Katsuhiro Masago

Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer

Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420. Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8. Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean ± SD CSF concentrations of erlotinib and OSI-420 were 54 ± 30 ng/ml and 10.8 ± 8.2 ng/ml, respectively. The mean ± SD CSF penetration rates of erlotinib and OSI-420 were 5.1% ± 1.9% and 5.8% ± 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene. Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non–Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI

Introduction: Epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Because T790M is mediated by TKI exposure, its penetration and “on–off” may affect T790M status. Methods: We retrospectively reviewed T790M status and clinical course of patients who had undergone multiple rebiopsies after acquired resistance to EGFR-TKI. Results: Of 145 patients with EGFR-mutant NSCLC receiving rebiopsy after acquired resistance, 30 underwent multiple site rebiopsies, and 24 received repeated rebiopsies at the same lesion. In 22 patients who underwent rebiopsies from both central nervous system (CNS; 20 cerebrospinal fluids [CSF] and 2 brain tumoral tissues) and thoracic lesions (7 lung tissues, 14 pleural effusions, and 1 lymph node), 12 were thoracic-T790M-positive. Of these 12 patients, 10 were CNS-T790M-negative, despite exhibiting thoracic-T790M-positive. All 10 thoracic-T790M-negatives were CNS-T790M-negative. Three patients revealed a spatial heterogeneous T790M status among their thoracic lesions. In 24 patients receiving repeated rebiopsies at the same lesion (12 lung tissues, 6 CSFs, and 6 pleural effusions), T790M status of lung lesions varied in five patients after TKI-free interval. In all five patients whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. In three of these five patients, after further TKI exposure, T790M status changed from negative to positive again. There was also a patient whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy. Conclusions: T790M status in an individual patient can be spatiotemporally heterogeneous because of selective pressure from EGFR-TKI.

Epidermal growth factor receptor gene mutations in papillary thyroid carcinoma.

Recent studies have indicated that somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of patients with nonsmall‐cell lung cancer (NSCLC) and are associated with sensitivity to the EGFR‐tyrosine‐kinase inhibitors. These mutations have been reported to be almost exclusively found in a pulmonary adenocarcinoma subgroup of NSCLC, with a low frequency in other solid tumors. We describe a patient with advanced‐stage papillary thyroid carcinoma (PTC) whose disease had been diagnosed as pulmonary adenocarcinoma at first, and who had a marked response to the EGFR‐tyrosine‐kinase inhibitor, gefitinib. An in‐frame deletion in exon 19 that eliminated 4 amino acids at positions 746 through 750, which is one of the common drug‐sensitive mutations in pulmonary adenocarcinoma, and a serine‐to‐proline substitution at codon 752, were found in a tumor specimen of the patient. We subsequently searched for mutations in the EGFR tyrosine kinase domain in primary tumors from 23 patients with PTC, and drug‐sensitive mutations commonly observed in pulmonary adenocarcinoma were found in 7 of these patients. Our observation of a high frequency of the EGFR‐activating mutations in PTC suggests that the EGFR mutation may be an important event in the development of PTC. EGFR gene amplification, also considered to be a predictor of response to EGFR‐tyrosine‐kinase inhibitors, was evaluated by fluorescence in situ hybridization (FISH); however, only 1 FISH‐positive tumor was detected. Our data suggest that EGFR‐tyrosine‐kinase inhibitors may deserve consideration in the treatment of a subset of patients with PTC, just as with pulmonary adenocarcinoma.

Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma

Although the association of multiple pulmonary metastases, and particularly miliary metastases, with response to gefitinib treatment in patients with nonsmall cell lung cancer has been reported, the association of miliary pulmonary metastases with epidermal growth factor receptor gene (EGFR) mutations remains unclear.

