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Modelo do estudo: Retrospectivo. Objetivos do estudo: Avaliar o efeito do treinamento físico aeróbico nas variáveis cardiovasculares em pacientes coronariopatas participantes do Programa de Reabilitação Cardiovascular. Metodologia: Foram incluídos pacientes portadores de coronariopatia estável e foram avaliadas as variáveis cardiovasculares de testes ergométricos seriados, realizados antes e após um período mínimo de 12 semanas de treinamento físico aeróbico em um Programa de Reabilitação Cardiovascular, de fevereiro de 2002 a julho de 2005. Resultados: Documentou-se incremento significativo (p < 0,0001) do consumo de oxigênio pico (VO2 pico) após a reabilitação cardiovascular (30,1 ± 9,5 versus 35,5 ± 8,8 ml/kg/min). Este delta do VO2 pico apresentou correlação negativa com a capacidade física inicial, com maiores ganhos nos pacientes com menores valores iniciais de VO2 pico. Não foram observadas diferenças significativas na pressão arterial sistólica e no duplo produto pico, e uma diferença de pequena magnitude foi observada na freqüência cardíaca pico. A melhora no limiar isquêmico do miocárdio, avaliada pelo consumo de oxigênio na positivação, foi ainda mais expressiva, com incremento de 7,4 ml/kg/min (p < 0,0001) (21,0 ± 6,9 versus 28,4 ± 8,2 ml/kg/min). Conclusões: A reabilitação cardiovascular melhorou a capacidade física e o limiar isquêmico de pacientes participantes do Programa de Reabilitação Cardiovascular. O benefício na capacidade física foi maior nos pacientes com menores valores iniciais de consumo de oxigênio pico.

Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy., Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated., Results: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41-79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6-6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5-4.2)., Conclusions: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation., (©2024 The Authors; Published by the American Association for Cancer Research.)

Local failure of non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) often occurs within 2 years and delayed local failure is uncommon. In the present study, features of late local failure (LLF; >2 years after SBRT) after SBRT were investigated and compared with those of early local failure (ELF; ≤2 years after SBRT) to explore whether these two local recurrence features have different prognostic implications. Patients who underwent SBRT for stage I-IIA NSCLC between July 2006 and March 2014 were retrospectively reviewed. Overall, 173 patients underwent SBRT for NSCLC. The median follow-up times after SBRT were 50 and 31 months for survival and computed tomography (CT) follow-up, respectively. LLF and ELF occurred in 7 and 13 patients, respectively. The median times to LLF and ELF were 42 months (range, 31-61 months) and 13 months (range, 4-16 months), respectively. Local-only failure occurred in 14% (1/7) of LLF cases and 77% (10/13) of ELF cases, which was significantly different (Fisher's exact test, P=0.02). Curative-intent salvage treatment was impossible in all of the LLF cases and 69% (9/13) of the ELF cases, which was significantly different (Fisher's exact test, P<0.01). The median survival times after local failure were 9 and 25 months for patients with LLF and ELF, respectively. Additionally, the 1-year overall survival rates after local failure were 29 and 83% in the LLF and ELF groups, respectively, which was significantly different (log-rank test, P<0.01 at 1-year). In summary, the prognosis after LLF was significantly unfavorable compared with after ELF. Curative-intent salvage treatment is often difficult for LLF due to metastases. Therefore, it seems reasonable to decrease the frequency of follow-up CT for detecting tumor recurrence after the first 2 years post-SBRT., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Makita et al.)

Background: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor., Methods: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing., Findings: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group., Interpretation: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival., Funding: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests YoS has received grants from Chugai Pharmaceutical; and personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, and Kyowa Kirin, all outside of the submitted work. ShN has received grants from AstraZeneca, Chugai Pharmaceutical, and MSD; consulting fees from Asahi Kasei Pharma; and personal fees from AstraZeneca, Bayer, Chugai Pharmaceutical, Asahi Kasei Pharma, Kyowa Hakko Bio, and MSD, all outside of the submitted work. SS has received grants from AnHeart Therapeutics, AstraZeneca, Chugai Pharmaceutical, MSD, Daiichi Sankyo, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Ono Pharmaceutical, AbbVie, Amgen, Taiho Pharmaceutical, Takeda, Accerise, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex, and Eisai, all outside of the submitted work. HidehH has received research fundings from MSD, AbbVie, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Janssen, Chugai Pharmaceutical, and Roche; personal fees from AstraZeneca, MSD, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Roche, Amgen, and Abbvie; and personal fees from AstraZeneca, Chugai Pharmaceutical, Roche, Ono Pharmaceutical, Bristol Myers Squibb, and AbbVie (served on the advisory board), all outside of the submitted work. YaY has received personal fees from Taiho Pharmaceutical and Takeda, all outside of the submitted work. HidetH has received grants from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi, Nippon Kayaku, Otsuka Pharmaceutical, Takeda, GSK, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, Ascent Development Services, Labcorp Development Japan, Eisai, Kobayashi Pharmaceutical, Bayer, and Pfizer Japan; royalties or licenses from Sysmex; personal fees from Ono Pharmaceutical, Merck, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex, Pfizer Japan, Takeda, Nippon Boehringer Ingelheim; and personal fees for serving on an advisory board from Daiichi Sankyo, Nippon Boehringer Ingelheim, AstraZeneca, Amgen, Chugai Pharmaceutical, Novocure, Eli Lilly Japan, Gilead Science, and Blueprint Medicine, all outside of the submitted work. KA has received lecture fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, Bristol Myers Squibb, and Takeda, all outside of the submitted work. SN has received grants from GSK, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Teijin, Kyowa Kirin, Shionogi, Boehringer Ingelheim, Daiichi Sankyo, Kyorin, and Nippon Kayaku; personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, MSD, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, and Kyowa Kirin; and personal fees for serving on advisory boards from AstraZeneca and Daiichi Sankyo, all outside of the submitted work. RM has received personal fees from Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, MSD, Amgen, and Merck; and personal fees for serving on an advisory board from Daiichi Sankyo, all outside of the submitted work. MY has received grants from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Taiho Pharmaceutical, and Takeda; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, all outside of the submitted work. TY has received grants from MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim Japan, Takeda, Delta-Fly Pharma, Janssen, AbbVie, Daiichi