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Objectives: The main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented., Materials and Methods: The single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777)., Results: The updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1-34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %-49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2-not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4-26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22-0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile., Conclusion: This follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seiji Niho reports receiving grants from Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., GlaxoSmithKline K.K., Kyowa Kirin Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd.; consulting fees from AstraZeneca K.K., Pfizer Japan Inc., and Daiichi Sankyo Co., Ltd.; and honoraria from AstraZeneca K.K., Amgen K.K., Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., KYORIN Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Merck Biopharma Co., Ltd., MSD K.K., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd. Jun Sato reports receiving honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Eisai Co., Ltd.; and payment for expert testimony from Amgen K.K. Miyako Satouchi reports receiving grants from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., and AbbVie G.K.; and honoraria from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Chugai Pharmaceutical Co., Ltd., Amgen K.K., Pfizer Japan Inc., Bristol-Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Eisai Co., Ltd., Bayer Yakuhin, Ltd., and Merck Ltd. Shoichi Itoh reports receiving honoraria from Bristol-Myers Squibb K.K., AstraZeneca K.K., Amgen K.K., Chugai Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Yusuke Okuma reports receiving grants from AbbVie G.K., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K. and MSD K.K.; honoraria from AstraZeneca K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd.; fees for participation on the advisory board for AstraZeneca K.K.; and participating leadership or fiduciary role at Daiichi Sankyo Co., Ltd. Hidenori Mizugaki has no conflicts of interest to declare. Haruyasu Murakami reports receiving grants from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., AbbVie G.K., IQVIA Services Japan K.K., Taiho Pharmaceutical Co., Ltd., and Bayer Yakuhin, Ltd.; honoraria from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Amgen K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., MSD K.K., Pfizer Japan Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Nippon Kayaku Co., Ltd.; and fees for participation on the advisory board for Chugai Pharmaceutical Co., Ltd., GAIA BioMedicine Inc., Daiichi Sankyo Co., Ltd., and Amgen K.K. Yasuhito Fujisaka reports receiving honoraria from Eisai Co., Ltd. Toshiyuki Kozuki reports receiving grants from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Kirin Co., Ltd., Merck Biopharma Co., Ltd., Daiichi Sankyo Co., Ltd., Amgen K.K., AbbVie G.K., Sanofi K.K., Eisai Co., Ltd., Labcorp Drug Development Japan Co., Ltd., IQVIA Services Japan K.K., Gilead Sciences, Inc., and Pfizer Japan Inc.; consulting fees from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and AbbVie G.K.; and honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Kyowa Kirin Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Merck Biopharma Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Sawai Pharmaceutical Co., Ltd., and Amgen K.K. Kenichi Nakamura reports receiving honoraria from Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and AstraZeneca K.K. Ryunosuke Machida has no conflicts of interest to declare. Yuichiro Ohe reports receiving grants from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., KYORIN Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Loxo Oncology, Inc.; honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., MSD K.K., Taiho Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Kyowa Kirin Co., Ltd.; and payments for expert testimony from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., KYORIN Pharmaceutical Co., Ltd., Celltrion Healthcare Japan K.K., Amgen K.K., Nippon Kayaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and AnHeart Therapeutics Inc. Toshiyuki Tamai and Hiroki Ikezawa are employees of Eisai Co., Ltd. Noboru Yamamoto reports receiving grants from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Pfizer Japan Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., AbbVie G.K., Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., MSD K.K., Merck Ltd., GlaxoSmithKline K.K., Sumitomo Pharma Co., Ltd., Chiome Bioscience Inc., Otsuka Pharmaceutical Co., Ltd., Carna Biosciences, Inc., Genmab K.K., Shionogi & Co., Ltd., Toray Industries, Inc., Kaken Pharmaceutical Co., Ltd., AstraZeneca K.K., CMIC Co., Ltd., InventisBio Co., Ltd., and Rakuten Medical Inc.; consulting fees from Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., CMIC Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Ltd., and HEALIOS K.K.; and honoraria