Good Clinical Response to Gefitinib in a Non-small Cell Lung Cancer Patient Harboring a Rare Somatic Epidermal Growth Factor Gene Point Mutation; Codon 768 AGC > ATC in Exon 20 (S768I)

Recently, two small-molecule kinase inhibitors targeting epidermal growth factor receptor have proven effective in the treatment of non-small cell lung cancer. There are specific activating mutations within the tyrosine kinase domain of epidermal growth factor receptor related to the sensitivity of tyrosine kinase inhibitors. However, it is unknown whether rare mutations in the N-lobe (exons 18-20) and the C-lobe (exon 21) of the epidermal growth factor receptor kinase domain other than L858R in exon 21 and the in-frame deletion in exon 19 may predict the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors. We reported a case of non-small cell lung cancer harboring a rare epidermal growth factor somatic mutation, codon 768 AGC > ATC in exon 20 (S768I), who showed a good clinical response to gefitinib. Therefore, we may suggest that this rare mutation (S768I in exon 20) may not be an insensitive epidermal growth factor receptor somatic mutation in vivo.

A Case of Radiation Recall Pneumonitis Induced by Erlotinib, Which Can be Related to High Plasma Concentration

To the Editor: A 78-year-old currently smoking Japanese man was diagnosed with nonsmall cell lung cancer (NSCLC). The histology was adenocarcinoma, and the primary stage was cT2N3M0. Epidermal growth factor receptor (EGFR) gene mutations were not evaluated. After he received four courses of chemotherapy (carboplatin and paclitaxel) and sequential radiation (60 Gy), he achieved partial response. The volume of lung receiving 20 Gy (V20) was 33% (Figure 1A). Seven months after finishing radiation, his chest computed tomography (CT) revealed pulmonary metastases and pleural disseminations (Figure 1B). The treatment started with daily administration of 150 mg erlotinib. Fourteen days after starting administration of erlotinib, his chest CT revealed right lung consolidation localized within the previously irradiated area (Figure 1C), so we diagnosed him with radiation recall pneumonitis induced by erlotinib (grade 3, Radiation Therapy Oncology Group scoring criteria). Twenty-four hours after last administration of erlotinib, we investigated his plasma concentration of erlotinib by high-performance liquid chromatography with ultraviolet detection as previously reported.1 The plasma concentration of erlotinib was 3817 ng/ mL, which was very high compared with previously reported mean concentration (1642.00 ng/mL).2 After he stopped administration of erlotinib and received systemic corticosteroid therapy, his symptoms improved. When radiotherapy is followed by chemotherapy, subclinical damage from irradiation can be unmasked and clinically manifested. This is called radiation recall phenomenon. Radiation recall pneumonitis is a very rare reaction in a previously irradiated area of pulmonary tissue after application of a pharmacological agent. Erlotinib is an EGFR tyrosine kinase inhibitor (TKI) and has been studied in patients with NSCLC. From Food and Drug Administration (FDA) drug approval summary, the incidence of interstitial lung disease (ILD), which is sometimes fatal, associated with erlotinib is estimated at 0.8%.3 The reaction of radiation recall pneumonitis is similar to that of druginduced ILD in that both are associated with a specific drug. No case of radiation recall pneumonitis induced by erlotinib has been reported. In this article, we present a first case report of radiation recall pneumonitis induced by erlotinib and investigate the plasma concentration of erlotinib. Fatal radiation pneumonitis is not usually observed with a lung V20 of 33%. In contrast, a case of symptomatic pneumonitis (grade 3) from radiation (V20 of 31%) and concurrent erlotinib has been reported.4 Moreover, EGFRTKIs have been reported to act as potent radiation sensitizers.5 From these findings, erlotinib can tend to induce radiation recall pneumonitis, especially in Japanese patients. In this case, the plasma concentration of erlotinib was very high compared with previous reported data.2 Although radiation recall pneumonitis induced by erlotinib could be related to a high plasma concentration of erlotinib, there is no report about this relationship. The relationship between ILD associated with erlotinib and erlotinib plasma concentration is also unclear. If ILD is related to erlotinib plasma concentration, the plasma concentration should be investigated when erlotinib is administered to a patient with the risk factors for ILD and the dose can be decreased.

Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis.

Introduction: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). Method: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. Results: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Conclusion: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib

We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment.

Clinical significance of pretreatment serum amphiregulin and transforming growth factor‐α, and an epidermal growth factor receptor somatic mutation in patients with advanced non‐squamous, non‐small cell lung cancer

Circulating amphiregulin and transforming growth factor‐α (TGF‐α) have been found to be correlated with an unfavorable response to gefitinib based on the identification of patients with a higher probability of resistance to the drug. However, the association between an epidermal growth factor receptor (EGFR) somatic mutation and the overexpression of its ligands has not been determined. To verify the clinical significance of the two serum markers and EGFR mutation status, we determined serum amphiregulin and TGF‐α levels by enzyme‐linked immunosorbent assay in 93 patients with advanced non‐squamous, non‐small cell lung cancer and EGFR somatic mutation status using the peptic nucleic acid‐locked nucleic acid clamp method in 46 cases. The relationship between each independent clinicopathological variable and the response to gefitinib therapy was examined. We also evaluated the risk factors associated with prognosis. Fourteen (41.0%) of 34 progressive disease cases were positive for amphiregulin (P = 0.007). Eleven (32.4%) of 34 progressive disease cases were positive for TGF‐α (P = 0.005). The median survival time of patients with the EGFR somatic mutation was significantly longer (P = 0.01). The same was true of amphiregulin‐ (P = 0.046) and TGF‐α‐negative patients (P < 0.01). In multivariate analysis, serum TGF‐α positivity (hazard ratio, 2.558; P = 0.005) and the wild type EGFR gene (hazard ratio, 1.894; P = 0.003) were significant independent prognostic factors. Our study demonstrates that the status of the serum EGFR ligand, in addition to EGFR activating mutation, is a predictive factor for response to gefitinib therapy. (Cancer Sci 2008; 99: 2295–2301)

Effect of vascular endothelial growth factor polymorphisms on survival in advanced-stage non-small-cell lung cancer

Polymorphisms have been identified in the vascular endothelial growth factor (VEGF) gene that may affect VEGF production. We hypothesized that such polymorphisms may correlate with survival outcomes among advanced‐stage non‐small‐cell lung cancer (NSCLC) patients. We evaluated the association between VEGF polymorphisms and overall survival among patients with advanced NSCLC who were treated with at least one cytotoxic regimen at Kyoto University Hospital between 2003 and 2008. We investigated the following VEGF polymorphisms: –460T > C (rs833061), +405G > C (rs2010963), +936C > T (rs3025039), –1154G > A (rs1570360), and –2578C > A (rs699947). Analyses of genotype associations with survival outcomes were performed using Cox proportional models, Kaplan–Meier methods, and the log‐rank test. There were 126 patients and 80 deaths. On a Cox regression analysis of a current and former smoker (hazards ratio [HR], 1.422; 95% confidence interval [CI], 1.111–1.859; P = 0.0046), poor performance status (PS) (HR, 2.524; 95% CI, 1.483–3.827; P = 0.0019), the VEGF –460CC genotype (HR, 1.719; 95% CI, 1.166–2.390; P = 0.0084), VEGF –1154AA and AG genotypes (HR, 1.482; 95% CI, 1.144–1.897; P = 0.0034), and VEGF –2578AA genotype (HR, 1.797; 95% CI, 1.219–2.495; P = 0.0047) had a significant prognostic effect on survival based on univariate analysis. Based on multivariate analysis of a current and former smoker (HR, 1.407; 95% CI, 1.095–1.840; P = 0.0070), poor PS (HR, 2.249; 95% CI, 1.309–3.468; P = 0.0058), and the VEGF –1154AA and AG genotypes (HR, 1.419; 95% CI, 1.033–1.901; P = 0.0316) were significant independent prognostic factors for survival. In this study, polymorphisms in VEGF may affect survival in advanced NSCLC. (Cancer Sci 2009; 100: 1917–1922)