Sankyo, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Nippon Kayaku, MSD, Novartis, and Merck, all outside of the submitted work. KY has received grants from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Pfizer, Taiho Pharmaceutical, and Takeda; and personal fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono Pharmaceutical, Otsuka, Taiho Pharmaceutical, and Takeda, all outside of the submitted work. TakayK has received grants from AstraZeneca, Amgen, MSD, Janssen, Takeda, and Daiichi Sankyo; and personal fees from AstraZeneca, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, Pfizer, and Nippon Kayaku, all outside of the submitted work. HO has received grants from Bristol Myers Squibb, MSD, and Taiho Pharmaceutical, all outside of the submitted work. TakasK has received personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol Myers Squibb, all outside of the submitted work. KK has received personal fees from AstraZeneca, MSD, Chugai Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical; payment for expert testimony from Eli Lilly Japan; and personal fees for serving on advisory boards from Eli Lilly Japan and AstraZeneca, all outside of the submitted work. YF has received personal fees from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; payment for expert testimony from Chiome Bioscience, Otsuka Pharmaceutical, and Ono Pharmaceutical; and personal fees for serving on advisory boards from AstraZeneca, Daiichi Sankyo, Micron, and Ono Pharmaceutical, all outside of the submitted work. SM has received grants from AstraZeneca, Takeda, Chugai Pharmaceutical, Sanofi, MSD, Daiichi Sankyo, Ono Pharmaceutical, and Janssen; and personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda, Eli Lilly, MSD, Pfizer, Novartis, and Taiho Pharmaceutical, all outside of the submitted work. SK has received personal fees from Boehringer Ingelheim Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, MSD, Ono Pharmaceutical, and Guardant Health Japan, all outside of the submitted work. HA reports grants from Amgen and Chugai Pharmaceutical; personal fees from Amgen, AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; personal fees for serving on advisory boards from Amgen, MSD, Janssen, and Sandoz; and a role on the WCLC Patient Advocacy Committee, all outside of the submitted work. HK has received grants from Eli Lilly; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Novartis, Eli Lilly Japan, Ono Pharmaceutical, and Takeda, all outside of the submitted work. ToshiK has received grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Labcorp Development Japan, IQVIA Services Japan, Gilead Sciences, Pfizer, and Bayer; consulting fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer Japan, Daiichi Sankyo, Bayer, and AbbVie; and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda, Bayer, Sawai, Amgen, and Eisai, all outside of the submitted work. HF has received grants from the National Cancer Center Research and Development Fund; and lecture fees from Kyowa Kirin, Chugai Pharmaceutical, and CMIC, all outside of the submitted work. YO reports grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, LOXO, Kirin, Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Kissei, Daiichi Sankyo, and Janssen; personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; personal fees for serving on an advisory board from Haihe Biopharma; and roles in the Japanese Society of Medical Oncology, Japan Lung Cancer Society, and Japan Clinical Oncology Group, all outside of the submitted work. IO has received grants from the National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development during the conduct of the study; grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, and Pfizer, all outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial., Methods: A total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening., Results: On the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22-2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26-1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial., Conclusions: Molecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices., Competing Interests: Disclosure Dr. Umemura reports receiving grants from Taiho Pharmaceutical and honoraria from Merck Sharp & Dohme and Chugai Pharmaceutical. Dr. Udagawa reports receiving grants from Takeda and Boehringer Ingelheim. Dr. Murakami reports receiving grants from Chugai Pharma, AstraZeneca, Takeda, Daiichi Sankyo, AbbVie, IQVIA, Taiho Pharmaceutical, and Bayer; receiving honoraria from Pfizer, Chugai Pharma, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Merck Sharp & Dohme, Novartis, Lilly Japan, Taiho Pharmaceutical, Eisai, and Nihonkayaku; and having participation on a data safety monitoring board or advisory board for Chugai Pharma, GAIA BioMedicine, Daiichi Sankyo, and Amgen. Dr. Daga reports receiving honoraria from AstraZeneca and Chugai Pharmaceutical. Dr. Toyozawa reports receiving grants from Pfizer, AbbVie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly Japan, Novartis Pharma, and Takeda Pharmaceutical and honoraria from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. Dr. Kozuki reports receiving grants from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., Merck Sharp & Dohme, Kyowa Hakko Kirin, Merck Biopharma, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, LabCorp Development Japan, IQVIA Services Japan, Gilead Sciences, and Bayer; consulting fees from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Ono Pharmaceutical Co., Daiichi Sankyo, Bayer, and AbbVie; and honoraria from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., Merck Sharp & Dohme, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck Biopharma, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda Pharmaceutical Co., Bayer, Sawai, and Amgen. Dr. Sakakibara-Konishi reports receiving grants from Lilly. Dr. Ohe reports receiving grants from Pfizer, AstraZeneca, Chugai, Lilly, ONO, Bristol-Myers Squibb, Kyorin, Dainippon-Sumitomo, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen, and Loxo; receiving payment for expert testimony from AstraZeneca, Chugai, ONO, Bristol-Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, and AnHeart Therapeutics Inc., and having leadership roles with JSMO, JLCS, and JCOG. Dr. Morise reports receiving grants from Boehringer Ingelheim and Eli Lilly; honoraria from Pfizer, Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme, Ono Pharmaceutical, and Taiho Pharmaceutical; and other financial or nonfinancial interests from Pfizer, Chugai, AstraZeneca, Ono, Merck Serono, Kissei, Taiho, and Novartis. Dr. Kato reports receiving grants from Pfizer, AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai, Daiichi Sankyo, Eli Lilly, Haihe, Merck KGaA, Merck Sharp & Dohme, Novartis, Regeneron, Takeda, and TurningPoint; receiving honoraria from Pfizer, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono, Taiho, and Takeda; having participation on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck KGaA, Merck Sharp & Dohme, and Novartis; and receiving other financial or nonfinancial interests for Eli Lilly. Dr. Furuya reports receiving honoraria from Pfizer, Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Chugai, Bristol-Myers Squibb, Taiho, and Novartis. Dr. Nakachi reports receiving honoraria from AstraZeneca, Chugai Pharmaceutical, and Novartis Pharma. Dr. Nomura reports receiving grants from AstraZeneca and Amgen and honoraria from AstraZeneca, Chugai, Kyowa