Katsuyuki Hotta

Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE It remains undetermined whether cisplatin and carboplatin are equally effective for advanced non-small-cell lung cancer (NSCLC). We therefore did a meta-analysis of trials that compared cisplatin-based chemotherapy with carboplatin-based chemotherapy. METHODS We performed a literature search to identify trials that had investigated the substitution of carboplatin for cisplatin in the treatment of advanced NSCLC. We evaluated these trials for inclusion, rated methodologic quality, and abstracted relevant data. RESULTS Of 1,191 reports, eight trials (2,948 patients) were identified, five of which investigated drug regimens containing platinum plus a new agent. Cisplatin-based chemotherapy produced a higher response rate, but the survival advantage was not significant (hazard ratio = 1.050; 95% CI, 0.907 to 1.216; P =.515). Subgroup analysis revealed that combination chemotherapy consisting of cisplatin plus a new agent yields 11% longer survival than carboplatin plus the same new agent (hazard ratio = 1.106; 95% CI, 1.005 to 1.218; P =.039). Patients on cisplatin-based chemotherapy frequently developed nausea and vomiting; thrombocytopenia was more frequent during carboplatin-based chemotherapy. No significant difference in treatment-related mortality was observed. CONCLUSION We found that combination chemotherapy consisting of cisplatin plus a new agent yields a substantial survival advantage compared with carboplatin plus a new agent in patients with advanced NSCLC, although we failed to find any survival difference in an analysis that included both new and old agents. The strength of our conclusion is limited because we used abstracted data, and careful interpretation is thus required. Nevertheless, our results raise a critical point that needs to be evaluated in future studies.

Role of Adjuvant Chemotherapy in Patients With Resected Non–Small-Cell Lung Cancer: Reappraisal With a Meta-Analysis of Randomized Controlled Trials

PURPOSE The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials. METHODS We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy. RESULTS Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild. CONCLUSION This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.

Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007

PURPOSE To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

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.

The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer.

We investigated the relationships between genetic factors and clinical outcome in Japanese non‐small‐cell lung cancer (NSCLC) patients treated with gefitinib. Ninety‐eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18–21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA‐SSR1) and single nucleotide polymorphisms in the promoter region (−216G/T and −191C/A), using a PCR‐based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug‐sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression‐free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA‐SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug‐sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug‐sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib‐treated Japanese patients with NSCLC. Our findings also suggest that the CA‐SSR1 length may influence the clinical outcome in patients with a drug‐sensitive EGFR mutation.

Twenty-Seven Years of Phase III Trials for Patients with Extensive Disease Small-Cell Lung Cancer: Disappointing Results

Background Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. Methods and Findings We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. Results: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine–based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome. Conclusions and Significance The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.

A Phase II Trial of Erlotinib Monotherapy in Pretreated Patients with Advanced Non-small Cell Lung Cancer Who Do Not Possess Active EGFR Mutations: Okayama Lung Cancer Study Group Trial 0705

Backgrounds: Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR)-mutation status in Asian patients with non-small cell lung cancer. Recently, the survival advantage of erlotinib, another tyrosine kinase inhibitor, was not affected by EGFR mutation status in a phase III trial, indicating that patients with EGFR-wild-type (EGFR-wt) tumors might also benefit from this tyrosine kinase inhibitor. The aim of this trial was to evaluate the efficacy and toxicity of erlotinib in Japanese patients with EGFR-wt tumors. Methods: The primary end point was an objective response. Patients with EGFR-wt tumors previously receiving one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Erlotinib was administered (150 mg/d) until disease progression or unacceptable toxicities occurred. Results: Thirty patients were enrolled between January and December 2008. Objective response was observed in one patient (3.3%), and the disease became stable in 18 patients (60.0%). Skin rash was the most common side effect. Grades 3–4 adverse events included pulmonary embolism, keratitis, and anemia. Two other patients developed interstitial lung disease (grades 1 and 2). Nevertheless, all these events were reversible, resulting in no treatment-related deaths. With a median follow-up time of 10.7 months, the median survival time and median progression-free survival times were 9.2 and 2.1 months, respectively. Conclusion: This is the first prospective biomarker study showing that erlotinib therapy for pretreated patients with EGFR-wt tumors seems to have a modest activity with no irreversible toxicity.