from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Eisai Co., Ltd., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy., Materials and Methods: Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints., Results: Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (<1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%., Conclusions: Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The LURET phase II study evaluated the efficacy and safety of the multikinase inhibitor vandetanib in patients with previously treatedRET-rearranged advanced non-small cell lung cancer (NSCLC). Among the eligible patients included in the primary analysis, the objective response rate met the primary endpoint (53 %, 90 % confidence interval [CI]: 31-74). Here, we report final survival outcomes of the LURET study., Materials and Methods: Nineteen patients with previously treated RET-rearranged advanced NSCLC continuously received 300 mg of oral vandetanib daily. This final analysis provides updated data on progression-free survival (PFS), overall survival (OS) and safety. This study was registered with UMIN-CTR (number UMIN 000010095)., Results: Among the 19 patients in the intention-to-treat population, 42 % had been heavily treated with 3 or more prior chemotherapy regimens. The median PFS was 6.5 months (95 % CI, 3.9-9.3) as determined by an independent radiology review committee. The median OS was 13.5 months (95 % CI, 9.8-28.1) and the overall survival rate at 12 months was 52.6 % (95 % CI 28.7-71.9). The most common adverse events were hypertension (84.2 %), diarrhea (78.9 %), and rash acneiform (63.2 %). Overall, 11 patients (57.9 %) had adverse events leading to a dose reduction, although the safety profile was consistent with that reported in previous studies., Conclusion: Our results indicated that vandetanib enabled a prolonged and clinically meaningful PFS and OS in patients with previously treatedRET-rearranged advanced NSCLC at the updated final analysis. The safety profile was consistent with that reported in previous studies, although most of the patients experienced off-target adverse events besides RET., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study., Materials and Methods: Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m 2 on day 1 and S-1 80 mg/m2 on days 1-14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m 2 + PEM 500 mg/m 2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients., Results: A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73-1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5-49.6)/32.1 % (95 %CI, 18.9-45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58-1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7-81.8)/66.4 % (95 %CI, 53.0-79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients)., Conclusion: The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities., Competing Interests: Declaration of Competing Interest S.N. reports grants and personal fees from AstraZeneca, Chugai, Taiho, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Shionogi, and Yakult, grants and personal fees from Pfizer, MSD, and Eli Lilly, grants from Merck Serono, outside the submitted work. T.Y. reports personal fees from Chugai, Boehringer Ingelheim, AstraZeneca, and Bristol‐Myers Squibb, outside the submitted work. K.S. reports personal fees from Chugai, Ono, Novartis, and Taiho, outside the submitted work. A.O. reports personal fees from Taiho, Ono, Chugai, Novartis, AstraZeneca, and MSD, outside the submitted work. T.S reports grants and personal fees from Astellas, AstraZeneca, Chugai, Eli Lilly, Kissei, MSD, Boehringer Ingelheim, Novartis, Pfizer, and Takeda, personal fees from Bristol-Myers Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche, Taiho, Thermo Fisher Scientific, and Yakult, grants from Bayer, Daiichi Sankyo, Eisai, LOXO Oncology, Merck Serono, outside the submitted work. M.N. reports grants and non-financial support from F. Hoffmann-La Roche, during the conduct of the study; grants and personal fees from Ono, Bristol-Myers Squibb, Pfizer, Chugai, Eli Lilly, Taiho, AstraZeneca, MSD, Novartis, personal fees from Boehringer-Ingelheim, Sankyo Healthcare, Taiho, Merck Serono, grants from Astellas, outside the submitted work. N.Y. reports grants and personal fee from Chugai, Eisai, Eli Lilly, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Ono, and Takeda, grants from Taiho, Quintiles, Astellas, Novartis, Daiichi-Sankyo, Kyowa-Hakko Kirin, Bayer, Janssen Pharma, MSD, and Merck, personal fees from AstraZeneca, Otsuka, Cimic, and Sysmex, outside the submitted work. T.H. reports grants and personal fees from Ono, Chugai, AstraZeneca, Boehringer Ingelheim, Novartis, Eli Lilly, Kissei, Taiho, Pfizer, Clovis Oncology, MSD, and Ignyta, grants from Merck Serono, Eisai, Takeda, Dainippon Sumitomo, Abbvie, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, Servier, Janssen, outside the submitted work. H.O. reports grants from Takeda, MSD, Ono, AstraZeneca, Merck, Chugai, Taiho, Bristol-Myers Squibb, Eli Lilly, Daiich Sankyo, outside the submitted work. T.K. reports grants and personal fee from AstraZeneca, MSD, and Chugai, personal