Hakko, JMDC, Byer, and Asahi-Kasei Pharma. Dr. Sato reports receiving grants from Taiho Pharmaceutical, Boehringer Ingelheim, Bayer, Chugai Pharma, Eisai, Ono Pharmaceutical, Takeda, Aspyrian Therapeutics, Pentax Medical Devices, and Daiichi Sankyo/UCB Japan. Dr. Ishii reports receiving grants from Daiichi Sankyo, Inc., Ono Pharmaceutical Co., Ltd., Noile-Immune Biotech, Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co., Ltd., Nihon Medi-Physics Co., Ltd., Indivumed GmbH, and H.U. Group Research Institute; consulting fees from Takeda Pharmaceutical Company Limited; and honoraria from Roche Diagnostics K.K., Chugai Pharmaceutical Co., Ltd., Novartis International AG, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AstraZeneca, Riken Genesis Co., Ltd., and Merck Biopharma Japan. Dr. Kirita reports receiving consulting fees from Eli Lilly and honoraria from Pfizer, Merck Sharp & Dohme Oncology, Boehringer Ingelheim, Novartis, Takeda Pharmaceuticals, Boston Scientific, Chugai Pharma, ONO Pharma, Merk BioPharma, Thermo Fisher Scientific, AstraZeneca, Taiho Pharmaceuticals, Amgen, and Bristol-Myers Squibb. Dr. Sakai reports receiving grants from Amgen and Daiichi Sankyo and honoraria from AstraZeneca, Chugai, Novartis, Merck Sharp & Dohme, Thermo Fisher Scientific, and Merck. Dr. Shibata reports receiving grants from Merck Sharp & Dohme and Blueprint Medicines Corporation and honoraria from Pfizer, Chugai, Bristol-Myers Squibb, Takeda, AstraZeneca, Merck, Ono Pharmaceutical Co., Ltd., and Eli Lilly Japan. Dr. Izumi reports receiving grants from AbbVie, AstraZeneca, Amgen, Takeda, Eisai, and Ono Pharmaceutical; receiving honoraria from Takeda, Merck, Ono Pharmaceutical, Merck Sharp & Dohme, Chugai, and Bristol-Myers Squibb Japan; and having participation on a data safety monitoring board or advisory board for Amgen. Dr. Nosaki reports receiving grants from AbbVie, AnHeart Therapeutics, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Merck Sharp & Dohme, and Takeda; receiving honoraria from Pfizer, AstraZeneca, Chugai Pharma, Lilly, Merck Sharp & Dohme, Taiho Pharmaceutical, Yansen Pharma, Ono, Takeda, Novartis, and Merck; and having participation on a data safety monitoring board or advisory board for Daiichi Sankyo/UCB/Japan and AbbVie. Dr. Zenke reports receiving grants from AstraZeneca, Merck Sharp & Dohme, Daiichi Sankyo, Amgen, GlaxoSmithKline, Roche, and Merck and honoraria from Pfizer, AstraZeneca, Lilly, Chugai, Ono, Bristol-Myers Squibb, Takeda, Boehringer Ingelheim, Taiho, Merck Sharp & Dohme, Novartis, Nihon Kayaku, Kyowa Kirin, and Amgen. Dr. Matsumoto reports receiving grants from Chugai Pharma, Janssen Pharmaceutical, and Merck Sharp & Dohme and honoraria from Eli Lilly, Merck Biopharma, Chugai Pharma, Novartis Pharma, Guardant Health, and AstraZeneca. Dr. Yoh reports receiving grants from Pfizer, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Taiho, and Takeda; receiving honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono, Otsuka, Taiho, and Takeda; and having participation on a data safety monitoring board or advisory board for Boehringer Ingelheim. Dr. Niho reports receiving grants from Chugai, Eli Lilly, Daiichi Sankyo, Boehringer Ingelheim, GlaxoSmithKline, Kyowa Kirin, Kyorin, Taiho, Nippon Kayaku, and Teijin; receiving consulting fees from Pfizer, AstraZeneca, and Daiichi Sankyo; and receiving honoraria from Pfizer, AstraZeneca, Amgen, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyorin, Kyowa Kirin, Merck Biopharma, Merck Sharp & Dohme, Nippon Kayaku, Novartis, Ono, and Takeda. Dr. Goto reports receiving grants from Pfizer, Amgen Inc., Amgen K.K., Amgen Astellas BioPharma K.K., AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Blueprint Medicines Corporation, Craif Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., LSI Medience Corporation, Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., Merck Sharp & Dohme K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Precision Medicine Asia Co., Ltd., Riken Genesis Co., Ltd., Sumitomo Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics, Inc., and Xcoo, Inc.; receiving honoraria from Amgen Inc., Amgen K.K., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Blueprint Medicines Corporation, Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Haihe Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Medpace Japan K.K., Merck Biopharma Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Riken Genesis Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Xcoo, Inc.; and having participation on a data safety monitoring board or advisory board for Amgen Inc., Amgen K.K., Daiichi Sankyo Co., Ltd., and Eli Lilly Japan K.K. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations., Methods: Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined., Results: We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores ( p < 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) ( p < 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO., Conclusions: Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MH received research grants and/or speaker fee from Abbvie, Asahi Kasei, Astellas, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Taisho Toyama, Tanabe Mitsubishi. K.U. received a research and/or speaker fee from Sumitomo Pharma, outside the submitted work. A.O. received a research and/or speaker fee from Daiichi-Sankyo, AbbVie G.K., Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan, GSK, Mitsubishi Tanabe, Asahi Kasei Pharma and Pfizer Inc. R.W. received a research grant from AbbVie and speaker’s fee from Asahi Kasei, Chugai, Eli Lilly, and GSK. K.K. received a research and/or speaker fee from GSK K. K. R.N received a research and/or speaker fee from Takeda and Medical & Biological Laboratories Co. Ltd, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Actelion Pharmaceuticals, and Mitsubishi Tanabe Pharma, outside the submitted work. H.Y. has received a research grant from GSK and honoraria from Chugai, unrelated to this work. R.U. received personal fees from Eisai, Sawai Pharmaceutical, Statcom, SAS Institute Japan, and EPS Corporation, outside the submitted work. M.T. received a research and/or speaker fee from AbbVie G.K., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Eisai Co., Ltd, Eli Lilly Japan K. K., Pfizer Inc., UCB Japan Co. Ltd, Janssen Pharmaceutical K. K., Mitsubishi Tanabe Pharma Corp., Novartis Pharma K. K., Taisho Pharma Co. Ltd. K.O. received research grants and/or speaker’s fees from AbbVie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi, and Takeda while the present study was being performed. A.M. received research grants and/or speaker’s fees from Eli Lilly Japan K.K., Ono Pharmaceutical Co., Pfizer Inc., UCB Japan, AbbVie G.K., Asahi Kasei Pharma., and Chugai Pharmaceutical Co. Ltd. M.T. and M.H. and A. O are in the endowed chair and are funded by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Mitsubishi Tanabe Pharma Corp., Chugai Pharmaceutical Co. Ltd, Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp., and UCB Japan Co. Ltd). H.D., Y.T., R.I., T.K., T.Y., T.I., M.T., M.T., Y.T., M.S., H.O., H.T., S.A., K.M., W.Y., and T.I. declared no conflicts of interest. The sponsors were not involved in the study design; the collection, analysis, and interpretation of data; writing this manuscript; or the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payment or other benefits from any commercial entity related to the subject of this article.