Clinical Significance of Epidermal Growth Factor Receptor Gene Mutations on Treatment Outcome after First-line Cytotoxic Chemotherapy in Japanese Patients with Non-small Cell Lung Cancer

Introduction: The relationship between the EGFR gene mutation status and clinical outcome has not fully been assessed in patients with non-small cell lung cancer (NSCLC) who received cytotoxic agents. The aim of this study was to clarify its association. We also examined whether this association could be affected by previous gefitinib treatment. Methods: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy in their treatment course were included in this study. An EGFR mutation was determined in exons 19 and 21 by direct sequencing. Results: Of 194 Japanese patients with advanced or relapsed NSCLC assessable for mutation analysis, 60 received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment courses. EGFR mutations significantly affected progression-free survival (PFS) in the first-line cytotoxic chemotherapy regimens in the multivariate analysis (hazard ratio for PFS = 0.422; p = 0.0422). In contrast, in 28 (47%) of the 60 patients who also received cytotoxic chemotherapy after the relapse to gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status, and its sensitivity was retained even in the second-line treatment setting in patients with EGFR mutations. Conclusions: EGFR mutations were therefore significantly associated with a better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, whereas gefitinib sensitivity was associated with an EGFR mutation even in the second-line or later treatment settings.

Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials.

Background: The association between the objective response to chemotherapy and survival has not yet been fully evaluated using large cohorts in advanced non-small cell lung cancer. Methods: We searched for phase III trials conducted between 1991 and 2006 to investigate the role of systemic chemotherapy for advanced non-small cell lung cancer. Associations were tested by multiple regression analysis. Results: Of the 1255 trials screened, 143 met our criteria, involving 50,569 patients with 309 chemotherapy regimens. In the first-line setting, the median intention-to-treat objective response rate (ORR) and disease control rate (DCR) were 26.4% and 62.5%, respectively (43,551 randomized patients; 290 trials). The median of the median survival time (MST) was 8.5 months in the first-line setting, and both the ORR and DCR were significantly associated with the MST in the multivariate analysis (regression coefficient = 0.0788 [p < 0.0001] and 0.0794 [p < 0.0001], respectively). Subgroup analysis showed no correlation between the ORR and MST in patients receiving chemotherapy containing molecular-targeted agents (p = 0.3817). In the second-line or later setting, the median ORR was only 6.8%, whereas the median DCR was 42.4% (4318 randomized patients; 19 trials). The median MST (6.6 months) was not associated with the ORR (p = 0.6992), but was associated with the DCR (p = 0.0129), despite the small sample size. Conclusions: We found that survival was associated with both the ORR and DCR in the first-line setting, although it should be interpreted cautiously because of the abstracted data–based analysis. Regarding chemotherapy regimens containing molecular-targeted agents and salvage chemotherapy regimens, further assessments are warranted to clarify the association between the parameters.

Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib : An analysis of risk factors and treatment outcomes in okayama lung cancer study group

ABSTRACTRisk factors for the development of interstitial lung disease in patients with non-small cell lung cancer receiving gefitinib and the prognostic factors after interstitial lung disease development have not been established. The aim of this study was to retrospectively identify and evaluate these possible factors. PATIENTS AND METHODSWe reviewed the clinical records and radiographs of 365 consecutive patients with non-small cell lung cancer who received gefitinib in West Japan between 2000 and 2003. RESULTSIn total, 330 patients were eligible for interstitial lung disease evaluation, and 15 patients (4.5%) were finally confirmed to have developed interstitial lung disease by blinded expert review. Multivariate analysis revealed that preexisting pulmonary fibrosis, poor performance status, and prior thoracic irradiation were independent risk factors for interstitial lung disease, with odds ratios of 21.0 (95% confidence interval, 5.12–86.3, P < 0.0001), 9.70 (2.27–41.4, P= 0.001), and 4.33 (1.27–14.8, P= 0.019), respectively. Among the 15 patients who developed interstitial lung disease, eight have died of the condition. Short interval from the initiation of gefitinib treatment to the onset of interstitial lung disease, acute interstitial pneumonia pattern, and the presence of pre-existing pulmonary fibrosis were associated with poor prognosis. DISCUSSIONOur results suggest the importance of patient selection for gefitinib treatment based on interstitial lung disease risk factors in the Japanese population identified.