Miyako Satouchi

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.

PURPOSE To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of <or=20%, 21-25%, 26-30%, and >or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

Phase III Study Comparing Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105

PURPOSE This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m(2) on days 1, 8)/carboplatin (AUC 5 on day 1); C, weekly paclitaxel (40 mg/m(2))/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m(2) on day 1)/carboplatin (AUC 5 on day 1). RESULTS The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. CONCLUSION Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

Randomized Phase III Trial of Platinum-Doublet Chemotherapy Followed by Gefitinib Compared With Continued Platinum-Doublet Chemotherapy in Japanese Patients With Advanced Non–Small-Cell Lung Cancer: Results of a West Japan Thoracic Oncology Group Trial (WJTOG0203)

PURPOSE Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). CONCLUSION This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial

BACKGROUND Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. METHODS J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). FINDINGS Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. INTERPRETATION These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. FUNDING Chugai Pharmaceutical Co, Ltd.

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study

BACKGROUND Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov, number NCT02094261. FINDINGS Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6-14·2). 140 (70%; 95% CI 64-77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven [3%]), prolonged electrocardiogram QT (five [2%]), decreased neutrophil count (four [2%]), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three [1%] each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. INTERPRETATION Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. FUNDING AstraZeneca.

An evaluation study of EGFR mutation tests utilized for non-small-cell lung cancer in the diagnostic setting

BACKGROUND Epidermal growth factor receptor (EGFR) mutation is predictive for the efficacy of EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC) treatment. We evaluated the performance, sensitivity, and concordance between five EGFR tests. MATERIALS AND METHODS DNA admixtures (n = 34; 1%-50% mutant plasmid DNA) and samples from NSCLC patients [116 formalin-fixed paraffin-embedded (FFPE) tissue, 29 matched bronchofiberscopic brushing (BB) cytology, and 20 additional pleural effusion (PE) cytology samples] were analyzed. EGFR mutation tests were PCR-Invader®, peptide nucleic acid-locked nucleic acid PCR clamp, direct sequencing, Cycleave™, and Scorpion Amplification Refractory Mutation System (ARMS)®. Analysis success, mutation status, and concordance rates were assessed. RESULTS All tests except direct sequencing detected four mutation types at ≥1% mutant DNA. Analysis success rates were 91.4%-100% (FFPE) and 100% (BB and PE cytology), respectively. Inter-assay concordance rates of successfully analyzed samples were 94.3%-100% (FFPE; kappa coefficients: 0.88-1.00), 93.1%-100% (BB cytology; 0.86-1.00), and 85.0%-100% (PE cytology; 0.70-1.00), and 93.1%-96.6% (0.86-0.93) between BB cytology and matched FFPE. CONCLUSIONS All EGFR assays carried out comparably in the analysis of FFPE and cytology samples. Cytology-derived DNA is a viable alternative to FFPE samples for analyzing EGFR mutations.BACKGROUND Epidermal growth factor receptor (EGFR) mutation is predictive for the efficacy of EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC) treatment. We evaluated the performance, sensitivity, and concordance between five EGFR tests. MATERIALS AND METHODS DNA admixtures (n = 34; 1%-50% mutant plasmid DNA) and samples from NSCLC patients [116 formalin-fixed paraffin-embedded (FFPE) tissue, 29 matched bronchofiberscopic brushing (BB) cytology, and 20 additional pleural effusion (PE) cytology samples] were analyzed. EGFR mutation tests were PCR-Invader, peptide nucleic acid-locked nucleic acid PCR clamp, direct sequencing, Cycleave, and Scorpion Amplification Refractory Mutation System (ARMS). Analysis success, mutation status, and concordance rates were assessed. RESULTS All tests except direct sequencing detected four mutation types at ≥1% mutant DNA. Analysis success rates were 91.4%-100% (FFPE) and 100% (BB and PE cytology), respectively. Inter-assay concordance rates of successfully analyzed samples were 94.3%-100% (FFPE; kappa coefficients: 0.88-1.00), 93.1%-100% (BB cytology; 0.86-1.00), and 85.0%-100% (PE cytology; 0.70-1.00), and 93.1%-96.6% (0.86-0.93) between BB cytology and matched FFPE. CONCLUSIONS All EGFR assays carried out comparably in the analysis of FFPE and cytology samples. Cytology-derived DNA is a viable alternative to FFPE samples for analyzing EGFR mutations.

Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin/paclitaxel/radiotherapy

PURPOSE To establish dosimetric predictors of radiation esophagitis (RE) in patients treated with a combination of carboplatin, paclitaxel, and radiotherapy. METHODS AND MATERIALS Three-dimensional radiotherapy plans of 26 patients with non-small-cell lung cancer who received 50-60 Gy of radiotherapy concurrently with weekly administration of carboplatin (AUC 2) and paclitaxel (40-45 mg/m(2)) were reviewed in conjunction with RE. The factors analyzed included the following: percentages of organ volumes receiving >40 Gy (V40), >45 Gy (V45), >50 Gy (V50), and >55 Gy (V55); the length of esophagus (total circumference) treated with >40 Gy (LETT40), >45 Gy (LETT45), >50 Gy (LETT50), and >55 Gy (LETT55); the maximum dose in the esophagus (Dmax); and the mean dose in the esophagus (Dmean). Data were obtained on the basis of superposition algorithm. RESULTS All factors except Dmax showed statistical correlation with RE. Good correlations were shown between RE and LETT45 (rho = 0.714) and V45 (rho = 0.686). CONCLUSIONS LETT45 and V45 appear to be useful dosimetric predictors of RE. It is also suggested that Dmax does not predict RE.

Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial

BACKGROUND RET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC. METHODS In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET-positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095. FINDINGS Between Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET-positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28-77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24-71]) achieved an objective response. At the data cutoff, median progression-free survival was 4·7 months (95% CI 2·8-8·5). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%]). INTERPRETATION Vandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy. FUNDING The Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED.

Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L

PURPOSE The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. PATIENTS AND METHODS Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). RESULTS Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). CONCLUSION The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.

Phase III Study Comparing Amrubicin Plus Cisplatin With Irinotecan Plus Cisplatin in the Treatment of Extensive-Disease Small-Cell Lung Cancer: JCOG 0509

PURPOSE This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). PATIENTS AND METHODS Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m(2) on days 1, 2, and 3 and cisplatin 60 mg/m(2) on day 1 every 3 weeks. RESULTS A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). CONCLUSION AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.