impact of the PD-1/PD-L1 axis, and support the existing preclinical evidence in the bioactive function of sPD-1.

Complete Pathologic Response in Lung Tumors in Two Patients with Metastatic Non-small Cell Lung Cancer Treated with Erlotinib

Introduction: Patients with non-small cell lung cancer with a sensitizing mutation in the epidermal growth factor receptor (EGFR) are likely to respond to treatment with an EGFR inhibitor. In some patients, residual tumor tissue can be visualized for several years without any signs of progression. Methods: Two patients with pathologically verified adenocarcinoma of the lung and multiple bone metastases were monitored after start of treatment with erlotinib by examining clinical parameters and imaging of lung tumors and bone metastases. Pretreatment biopsies and blood samples were examined for the presence of EGFR mutations, and lobectomy was performed according to standard procedures after 10 months of treatment in one patient and 30 months in the other. Results: Both patients responded to treatment with erlotinib and displayed a mutated EGFR. At the time of surgery, tumor was still visible in the lungs of both patients, but cancer cells could not be identified in the resected lung tumor tissue. In one patient, blood samples were available and the EGFR mutation was detected in the circulating DNA in the pretreatment blood sample but was no longer detectable 4 weeks after start of treatment and could not be detected in any of the following 12 blood samples. Conclusions: Treatment with erlotinib may induce complete response in patients with metastatic non-small cell lung cancer. It remains to be shown whether treatment with erlotinib can be discontinued in such patients. The disappearance of EGFR mutations in the DNA of the blood sample early in treatment might be used as an indicator of response to erlotinib.

Successful treatment of hepatic oligometastases with stereotactic ablative radiotherapy and radiofrequency ablation in an anaplastic lymphoma kinase fusion‐positive lung cancer patient

Local ablative therapy with stereotactic ablative radiotherapy may improve survival in oncogene‐addicted lung cancer patients with extracranial oligometastatic disease treated with targeted therapies. There is limited data on the use of radiofrequency ablation (RFA) in this same setting. We present a case of an anaplastic lymphoma kinase (ALK)‐positive lung cancer patient with hepatic oligometastatic progression who was successfully treated with both stereotactic ablative radiation and RFA while continuing with an ALK inhibitor.

EGFR CA repeat polymorphism predict clinical outcome in EGFR mutation positive NSCLC patients treated with erlotinib

OBJECTIVES Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib. MATERIALS AND METHODS Number of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA≤16 in any allele) or long alleles (CA>16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. RESULTS In EGFR mutation positive patients (N=62) we demonstrate a significantly higher median progression free survival (HR=0.39 (0.22-0.70); p=0.002) and overall survival (HR=0.43 (0.23-0.78); p=0.006) in patients also harboring a short CA repeat length vs. a long (median follow-up time of 52.2 months). The result remained highly significant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. CONCLUSION Our study demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for both longer progression free survival and overall survival.

Automatic online and real-time tumour motion monitoring during stereotactic liver treatments on a conventional linac by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK)

The purpose of this study was to develop, validate and clinically demonstrate fully automatic tumour motion monitoring on a conventional linear accelerator by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK). COSMIK combines auto-segmentation of implanted fiducial markers in cone-beam computed tomography (CBCT) projections and intra-treatment kV images with simultaneous streaming of an external motion signal. A pre-treatment CBCT is acquired with simultaneous recording of the motion of an external marker block on the abdomen. The 3-dimensional (3D) marker motion during the CBCT is estimated from the auto-segmented positions in the projections and used to optimize an external correlation model (ECM) of internal motion as a function of external motion. During treatment, the ECM estimates the internal motion from the external motion at 20 Hz. KV images are acquired every 3 s, auto-segmented, and used to update the ECM for baseline shifts between internal and external motion. The COSMIK method was validated using Calypso-recorded internal tumour motion with simultaneous camera-recorded external motion for 15 liver stereotactic body radiotherapy (SBRT) patients. The validation included phantom experiments and simulations hereof for 12 fractions and further simulations for 42 fractions. The simulations compared the accuracy of COSMIK with ECM-based monitoring without model updates and with model updates based on stereoscopic imaging as well as continuous kilovoltage intrafraction monitoring (KIM) at 10 Hz without an external signal. Clinical real-time tumour motion monitoring with COSMIK was performed offline for 14 liver SBRT patients (41 fractions) and online for one patient (two fractions). The mean 3D root-mean-square error for the four monitoring methods was 1.61 mm (COSMIK), 2.31 mm (ECM without updates), 1.49 mm (ECM with stereoscopic updates) and 0.75 mm (KIM). COSMIK is the first combined kV/optical real-time motion monitoring method used clinically online on a conventional accelerator. COSMIK gives less imaging dose than KIM and is in addition applicable when the kV imager cannot be deployed such as during non-coplanar fields.