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Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited., Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group., Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001)., Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown., Competing Interests: Conflict of interest statement K.I. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme (MSD), Ono Pharmaceutical and Taiho Pharmaceutical. T.Y. reported receiving grants from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Bayer, Astellas and Eli Lilly and receiving personal fees from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Bayer, Merck Serono, Pfizer, Huya Bioscience, Gilead Sciences and EP-CRSU. H.H. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Shanghai Haihe Biopharm and Taiho Pharmaceutical. Y.H. reported receiving grants from Janssen Pharmaceutical, MSD and Ono Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical and Taiho Pharmaceutical. K.N. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Ono Pharmaceutical and Roche Diagnostics. H.K. reported receiving personal fees from Eli Lilly and Taiho Pharmaceutical. Y.O. reported no relevant conflicts of interests. T.Y. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Chugai Pharmaceutical, Novartis, Pfizer and MSD. T.S. reported receiving grants from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, LOXO Oncology and Merck Serono and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, Astellas, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific and Precision Medicine Asia Co. Ltd. K.A. reported receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb and Ono Pharmaceutical. T.F. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.K. reported receiving grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb and Merck Biopharma and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku and Novartis. A.N. reported receiving personal fees from MSD, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim and Kyowa Kirin. K.T. reported receiving grants from Boehringer Ingelheim, Chugai Pharmaceutical and Ono Pharmaceutical and receiving personal fees from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, AbbVie, Pfizer, SRL, MSD, Novartis and Kyowa Kirin. K.H. reported receiving personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.Y. reported receiving grants from Ono Pharmaceutical and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD and Boehringer Ingelheim. H.D. reported receiving grants from Chugai Pharmaceutical, Pfizer and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Boehringer Ingelheim. S.S. reported no relevant conflicts of interests. D.F. reported receiving grants from AstraZeneca and Chugai Pharmaceutical and receiving personal fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Eli Lilly and Novartis. M.M. reported receiving personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Shionogi, Taiho Pharmaceutical and Novartis. K.M. reported receiving grants from Boehringer Ingelheim and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Novartis. T.A. reported no relevant conflicts of interests. A.T. reported no relevant conflicts of interests. S.M. reported receiving personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, Bristol Myers Squibb and Kyowa Hakko Kirin. S.W. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol Meyers Squibb, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical. H.A. reported receiving grants from Chugai Pharmaceutical and receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. O.H. reported receiving grants from GlaxoSmithKline, AstraZeneca, Novartis, Kyorin, Bayer Yakuhin, Boehringer Ingelheim and Daiichi Sankyo and receiving personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Bayer Yakuhin and Boehringer Ingelheim. K.S. reported no relevant conflict of interests. S.H. reported no relevant conflict of interests. K.A. reported no relevant conflict of interests. A.B. reported receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. A.K. reported receiving grants from the Japan Society for the Promotion of Science, Boehringer Ingelheim, Chugai Pharmaceutical, Lilly and Ono Pharmaceutical and receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical and Pfizer. M.O. reported no relevant conflict of interests. K.N. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical; receiving personal fees from AstraZeneca, Nichi-Iko Pharmaceutical, Astellas, Takeda Pharmaceutical, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb company, Boehringer Ingelheim, Eli Lilly, Novartis, SymBio Pharmaceuticals Limited, Pfizer, Chugai Pharmaceutical, Clinical Trials Co., NANZANDO Co., MEDICUS SHUPPAN, Publishers Co., YODOSHA CO., Care Net, Nikkei Business Publications, Reno. Medical, Daiichi Sankyo, KYORIN Pharmaceutical, Thermo Fisher Scientific, Medical Review Co., YOMIURI TELECASTING CORPORATION, Roche Diagnostics, Nippon Kayaku Co., Bayer Yakuhin, Merck Biopharma Co., Medical Mobile Communications Co., AbbVie and 3H Clinical Trial Inc. and receiving consulting and advisor fees from Takeda Pharmaceutical, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer and Eli Lilly. N.Y. reported receiving grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas, MSD, Pfizer, Takeda, AstraZeneca, Terumo and Toppan and receiving personal fees from Chugai Pharmaceutical, Eli Lilly, MSD, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer and Boehringer Ingelheim., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Although aprepitant is effective in preventing CINV, an increment in financial burden for uniform use of aprepitant is a concern. The aim of the present study was to define the cost-effectiveness of aprepitant from the perspective of the Japanese National Health Insurance system. Based on the results of a randomized phase II trial comparing an aprepitant-containing regimen versus a nonaprepitant regimen in Japanese patients who received cisplatin-containing highly emetogenic chemotherapy, a decision analytic model was developed. The incremental cost-effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). The use of the aprepitant-containing regimen was associated with improved quality of life compared with the nonaprepitant regimen, with an increment in quality-adjusted life years (QALY) of 0.0016. The incremental total medical costs associated with the use of the aprepitant regimen were lower in the OCS than in the ICS, 6192 JPY (56.92 USD) and 9820 JPY (90.27 USD), respectively. The ICER was calculated as 3 906 698 JPY (35 910 USD) per QALY gained in the OCS and 6 195 781 JPY (56 952 USD) per QALY gained in the ICS. Cost-effectiveness of the aprepitant-containing antiemetic therapy was limited to the OCS, considering the threshold of willingness-to-pay commonly accepted (5 million JPY [45 960 USD] in Japan and 50 000 USD in the USA). The efficacy of aprepitant offsets the costs for revisiting clinics or rehospitalization added with rescue medications in the OCS., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 47-year-old man was referred to our department due to multiple metastases in the lungs and liver with pleural dissemination six weeks after undergoing curative surgery for lung pleomorphic carcinoma. He received two regimens of chemotherapy, both of which resulted in disease progression. Considering his good general condition, he was treated with cisplatin plus gemcitabine (GP). The metastatic lesions exhibited a complete response after six courses of GP, and the patient has remained free from recurrence for over six years. An immunohistochemical analysis revealed that the tumor was highly expressive of gemcitabine transporter human equilibrative nucleoside transporter 1, thus suggesting a high sensitivity to gemcitabine.

Purpose: To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11)., Methods: Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed., Results: Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate., Conclusions: This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Introduction: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied., Methods: We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe., Results: We identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55-3.45, p < 0.001), CV (OR = 2.99-4.43, p < 0.001), and CP (OR = 4.79-6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10-3.27, p < 0.001), CV (OR = 1.99-2.43, p < 0.001), and CP (OR = 1.34-1.52, p < 0.001-0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66-2.04, p < 0.001-1.000), CV (OR = 0.42-0.57, p = 0.097-0.323), or CP (OR = 1.21-1.39, p = 0.114-0.152)., Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.

Introduction: The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer., Methods: In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II., Results: The recommended dose of docetaxel was 40 mg/m in combination with S-1 80 mg/m/d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis., Conclusions: This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC., Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m2) on day 1 and with oral S-1 (80 mg/m2) on days 1 to 14 every 3 weeks., Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment., Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.