Background: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX., Methods: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled., Discussion: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL., Ethics and Dissemination: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences., Trial Registration: Japan Registry of Clinical Trials (registration number jRCTs061210047)., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings., Methods: We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018., Results: Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone., Conclusions: Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC., (© 2024 Astrazeneca and The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: There is no established standard 3 rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1 st or 2 nd line treatment are administrated as 3 rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3 rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies., Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3 rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years., Discussion: Currently, there is no standard 3 rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication., Trial Registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1858/coif). T.M. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd. and Kyowa Kirin Co., Ltd. outside the submitted work. T.S. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Amgen Inc., Daiichi-Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co., Inc. and Illumina, Inc. outside the submitted work. Y.T. reports honoraria from Daiichi Sankyo Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., TAIHO PHARMACEUTICAL Co., Ltd. and Bristol-Myers Squibb K.K. outside the submitted work, in addition to grants from Pfizer Health Research Foundation outside the submitted work. E.I. reports grants from Janssen Pharmaceutical K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd., outside the submitted work and honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Novartis Pharma K.K. and Boehringer-Ingelheim Japan Inc., outside the submitted work and research material from AstraZeneca K.K. and Janssen Pharmaceutical K.K. outside the submitted work. T.K. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Novartis Pharma K.K., Taiho Pharmaceutical Co., Ltd., MSD K.K., Kyowa Kirin Co., Ltd., Boehringer-Ingelheim Japan Inc., Nippon Kayaku Co., Ltd., Daiichi-Sankyo Co., Ltd., Amgen Inc., Eisai Co. Ltd., Merck Biopharma Co., Ltd., Bayer Holding Ltd., Sawai Pharmaceutical Co., Ltd. outside the submitted work and grants from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., MSD K.K., Kyowa Kirin Co., Ltd., Daiichi-Sankyo Co., Ltd., Amgen Inc., Eisai Co. Ltd., Merck Biopharma Co., Ltd., Bayer Holding Ltd., Pfizer Japan Inc., AbbVie GK., LabCorp Japan, G.K., IQVIA Inc., Gilead Sciences, Inc. outside the submitted work, and consulting fee from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Daiichi-Sankyo Co., Ltd., Bayer Holding Ltd., AbbVie GK. outside the submitted work. S.H. reports honoraria from Bristol-Myers Squibb Co. Ltd. outside submitted work. Y.O. reports consulting fee from Kitasato University Hospital and Association of Medical Education and Ethics outside submitted work, and honoraria for lectures of biostatistics from Tokai University, Graduate School of Medicine outside submitted work and is Data Monitoring Committee member of EVA-001-02 study sponsored by Evastem Co., Ltd., and Certified Committee member for Regenerative Medicine, Tokai University outside the submitted work. T.M. declares research grants from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and KOWA DENTAL HEALTH K.K. and Renascience Inc. outside the submitted work, and honoraria from Renascience Inc. outside the submitted work, and stocks of Renascience Inc. N.H. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb Co. Ltd. outside the submitted work. N.H. reports that this study is supported by Renascience Inc. (to Hiroshima University Hospital). The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background and Purpose: Spread-through air space (STAS) is an unfavorable factor in patients with lung cancer treated with surgery. However, the relationship between the treatment outcomes of stereotactic body radiation therapy (SBRT) for lung cancer and STAS has not been adequately investigated. This study aimed to evaluate the impact of tumor cells in the air space (TCIAS), which show a STAS burden, on treatment outcomes in patients with early-stage lung cancer treated with SBRT., Materials and Methods: Data of patients who underwent SBRT for early-stage lung cancer treated with SBRT were retrospectively reviewed. The influence of the TCIAS status on local progression-free (LPF), regional failure-free (RFF), distant failure-free (DFF), progression-free survival (PFS), and overall survival (OS) rates was assessed using univariate and multivariate analyses., Results: Overall, 68 patients were included. The median follow-up time was 24.3 months. For patients positive/negative for TCIAS, the 2-year LPF, RFF, DFF, PFS, and OS rates were 81.4 %/91.1 %, 73.7 %/96.2 %, 55.9 %/75.3 %, 55.0 %/84.6 %, and 67.8 %/92.2 %, respectively. In the multivariate analysis, TCIAS-positive was a significant unfavorable factor for RFF (hazard ratio [HR]: 4.10; 95 % confidence interval [CI]: 1.04-16.16, p = 0.04), DFF (HR: 2.61, 95 % CI: 1.03-6.57, p = 0.04), and PFS (HR: 2.36; 95 % CI: 1.05-5.30, p = 0.04). By contrast, TCIAS-positive was not a significant risk factor for LPF and OS., Conclusion: TCIAS-positive is an unfavorable factor for regional and distant failure after SBRT. TCIAS status may be useful in predicting the treatment outcome of SBRT for early-stage lung cancer., Competing Interests: Toshiyuki Kozuki received honorarium from MSD, Ono, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim, Chugai, TAIHO, Eli Lilly, Bristol Myers Squibb, Pfizer, Merck Biopharma, Nippon Kayaku, Novartis, Bayer, Sawai and AMGEN, consulting fee from Chugai, AstraZeneca, Ono, Pfizer, Daiichi-Sankyo, Bayer, and Abbvie, and received research funding MSD, Kyowa Hakko Kirin, AstraZeneca, Eli Lilly, Pfizer, Chugai, TAIHO, Ono, Bristol-Myers, Merck Biopharma, Daiichi-Sankyo, AbbVie, AMGEN, Sanofi, Eisai, Labcorp Development, IQVIA Services, Gilead Sciences, Pfizer, and Bayer. All other authors declare that they have no conflict of interest., (© 2024 The Author(s).)

