Tomohiro Suzumura

Reaction of plasma hepatocyte growth factor levels in non-small cell lung cancer patients treated with EGFR-TKIs

Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non‐small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post‐treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty‐one patients were enrolled. Plasma hepatocyte growth factor levels on post‐treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post‐treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut‐off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.

Plasma RANTES, IL-10, and IL-8 levels in non–small-cell lung cancer patients treated with EGFR-TKIs

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), routinely used to treat advanced non-small-cell lung cancer (NSCLC) patients with activated EGFR mutations, are associated with excellent response and improved performance status. Recently, pro-inflammatory cytokines, such as regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-10 and IL-8 have been proposed as mediators of cancer development. EGFR-TKIs have been found to affect this network of pro-inflammatory cytokines.MethodsEGFR-TKIs (erlotinib, 150 mg/day; and gefitinib, 250 mg/day) were administered once per day. Treatment was continued until disease progressed or the patient developed intolerable symptoms of toxicity, or withdrew his/her consent for study participation. The treatment was a part of standard care. We investigated the correlation between plasma pro-inflammatory cytokines (including plasma RANTES, IL-10, and IL-8) levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs.ResultsOverall, 33 patients were enrolled. Plasma pro-inflammatory cytokine levels were determined for all patients at diagnosis. Plasma samples from 26 patients were obtained on treatment day 30. High level of RANTES at diagnosis was associated with severe general fatigue (P = .026). Low level of RANTES at diagnosis was significantly associated with long-term survival (P = .0032). Percent decrease change of IL-10 was associated with severity of rash (P = .037). The plasma IL-8 level on treatment day 30 (median, 5.48 pg/mL; range, 0.49–26.13 pg/mL) was significantly lower than the level at diagnosis (median 10.45 pg/mL; 3.04–54.86 pg/mL; P = .021).ConclusionsThese results suggest that EGFR-TKIs may suppress systemic inflammation and promote tumor shrinkage. The network of pro-inflammatory cytokines was affected by EGFR-TKI treatment for NSCLC. In addition, the clinical outcomes of EGFR-TKI treatment were influenced by the status of the plasma pro-inflammatory cytokines at diagnosis.

Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer

BackgroundRash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies.MethodsThe frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types.ResultsA total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21–0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17–1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52–2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54–6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21–7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20–5.07; *p = 0.93).ConclusionsThe frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.

Magnesium supplementation and high volume hydration reduce the renal toxicity caused by cisplatin-based chemotherapy in patients with lung cancer: a toxicity study.

BackgroundRenal toxicity is a clinical problem that affects 28 − 42% of patients undergoing treatment with cisplatin. Renal toxicity can be minimized by high volume hydration with mannitol diuresis. Recent reports have shown that cisplatin induces depletion of Mg and that Mg supplementation can reduce renal toxicity. We hypothesized that Mg infusion combined with low volume hydration may not be sufficient to overcome cisplatin-induced renal toxicity.MethodsIn total, 85 patients with lung cancer receiving their first cycle of cisplatin-based chemotherapy at the Osaka City University Hospital were classified into three groups: those administered high volume hydration without Mg infusion (high-volume Mg-), high volume hydration with Mg infusion (high-volume Mg+), and with low volume hydration with Mg infusion (low-volume Mg+). Serum creatinine (sCr) and creatinine clearance (CrCl) were examined before and after treatment with cisplatin. Multivariable analysis was carried out to identify the most important contributing factors.ResultsThere were no significant differences in pre-treatment sCr levels or CrCl between groups. In the high-volume Mg- group, post-treatment sCr significantly increased compared with pre-treatment levels, while post-CrCl significantly decreased compared with pre-treatment CrCl (p < 0.001 and p < 0.001, respectively). In the high-volume Mg+ group, there was no significant difference between pre- and post-treatment levels of sCr, or between pre- and post-treatment CrCl (p = 0.118 and p = 0.254, respectively). In the low-volume Mg+ group, there was a trend towards increased sCr levels and decreased CrCl after treatment (p = 0.068 and p = 0.055, respectively). Multivariate analysis revealed that the absence of Mg infusion and low-volume hydration were both independent factors for decreased CrCl (p < 0.001 and p = 0.001, respectively).ConclusionsHigh-volume hydration and Mg infusion reduces the renal toxicity induced by cisplatin. A low-volume Mg+ regimen may be considered for patients with adequate renal function. Trial Registration: Observational Study UMIN000013950; Registered 13 May 2014

C609T Polymorphism of NADPH Quinone Oxidoreductase 1 Correlates Clinical Hematological Toxicities in Lung Cancer Patients Treated with Amrubicin.

Background Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that NQO1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes. Methods Patients received AMR doses of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the NQO1 C609T polymorphism was assayed by RT-PCR. Results A total of 35 patients were enrolled. At a dose of 40 mg/m2, the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities (P < 0.05). Conclusions NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.

