Takahisa Kawamura

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

Although third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) can overcome T790M‐mediated resistance in non‐small‐cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR‐TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)‐guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR‐TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.

Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy

Background Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI. Results Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years–8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years–NR) in the non-PCI group (p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404). Conclusions Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy. Patients and Methods We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan–Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics.

Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non–small-cell Lung Cancer

Micro‐Abstract A higher T790M detection rate is desirable for introducing third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitor treatment. This study evaluated the clinical factors influencing the incidence of T790M. Postsurgery recurrence and longer total duration of epidermal growth factor receptor‐tyrosine kinase inhibitor treatment before rebiopsy correlated with high incidence of T790M mutation. Therefore, rebiopsy after disease progression is aggressively encouraged in patients with these factors. Background: T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR‐tyrosine kinase inhibitors (TKIs). To facilitate the use of third‐generation EGFR‐TKIs to potentially overcome T790M‐mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation. Patients and Methods: We retrospectively screened patients with non–small‐cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016. Factors influencing T790M status were evaluated by univariate and multivariate analysis. Results: Among 131 rebiopsied patients for whom EGFR mutation status was available, 58 (44%) had T790M mutations. Patient characteristics at rebiopsy were not significantly different between T790M‐positive and ‐negative groups, except for surgical history (postsurgery recurrence). Total duration of EGFR‐TKI treatment before rebiopsy, TKI‐free interval, EGFR‐TKI treatment history immediately before rebiopsy, continuation of initial EGFR‐TKI beyond progressive disease, progression‐free survival after initial TKI treatment, and rebiopsy site (other than fluid samples) significantly influenced T790M status. The incidence of T790M mutation was shown by multivariate analysis to be significantly higher in patients with postsurgery recurrence and total duration of EGFR‐TKI treatment ≥ 1 year before rebiopsy (odds ratio, 4.2; 95% confidence interval, 1.3‐15.7 and odds ratio, 4.4; 95% confidence interval, 1.1‐19.8, respectively). Conclusion: Postsurgery recurrence and longer total duration of EGFR‐TKI treatment before rebiopsy may represent useful predictive markers for T790M detection. In patients with these clinical factors, rebiopsies are more recommended to detect T790M mutation.

PD-L1 expression in patients with unresectable stage III non-small cell lung cancer receiving chemoradiotherapy.

e20530Background: Approximately 30% of patients with stage IV non-small cell lung cancer (NSCLC) are reported to have with high tumor PD-L1 expression (tumor proportion score: TPS ≥ 50%). PD-L1 sta...

Crizotinib-induced simultaneous multiple cardiac toxicities

SummaryCrizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data

Postmarketing surveillance is useful to collect safety data in real‐world clinical settings. In this study, we applied postmarketing real‐world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin‐treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony‐stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h−1, neutrophil elimination rate constant = 0.0295 h−1, and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model‐based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

Prophylactic cranial irradiation (PCI) in limited-disease small-cell lung cancer (LD-SCLC) patients with brain imaging.

e20010Background: PCI is recommended for patients with LD-SCLC who have a good response to initial therapy. But this recommendation has been made based on studies in which brain imaging was not a s...

The incidence and risk factors of febrile neutropenia in chemotherapy-naïve lung cancer patients receiving etoposide plus platinum

PurposeThis study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer.MethodsThe study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated.ResultsEighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia.ConclusionsThese results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

Dabrafenib in patients with BRAF -mutated non-small cell lung cancer

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung cancer (NSCLC) accounts for more than 85% of all cases of lung cancer. Molecular targeted drugs, which specifically inhibit a particular molecular target, have been developed actively and have contributed to improved outcomes of advanced NSCLC patients. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (e.g., gefitinib, erlotinib, icotinib, afatinib, olmutinib and osimertinib) and anaplastic lymphoma kinase (ALK) TKIs (e.g., crizotinib, ceritinib and alectinib) have been reported to demonstrate dramatic efficacy in patients with EGFR mutation-positive and ALK -rearranged advanced NSCLC, respectively. However, other targeted treatment options for patients with advanced NSCLC have so far been limited.