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.)

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this., Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC., Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020., Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population., Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group., Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Purpose: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD)., Methods: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD., Results: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively., Conclusion: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD., (© 2024. The Author(s).)

Purpose: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort., Experimental Design: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers., Results: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed., Conclusions: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy., Significance: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential., Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system., Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021., Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels., Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point., Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03)., Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

Background: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC., Patients and Methods: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee., Conclusions: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bronchoscopy is a common diagnostic procedure used to identify lung cancer. Specimens acquired through transbronchial biopsy are pivotal in the diagnosis and molecular characterization of this disease. The occurrence of benign mesothelial cells during a transbronchial biopsy (TBB) is relatively rare. Furthermore, these lesions can sometimes be erroneously identified as malignant, potentially resulting in unwarranted or inappropriate treatment for patients with and without lung cancer. In this retrospective analysis, we examined 619 TBB cases at our institute from 2019 to 2021. Benign mesothelial cells were identified via immunohistochemical studies in eight (1.3%) of 619 cases. These cells were classified into three patterns based on their cellular morphology: monolayer, lace, and cobblestone. Recognizing this phenomenon during the procedure is crucial to accurately distinguish benign mesothelial cells from their cancerous counterparts., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Purpose: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC)., Methods: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR- mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data., Results: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations., Conclusion: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR- mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Objectives: Although the SLE Disease Activity Score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs., Methods: We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the lupus patient-reported outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA) and physician global assessment (PhGA)., Results: Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike information criterion, and Bayesian information criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission and categories of disease activity (remission, mild and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC and PhGA, but not SF-36 or PtGA., Conclusion: No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

High-level MET amplification (METamp) is a primary driver in ∼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992)., Competing Interests: Declaration of interests X.L. reported personal/consulting fees from EMD Serono during the conduct of the study; personal or consulting fees from AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Janssen, Blueprint Medicines, Bayer, and Albion; grants from ArriVent, Eli Lilly, Boehringer Ingelheim, and Regeneron; and personal fees from AbbVie outside the submitted work. L.G.P.-A. reported consulting roles with AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, and Daiichi Sankyo/Eli Lilly; research funding from Lilly and Boehringer Ingelheim; leadership roles from Genomica and ALTUM Sequencing; speakers bureau from Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Roche, Pfizer, Lilly, AstraZeneca, and the healthcare business of Merck KGaA, Darmstadt, Germany; travel/accommodations/expenses from Roche, AstraZeneca, Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Pfizer, and Takeda; and honoraria from Roche, Lilly, Pfizer, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, AstraZeneca, the healthcare business of Merck KGaA, Darmstadt, Germany, PharmaMar, Novartis, Celgene, Amgen, Sanofi, Ipsen, Servier, Bayer, Blueprint Medicines, Mirati Therapeutics, and Takeda outside the submitted work. J.V.M. reported an advisory role with Amgen outside the submitted work. S.V. reported consulting or advisory role from the healthcare business of Merck KGaA, Darmstadt, Germany, AbbVie, Bristol-Myers Squibb, AstraZeneca, Merck & Co., Kenilworth, NJ, and Roche; non-financial support from OSE Immunotherapeutics; and personal fees from Janssen and Puma Biotechnology outside the submitted work. C.C.G. reported a consulting/advisory role with Boehringer Ingelheim and travel/accommodations/expenses from Roche and Merck & Co., Kenilworth, NJ, outside the submitted work. E.F.S. reported an advisory/consultancy role (institution) with Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo, and Seattle Genetics; and research funding (institution) from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, and Bristol-Myers Squibb outside the submitted work. M.G. reported personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; grants and personal fees from AstraZeneca; and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, Bayer, Bristol-Myers Squibb, AbbVie, Takeda, Janssen, Roche, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, and Blueprint outside the submitted work. R.V. reported research funding from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; personal consulting fees from Janssen; personal speaker fees from Bristol-Myers Squibb and Takeda; personal speaker bureau fees from Amgen, Sanofi, Roche, and AstraZeneca; and travel fees from Pfizer Travel and Janssen outside the submitted work. D.V.B. reported advisory/consultancy honoraria from Roche, the healthcare business of Merck KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, and Takeda; and speaker honoraria from Roche, the healthcare business of Merck, KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, and Boehringer Ingelheim outside the submitted work. J.F.P. reported consulting/advisory roles with Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and GlaxoSmithKline outside the submitted work. M.S. reported an advisory/consulting role with Roche, AstraZeneca, Bristol-Myers Squibb, and Merck & Co., Kenilworth, NJ, outside the submitted work. T.K. reported grants and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and Kyowa Hakko Kirin; personal fees from Ono Pharmaceutical, Pfizer Japan, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, and Daiichi-Sankyo; and grants from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. Y.