fees from Eli Lilly, Ono, Bristol-Myers Squibb, and Boehringer Ingelheim, outside the submitted work. M.S. reports grants and personal fees from Chugai, Eli Lilly, Pfizer, AstraZeneca, Bristol-Myers Squibb, Ono, MSD, and Novartis, grants from Takeda, AbbVie, Ignyta, and Loxo Oncology, personal fees from Taiho, and Boehringer Ingelheim, outside the submitted work. K.G. reports grants and personal fees from Taiho, Chugai, Ono, AstraZeneca, Bristol-Myers Squibb, MSD, DAIICHI SANKYO, Pfizer, Novartis, Takeda, Eli Lilly, Merck Serono, Boehringer Ingelheim, RIKEN GENESIS, AbbVie, and Life Technologies, grants from Sumitomo Dainippon, Astellas, Eisai, Kyowa Hakko Kirin, Ignyta, Janssen, Loxo Oncology, Sysmex Corporation, and Oxonc, personal fees from F.Hoffmann-La Roche, SRL, and Nippon Kayaku, outside the submitted work. T.Y. reports grants and personal fees from Takeda, Chugai, Boehringer Ingelheim, Daiichi-Sankyo, and Bayer, grants from Ono, Merck Serono, Astellas, and Eli Lilly, personal fees from Taiho, Pfizer, Sysmex, Huya Biosciences, and Gilead Sciences, outside the submitted work. Y.O. reports grants and personal fees from Lilly, Bristol-Myers Squibb, Taiho, AstraZeneca, Chugai, ONO, Pfizer, MSD, Kyorin, Takeda, Novartis, AbbVie, grants from Amgen, Boehringer Ingelheim, LOXO, and Janssen, personal fees from Celltrion, outside the submitted work. T.A. declares no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018)., Methods: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018., Results: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib)., Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC)., Patients and Methods: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m 2 ) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL -1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation., Results: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m 2 , which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached., Conclusion: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m 2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial. However, various clinical trials have suggested that EGFR-TKI beyond PD plus single-agent chemotherapy may be a possible treatment strategy., Materials and Methods: This study was a single-arm phase II trial. Patients with EGFR-activating mutations (del19 and L858R) that progressed using first-line gefitinib treatment were enrolled and treated with gefitinib beyond PD plus pemetrexed 500 mg/m 2 q3w. The primary endpoint was progression-free survival (PFS). Mutation-biased polymerase chain reaction quenching probe, which is the original method for detecting T790M mutations in cell-free plasma DNA, was used prior to treatment., Results: Thirty-six patients were enrolled between May 1, 2013, and March 31, 2016. One patient was excluded before starting the treatment. Among the 35 patients, 15 patients had del19 mutations, and 20 patients had L858R mutations; 33 patients were evaluable for response by using radiographic findings. The median PFS was 6.7 months (95% confidence interval: 4.4-7.7 months). Nineteen patients were T790M positive. No significant difference in PFS was found in a subgroup analysis of EGFR mutation status and T790M positivity. All toxicities were tolerable., Conclusion: Gefitinib plus pemetrexed treatment following relapse using gefitinib in patients with Non-small cell lung cancer harboring EGFR mutations demonstrated preferable PFS with mild toxicity. This combination therapy may be considered for platinum-unfit patients without T790M with disease progression using first-line gefitinib. (This clinical trial was registered in UMIN-CTGR as UMIN000010709)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Detection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing. The cobas ® EGFR Mutation Test (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) is approved as a companion diagnostic for osimertinib, a third-generation EGFR-tyrosine kinase inhibitor approved in Japan. However, it is not clear whether the EGFR T790M mutation can be detected in cytology samples using this test. The primary objective of this study was to assess concordance of EGFR T790M gene mutation detection between histology and matched cytology samples using the cobas ® EGFR Mutation Test., Materials and Methods: We conducted a multicenter, observational study in Japan. Overall, 41 EGFRm NSCLC patients who had both histology and cytology samples collected at the same time at re-biopsy and with the results of EGFR mutation test using histology samples were enrolled. The EGFR mutation status of both sample types was tested using the cobas ® EGFR Mutation Test and the concordance rates were calculated., Results: The EGFR T790M mutation detection rate in histology and cytology samples was 42.5% and 37.5%, respectively. The overall percent agreement between the histology and cytology samples was 91.7%., Conclusions: These data demonstrate that the cobas ® EGFR Mutation Test can detect the EGFR T790M mutation in both cytology and histology samples., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Unresectable stage III NSCLC (non-small