Interstitial Lung Disease Induced by Osimertinib for Epidermal Growth Factor Receptor (EGFR) T790M-positive Non-small Cell Lung Cancer

A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration. We diagnosed the patient to have interstitial lung disease induced by osimertinib.

Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR.

ABSTRACT Introduction: While epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC. Areas covered: This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article. Expert opinion: Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.

Abstract 2613: Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors

Background: T790M mutation in EGFR accounts for nearly 50% of the acquired mechanism of resistance to EGFR-tyrosine kinase inhibitors (TKIs). Previous studies suggested that EGFR T790M mutation was also detected in a considerable number of EGFR-TKI-naive non-small-cell lung cancer (NSCLC) patients utilizing ultrasensitive detection methods such as droplet digital PCR (ddPCR). Here we investigated the significance of low-frequency pretreatment EGFR T790M mutation (preT790M) and its association with cancer molecular heterogeneity in the efficacy of EGFR-TKIs. Materials and methods: Fifty-two advanced NSCLC patients harboring activating EGFR mutations treated with first-line EGFR-TKIs at Osaka City University Hospital between August 2013 and July 2016 were enrolled in the study. DNAs from tumor biopsies at diagnosis were available from 44 patients for detecting preT790M by the cobas® EGFR Mutation Test v2 (cobas) and ddPCR (RainDance Technologies) and those from 33 were available for assessing the actionable mutations in 50 genes by next-generation sequencing (NGS). NGS was performed on the Ion PGM using Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies). Paired biopsies before EGFR-TKIs treatment and at disease progression (PD) were obtained from 15 patients to assess the T790M mutation by cobas. Results: The overall detection rate of preT790M by ddPCR was 40.9% (18/44), while not detected in any case by cobas. The median progression free survival (mPFS) was 10.0 months for the patients with preT790M and 13.5 months for those without preT790M (p=0.288), respectively. When divided into 3 categories based on the frequency of preT790M such as high with T790M allele frequency (AF) >0.3%, low with AF ≤0.3% and undetected, 12 patients with high AF had a relatively shorter mPFS than 6 with low AF (p=0.090) and 26 without detectable preT790M (p=0.046) (7.7 vs 17.1 vs 13.5 months, respectively). NGS revealed 18 additional coexisting actionable mutations in 15 out of 33 patients: TP53 (n=7), PIK3CA (n=5), CTNNB1 (n=3) and uncommon EGFR (n=3). There was a trend for patients with higher preT790M AF to harbor less additional coexisting mutations (27% with high AF, 60% with low AF and 53% without preT790M, p=0.320). In 15 paired biopsies, T790M mutation was detected in 60% (9/15) at PD by cobas in the clinical setting; 67% (2/3) with high AF, 50% (1/2) with low AF and 60% (6/10) without detectable preT790M, suggesting T790M mutation after first-line EGFR-TKIs developed from both clonal selection and secondary acquisition models. Conclusion: Results of our study indicated that EGFR-mutated NSCLCs with higher AF preT790M >0.3% had significantly shorter duration of response to EGFR-TKIs. In addition, the AF of preT790M in EGFR-mutated NSCLC may be associated with coexisting actionable mutation load potentially affecting the efficacy of EGFR-TKIs. Citation Format: Yoshiya Matsumoto, Kenji Sawa, Jun Oyanagi, Mitsuru Fukui, Naoki Yoshimoto, Tomohiro Suzumura, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Tomoya Kawaguchi, Kazuto Hirata, Yasuhiro Koh. Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2613.

Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage Iii Non–small Cell Lung Cancer: The Final Report

Objectives: A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non–small cell lung cancer was conducted. Materials and Methods: We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non–small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week. Results: Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively. Conclusions: Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.

Comparison of adverse events of erlotinib with those of gefitinib in Japanese patients with NSCLC.

7566 Background: Liver dysfunction, diarrhea, skin disorder, and interstitial pneumonia are known as adverse events of EGFR-TKI. However, clinical trials of gefitinib reported difference profiles in adverse events compared to those of erlotinib. The hypothesis is that there may be some differences in adverse event of gefitinib and erlotinib. Methods: We retrospectively analyzed mainly adverse events, patient backgrounds, treatment efficacy and treatment periods for patients treated erlotinib or gefitinib for 30 or more days. Results: Forty-six patients were received erlotinib therapy and 41 patients were received gefitinib therapy in 2007 to 2009 in our hospital. There were no significant differences in patient backgrounds except for EGFR mutations. Erlotinib was administered in more patients without mutations than gefitinib (p = 0.003). Skin disorders had significant differences of erlotinib and gefitinib with 96% and 73% in all grades, respectively (p < 0.001). Skin disorders in grade 2/3 of erlotinib a...