-C.K. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. S.S.Y. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. J.-Y.H. reported research funding from Hoffmann-La Roche, Ltd., Ono Pharmaceutical, Pfizer, and Takeda outside the submitted work. J.-H.K. reported honoraria from Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, and Bristol-Myers Squibb; consulting roles with Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, AstraZeneca, and Yuhan; speakers bureau for Pfizer, Merck & Co., Kenilworth, NJ, and Roche; and research funding from Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, and Yuhan outside the submitted work. Y.J.C. reported consulting/advisory role with Astella, Yuhan, Merck & Co., Kenilworth, NJ, Roche, and Chong Kun Dang outside the submitted work. C.S. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. D.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. H.V. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. R.B. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. G.O. was an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, at the time of the study and holds stock in Novartis. A.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. P.K.P. reported an advisory/consulting role from Takeda, Xencor, Janssen, CrownBio, Bicara, Mirati, and EMD Serono; and research funding (institution) from Bicara, Boehringer Ingelheim, and EMD Serono outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study investigated the differences between digital [18F]-Fluorodeoxyglucose (FDG) positron emission tomography [PET]/computed tomography [CT] (dPET/CT) and conventional PET/CT (cPET/CT) in delineating the clinical target volume (CTV) in patients with advanced lung cancer in the involved field radiation therapy (IFRT) era. Patients with advanced lung cancer were scanned using two dual-imaging protocols (dPET/CT and cPET/CT). Two virtual delineations contoured with reference to dPET/CT and cPET/CT images were created for each patient by five radiation oncologists. Changes in the delineation of target volumes in each patient were examined. A total of 10 patients [male/female, 9/1; median age, 65 years (range, 58-80 years)] were enrolled between April 2020 and September 2020. Significant changes in the delineation of CTVs were uncommon between dPET/CT and cPET/CT. A notable increase in CTVn was observed in 10% of the patients (1/10; P<0.05; Smirnov-Grubbs analysis). In this patient, a node that was not assessed as lymph node metastasis when cPET/CT was used was assessed as lymph node metastasis when dPET/CT was used and was included in the CTVn by all five radiation oncologists. In patients with advanced lung cancer, notable changes in CTV delineations are uncommon, regardless of whether dPET/CT or cPET/CT is used. However, in some cases, CTVn delineation with reference to dPET/CT may improve the treatment outcomes of IFRT for advanced lung cancer., Competing Interests: TKo received an honorarium from MSD, Ono, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim, Chugai, TAIHO, Eli Lilly, Bristol Myers Squibb, Pfizer, Merck Biopharma, Nippon Kayaku, Novartis, Bayer, Sawai, and AMGEN; consulting fee from Chugai, AstraZeneca, Ono, Pfizer, Daiichi-Sankyo, Bayer, and Abbvie; and received research funding from MSD, Kyowa Hakko Kirin, AstraZeneca, Eli Lilly, Pfizer, Chugai, TAIHO, Ono, Bristol-Myers, Merck Biopharma, Daiichi-Sankyo, AbbVie, AMGEN, Sanofi, Eisai, LabCorp Development, IQVIA Services, Gilead Sciences, Pfizer, and Bayer. All other authors declare that they have no competing interests., (Copyright: © Makita et al.)

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown., Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS)., Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months ( p  = 0.24); 15.7 months, 11.6 months, and 10.1 months ( p  = 0.06); and 31.0%, 13.6%, and 37.5% ( p  = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS ( p < 0.05) and OS ( p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths., Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy., (© 2023 The Authors.)

Background: Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment., Patients and Methods: Untreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group., Results: Between August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group., Conclusions: This study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ninomiya reports receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan and Eisai. Dr. Ishikawa reports receiving personal fees from Boehringer Ingelheim. Dr. Kozuki reports receiving grants from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co, MSD, Kyowa Hakko Kirin, Merck Biopharma, Daiichi-Sankyo, AMGEN, Abbvie. Sanofi, Eisai and Labcorp Development Japan; and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Ono Pharmaceutical Co., Pfizer Japan, Daiichi-Sankyo, Bayer, Abbvie, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, MSD, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck Biopharma, Nippon Kayaku, Novartis, Takeda Pharmaceutical Co., Bayer, Sawai and AMGEN. Dr. Kuyama reports receiving personal fees from Chugai Pharmaceutical Co., AstraZeneca, Pfizer Japan, Daiichi-Sankyo, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, MSD, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku, Novartis, Sanofi and Hisamitsu pharmaceutical Co. Inc. Dr. Yokoyama reports receiving grants from MSD, Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Boehringer Ingelheim Japan Inc., Takeda Pharmaceutical Co. Ltd., Delta-Fly Pharma and Janssen Pharmaceutical K.K.; and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc, Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd. and Nippon Kayaku Co. Ltd. Dr. Shibayama reports receiving grants from Ono Pharmaceutical Co.; and personal fees from AstraZeneca, Nippon Boehringer Ingelheim and Daiichi-Sankyo. Dr. Aoe reports receiving grants from Ono Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Bristol-Myers Squibb, MSD, Novartis and Pfizer; and personal fees from Ono Pharmaceutical Co., Bristol-Myers Squibb. Dr. Bessho reports receiving grants from Chugai Pharmaceutical Co., AstraZeneca, MSD, Abbvie and Pfizer; and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co, Bristol-Myers Squibb, Ono Pharmaceutical Co., Nippon Boehringer Ingelheim, Novartis and Pfizer. Dr. Hotta reports receiving grants from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Bristol-Myers Squibb, MSD and Abbvie; and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Pfizer Japan, Takeda Pharmaceutical Co. and Nippon Boehringer Ingelheim. Dr. Kiura reports receiving grants from Chugai Pharmaceutical Co., Taiho Pharmaceutical Co., Ono Pharmaceutical Co., Nippon Boehringer Ingelheim, Nippon Kayaku Co. Ltd., Bristol-Myers Squibb K.K., MSD K.K., Pfizer Japan, TEIJIN Pharma Limited., SHIONOGI Co. Ltd., KYORIN Pharmaceutical Co. Ltd. and Merck Biopharma Co. Ltd. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aimed to devise a simple assessment system for bone metastases (BMs) from lung cancer (LC)., Methods: A total of 368 LC patients with BMs who underwent radiotherapy (RT) were retrospectively reviewed. Prognostic factors were evaluated using multivariate analysis, and a scoring system based on regression coefficients was devised., Results: The median follow-up time for survival was 4.3 months, and the 0.5-year overall survival (OS) rate was 44.7%. In the multivariate analysis, the significant prognostic factors were performance status (PS), metastases to internal organs, and post-RT molecular-targeting therapies (MTs) (tyrosine kinase inhibitors, and/or immune checkpoint inhibitors). A scoring system aggregating points assigned to each risk factor was created (2 points; non-administration of post-RT MTs, 1 point; PS ≥3 and metastases to internal organs). The median OSs were 25.0 months, 12.8 months, and 2.5 months in patients with a total score of 0 (n = 22), 1-2 (n = 124), and 3-4 (n = 221), respectively (p < 0.01)., Conclusion: This easy-to-use scoring system is useful for selecting patients who received comparatively high-dose fractionated RT for BMs from LC. Updates are required to follow the progress of systemic therapy., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background and Purpose: Acute exacerbations or acute lung injury, including radiation pneumonitis (AE-ALI/RP) of interstitial lung disease (ILD), has a fatal prognosis. We evaluated the risk of palliative-intent radiotherapy (RT), with or without lung irradiation, for AE-ALI/RP of ILD., Materials and Methods: The data of patients with ILD who received palliative-intent RT between January 2011 and January 2022 were retrospectively reviewed. Factors associated with AE-ALI/RP grade ≥ 3 were assessed using univariate and multivariate analyses., Results: One hundred and three patients were examined, with median imaging and survival follow-up times of 88 (2-1440) and 144 (8-1441) days. The median time to onset of AE-ALI/RP grade ≥ 3 was 72 (5-206) days. In multivariate analysis, a higher pulmonary fibrosis score (PFS ≥ 3) (hazard ratio, HR: 2.16; 95% confidence interval, CI: 1.36-3.43; p < 0.01) and lung irradiation (lung-RT) (HR: 3.82; 95% CI: 1.01-15.73; p = 0.04) were significant factors for AE-ALI/RP grade ≥ 3. In patients who received lung-RT, the 100-day survival rate and cumulative incidence of AE-ALI/RP grade ≥ 3 were 56.8% and 13.7%, respectively. In patients with PFS ≥ 3 and who underwent lung-RT, the 100-day cumulative incidence of AE-ALI/RP grade ≥ 3 was 37.5%; all patients with AE-ALI/RP grade ≥ 3 had grade 5. In patients with PFS ≥ 3 without lung-RT, the 100-day cumulative incidence of AE-ALI/RP grade ≥ 3 was 4.8%., Conclusion: High PFS and lung-RT are significant risk factors for AE-ALI/RP grade ≥ 3. Even with relatively low doses, palliative-intent lung-RT carries an extremely high risk of AE-ALI/RP when PFS is high., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bone metastasis is common in advanced lung cancer, with the incidence reported to be 30%, and radiotherapy (RT) is used for pain relief from bone metastasis. The present study aimed to identify factors affecting local control (LC) of bone metastasis from lung cancer and to assess the significance of moderate RT dose escalation. This was a retrospective cohort study, where LC of bone metastasis from lung cancer that had received palliative RT was reviewed. LC at RT sites was evaluated with follow-up computed tomography (CT). The influence of treatment-, cancer- and patient-related risk factors for LC was assessed. A total of 317 metastatic lesions in 210 patients with lung cancer were evaluated. The median RT dose (biologically effective dose calculated using an α/β of 10 Gy; BED10) was 39.0 Gy (range, 14.4-50.7 Gy). The median follow-up time for survival and median radiographic follow-up time were 8 (range, 1-127) and 4 (range, 1-124) months, respectively. The 0.5-year overall survival and LC rates were 58.9 and 87.7%, respectively. The local recurrence rate in RT sites was 11.0%, and bone metastatic progression, except in RT sites, was observed in 46.1% at the time of local recurrence or the last follow-up CT of the RT sites. According to multivariate analysis, RT sites, pre-RT neutrophil to lymphocyte ratio (NLR), post-RT non-administration of molecular-targeting agents (MTs), and non-administration of bone modifying agents (BMAs) were significant unfavorable factors for LC of bone metastasis. Moderate RT dose escalation (BED10 >39 Gy) tended to improve the LC of RT sites. In cases without MTs, moderate dose escalation of RT dose improved the LC of RT sites. In conclusion, treatment (post-RT MTs and BMAs), cancer (RT sites) and patient (pre-RT NLR)-related risk factors had a large impact on improving the LC of RT sites. Moderate RT dose escalation seemed to have a small impact on improving the LC of RT sites., Competing Interests: Toshiyuki Kozuki received an honorarium from MSD, Ono, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim, Chugai, TAIHO, Eli Lilly, Bristol Myers Squibb, Pfizer, Merck Biopharma, Nippon Kayaku, Novartis, Bayer, Sawai and AMGEN, received consulting fees from Chugai, AstraZeneca, Ono, Pfizer, Daiichi-Sankyo, Bayer, and Abbvie, and received research funding from MSD, Kyowa Hakko Kirin, AstraZeneca, Eli Lilly, Pfizer, Chugai, TAIHO, Ono, Bristol-Myers, Merck Biopharma, Daiichi-Sankyo, AbbVie, AMGEN, Sanofi, Eisai and Labcorp Development. All other authors declare that they have no conflict of interest., (Copyright: © Makita et al.)

Aims: Durvalumab (Durva) administration after chemoradiation therapy (CRT) in locally advanced non-small-cell lung cancer (NSCLC) is the standard of care, associated with relatively prolonged progression-free (PFS) and overall survival. However, pneumonitis occurs in 73.6% of Japanese patients. This retrospective study aimed to identify factors associated with Durva efficacy and safety, specifically, the risk of pneumonitis., Methods: This study included data from 26 consecutive patients with locally advanced NSCLC who underwent CRT followed by Durva. The rates of adverse events and PFS were examined., Results: The median PFS time was 15.6 months (95% confidence interval [CI]: 8.7-not available). Patients developed pneumonitis of grade 1, 2, 3, and 4 at the rate of 62%, 27%, 12%, and 0%, respectively. The median PFS time was 6.4 months for patients with programmed death ligand 1 (PD-L1) expression level of <50% and not reached for patients with PD-L1 expression level of ≥50% (hazard ratio [HR], 0.19; 95% CI: 0.04-0.89), which was significantly prolonged. The cumulative incidence of pneumonitis grade 2 or above was significantly higher when the time between the last day of thoracic radiotherapy (TRT) and the start of Durva therapy was within 14 days compared to >14 days (HR: 0.19; 95% CI: 0.06-0.59). This association was statistically significant in multivariate analysis., Conclusions: The initiation of Durva therapy within 14 days after TRT may increase the risk of pneumonitis grade 2 or above. Careful observation and suitable treatment are recommended., (© 2022 John Wiley & Sons Australia, Ltd.)