cell lung cancer) confers a poor prognosis and interest is growing in the use of immunotherapy to improve outcomes for patients with this disease. We investigated the safety and efficacy of maintenance tecemotide, a mucin 1 (MUC1)-specific agent that induces T-cell responses to MUC1, versus placebo in Japanese patients with stage III unresectable NSCLC and no disease progression after primary chemoradiotherapy., Materials and Methods: Patients aged ≥20 years with unresectable stage III NSCLC, stable disease or clinical response after primary chemoradiotherapy and performance status ≤1, were recruited across 25 centers in Japan. Patients were randomized 2:1 to tecemotide (930μg as lipopeptide) or placebo subcutaneously once weekly for 8 weeks, then every 6 weeks until disease progression or treatment withdrawal. Cyclophosphamide 300mg/m 2 (maximum dose 600mg) was given intravenously 3days before the first dose of tecemotide. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival, time to progression, time to treatment failure and safety., Results: The intent-to-treat population comprised 172 patients; 114 received tecemotide and 58 placebo. Baseline characteristics were comparable between treatment arms. Most patients (94%) received primary concurrent chemoradiotherapy. There was no apparent trend toward increased OS time with tecemotide over placebo (median 32.4 versus 32.2 months, hazard ratio 0.95, 95% confidence interval 0.61-1.48; P=0.83). No improvements in secondary efficacy endpoints were observed. The frequency of treatment-related adverse events was similar, and serious adverse event rates were the same in both arms. There were no new safety signals., Conclusions: These results do not support those from a randomized phase III study (START) of improved OS with tecemotide in the subgroup of patients treated with primary concurrent chemoradiotherapy., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Drug-induced interstitial lung disease (ILD) is often associated with high mortality; however it is difficult to predict and manage. we examined the clinical findings and imaging characteristics of nivolumab induced ILD reported in the two phase II studies patients with recurrent or advanced non-small-cell lung cancer., Materials and Methods: We examined the clinical findings and imaging characteristics of all cases of ILD reported in two phase II trials of nivolumab, an anti-programmed death-1 antibody, in Japanese patients with recurrent or advanced non-small-cell lung cancer. These studies are registered with the Japan Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073., Results: Eight (7.2%; two with squamous cell carcinoma, six with non-squamous cell carcinoma) of the 111 patients included in these two studies experienced ILD, and a causal relationship with nivolumab could not be ruled out in any of them. ILD of ≥grade 3 severity was found in four patients (3.6%), and ILD was considered a serious treatment-related adverse event in seven patients (6.3%). All of the patients who experienced ILD were male and had a history of smoking, with a median age of 65 years (range 52-78 years). In seven of the eight patients who experienced ILD, their events were rapidly resolving or resolved spontaneously or with steroid therapy; one patient died of respiratory failure without resolution of ILD, after docetaxel treatment was initiated following nivolumab discontinuation. Chest computed tomography images for the seven patients with resolving or resolution of ILD showed a pattern of organizing pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis, while the patient who died had traction bronchiectasis., Conclusion: Although the risk factors for nivolumab-induced ILD were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Disease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy., Patients and Methods: This was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed., Results: Overall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax., Conclusions: Success rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs., (Copyright © 2016 AstraZeneca K.K. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objectives: TAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer., Methods: This was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35mg/m(2)/dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled., Results: Eighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9-1.8) versus 2.7 months (range 1.0-6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68-8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients., Conclusion: TAS-102 showed no evidence of activity in second-line small cell lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This randomized phase II trial investigated the efficacy and safety of docetaxel plus bevacizumab and S-1 plus bevacizumab in the second-line treatment of non-squamous (non-Sq) non-small-cell lung cancer (NSCLC)., Materials and Methods: Patients with non-Sq NSCLC who experienced disease progression after prior platinum-based chemotherapy with or without bevacizumab were randomly assigned to receive docetaxel plus bevacizumab (DB) once every 3 weeks or S-1 orally twice daily on days 1-14 plus bevacizumab (SB) on day 1 every 3 weeks until disease progression., Results: Ninety patients were randomized. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]=3.0-6.5) in DB and 3.5 months (95% CI=2.9-5.9) in SB. The objective response rate was significantly higher in DB than in SB (22.2% vs. 2.2%; P=0.004), whereas the disease control rates of the arms were identical (62.2% vs. 62.2%; P=1.00). Patients receiving DB were more likely to have ≥grade 3 neutropenia (93.4% vs. 4.4%) and febrile neutropenia (33.3% vs. 0%) than SB. In DB, PFS and overall survival (OS) were significantly longer among bevacizumab-naïve patients than among bevacizumab-experienced patients (median PFS: 7.2 vs. 2.9 months; P=0.004; and median OS: 21.3 vs. 14.1 months; P=0.012)., Conclusion: DB and SB produced modest PFS benefits in the second-line treatment of patients with advanced non-Sq NSCLC. Because of the toxicity of DB and the low response rate of SB, neither regimen warrants further investigation, excluding DB in bevacizumab-naïve patients with advanced non-Sq NSCLC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We have conducted a phase 2 study to evaluate the efficacy and safety of carboplatin, paclitaxel, and bevacizumab in patients with non-squamous non-small-cell lung cancer (NSCLC) who are epidermal growth factor receptor (EGFR) mutation positive and for whom EGFR-tyrosine kinase inhibitor (TKI) 1st-line has failed., Materials and Methods: Patients with stage IIIB or IV non-squamous NSCLC harbored activating EGFR mutations that has failed 1st-line EGFR-TKI and an Eastern Cooperative Oncology Group performance status of 0 or 1 were included in this study. Patients received carboplatin at an area under the concentration-time curve 5 or 6, paclitaxel 200mg/m(2), and bevacizumab 15mg/kg on D1. The combination therapy was repeated every 21 days for up to three to six cycles. Bevacizumab was continued until disease progression or unacceptable toxicity for patients without disease progression (PD). The primary endpoint was objective response rate (ORR)., Results: Thirty-one patients were enrolled between March 2010 and January 2013, with 30 patients being eligible. ORR was 37% (90% CI; 24-52%) and disease control rate, 83% (95% CI; 66-92%). The median progression free survival (PFS) was 6.6 months (95% CI; 4.8-12.0 months) and median overall survival, 18.2 months (95% CI; 12.0-23.4 months). The most common grade ≥3 hematologic toxicity was neutropenia (93%), and non-hematologic toxicity, febrile neutropenia (20%). There were no clinically relevant grade ≥3 bleeding events and no treatment-related deaths., Conclusion: The combination therapy of carboplatin, paclitaxel and bevacizumab did not achieve the initial treatment goal., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC)., Patients and Methods: Patients with chemotherapy-refractory SCLC received 40 mg/m(2) AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety., Results: Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1-22 cycles). ORR was 32.9% [P<0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9-44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0-4.3 months) and 8.9 months (95% CI, 7.6-11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P=0.034), PFS (median, 2.9 v 5.1 months; P=0.0009), and OS (median, 7.9 v 13.1 months; P=0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred., Conclusions: AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: In a large multicenter international phase III study (CA031) of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C, conducted in 6 countries including Japan, nab-PC produced significantly higher overall response rate (ORR), primary end point compared with sb-PC, and acceptable safety profile. The aim of this analysis was to evaluate the efficacy and tolerability of nab-PC vs sb-PC in Japanese patients with advanced non-small-cell lung cancer (NSCLC) who were enrolled in the CA031 study., Patients and Methods: In the CA031 study, a total of 1052 patients were randomized to receive either nab-P 100 mg/m(2) weekly or sb-P 200 mg/m(2) every 3 weeks both in combination with C at area under the concentration-time curve (AUC) = 6 on day 1 of each 3-week cycle. This analysis included 149 Japanese patients with previously untreated stage IIIB or IV NSCLC., Results: The baseline and histologic characteristics of patients were well balanced between the two arms. ORR was higher with nab-PC vs sb-PC (35% vs 27%; response rate ratio = 1.318). Progression-free survival (median 6.9 vs 5.6 months; hazard ratio [HR] = 0.845) and overall survival (median 16.7 vs 15.9 months; HR = 0.930) were better with nab-PC vs sb-PC. Of the grade ≥3 treatment-related adverse events, anemia and thrombocytopenia were more common in nab-PC arm, but sensory neuropathy was less common., Conclusion: The nab-PC treatment yielded promising results regarding the efficacy endpoint, and it was generally well tolerated as first-line therapy for Japanese patients with advanced NSCLC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)