In a phase II trial of nivolumab in advanced thymic carcinoma (UMIN000022007), long SD (SD for more than 24 weeks) was seen in three patients and irAE (Gr2 or higher) was seen in four patients among 15 patients. Here, we report preplanned comprehensive biomarker analyses. We obtained tumor samples for immunohistochemistry, peripheral blood mononuclear cells (PBMCs), plasma and serum for pharmacokinetic analysis of nivolumab and cytokine evaluations, and whole blood for immuno pharmacogenomic (PGx) analysis. PD-L1 expression on tumor cells were not associated with therapeutic efficacy, but FOXP3 expression in tumor area and stroma, CD204 expression in stroma, and MHC class I in tumor area were all low among long SD patients. PBMC of long SD patients presented with larger number of naïve/memory cells prior to treatment, suggesting priming after nivolumab administration. Immuno-PGx analysis showed non-synonymous SNVs in ITGAX and PDCD1 had some correlation with PFS. Concentration of nivolumab in blood during the treatment was not related to PFS, with their overall trend towards decreased nivolumab concentration in patients with irAEs. Low immunogenicity of thymic carcinoma demonstrated in our study may require the activation of immune systems via a combination of immune checkpoint blockades., Competing Interests: SK reports grants and personal fees from Astra Zeneca, grants and personal fees from Pfizer, grants and personal fees from Boehringer Ingelheim, personal fees from Taiho, personal fees from Novartis, grants and personal fees from MSD, personal fees from Sumitomo Dainippon Pharma, grants and personal fees from Eisai, grants from Astellas, grants from Gilead Sciences, grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb, grants and personal fees from REGENERON, personal fees from Rakuten Medical, grants from PACT Pharma, grants from Takara Bio Inc., personal fees from GSK, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Chugai, personal fees from ImmuniT Research Inc., grants from AMED(Japan Agency for Medical Research and Development), grants from JSPS(Japan Society for the Promotion of Science), personal fees from PMDA(Pharmaceuticals and Medical Devices Agency), outside the submitted work. SY reports grants from Nippon Boheringer Ingelheim, outside the submitted work. AH reports Grants or contracts from Eisai, Healios, Eli Lilly, Daiichi Sankyo, Chordia Therapeutics, Konica Minolta, outside the submitted work. TSe reports Grants or contracts from Abbvie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Novartis Pharma. Pfizer Japan, Takeda Pharmaceutical, and Payment of honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, Towa Pharmaceutical, and other interests from Precision Medicine Asia, outside the submitted work. SU reports Payment of honoraria from Chugai Pharmaceutical, outside the submitted work. YH reports Payment of honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Eisai, outside the submitted work. MS reports Grants or contracts from Ono, Bristol Myers Squibb, Chugai, MSD, IQVIA, EPS, Janssen, Amgen, Taiho, Pfizer, Abbvie, Daiichi-Sankyo, Takeda, Eisai, and Payment of honoraria from Ono, Bristol Myers Squibb, Chugai, MSD, AstraZeneca, Eli Lilly, Taiho, Pfizer, Novartis, Takeda, Merck, outside the submitted work. MN reports grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Eli Lilly, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, grants and personal fees from MSD, grants and personal fees from Novartis, personal fees from Merck Biopharma, grants and personal fees from Daiichi Sankyo, grants and personal fees from Takeda Pharmaceutical Company Limited, personal fees from Teijin Pharma Limited., personal fees from AbbVie, outside the submitted work. TK reports Consulting fees from Chugai Pharmaceutical Co., AstraZeneca, Ono Pharmaceutical Co., Pfizer Japan, Daiichi-Sankyo, Bayer, Abbvie, and Payment of honoraria from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Beohringer Ingelheim, Merck Biophama, Nippon Kayaku, Novartis, Daiichi-Sankyo, Takeda Pharmaceutical Co., Bayer, Sawai, outside the submitted work. TH reports Payment or honoraria from ONO Pharmaceutical, Bristol-Meyers Squibb, MSD, outside the submitted work. YO is an editorial board member, and reports Grants or contracts from AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon- Sumitomo, Pfizer, Taiho, Novartis, Takeda, Kissei, Daiichi-Sankyo, Janssen, LOXO, and Payment or honoraria from AstraZeneca, Chugai, Eli Lilly, ONO, BMS,Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, and Payment for expert testimony from AstraZeneca, Chugai, ONO, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics Inc., and Leadership or fiduciary role in JSMO, JLCS, JCOG, outside the submitted work. HH reports Grants or contracts from MSD, Abbvie, AstraZeneca, BMS, Ono, Merck Biophama, Daiichi-Sankyo, Janssen, Genomic Helath, Chugai, Roche, and Novartis, and Payments or honoraria from AstraZeneca, MSD, Eli Lilly, Ono, BMS, Chugai, Roche, Kyowa-Kirin, and Novartis, and Participation on an Advisory board for AstraZeneca, Eli Lilly, Chugai, Roche, ONO, BMS, and MSD, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Katsuya, Kitano, Yamashita, Ouchi, Yagishita, Hamada, Nakamura, Hosoda, Shibata, Motoi, Nakayama, Seto, Umemura, Hosomi, Satouchi, Nishio, Kozuki, Hida, Ohe and Horinouchi.)

Background: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation., Methods: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation., Results: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively., Conclusions: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved., Competing Interests: No potential conflict of interest relevant to this article was reported.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC). The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation. Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Balance in the mediolateral direction is usually maintained in patients with early-stage Parkinson's disease (PD), but not in moderate-stage PD as revealed by the Tandem Gait Test. Although mediolateral postural control in PD patients remains controversial, previous studies have shown that the Tandem Gait Test may predict the risk of future falls in patients with PD. This study aimed to clarify postural control differences among PD patients with and without mediolateral balance impairments (MLBI: mediolateral balance impairments, nMLBI: non-mediolateral balance impairments, respectively) and healthy controls (HCs)., Methods: We recruited 40 PD patients and 20 HCs. According to the Tandem Gait Test score, PD patients were divided into MLBI and nMLBI groups. Primary outcome measures were the ambulatory movement trajectory amplitude of the center of mass and its coefficient of variation (CV) during gait., Results: Mediolateral movement trajectory amplitudes and CV were not significantly different between the nMLBI group and HCs, whereas the mediolateral movement trajectory amplitude in the MLBI group was significantly higher than that in the nMLBI group. Moreover, the CV of the mediolateral movement trajectory amplitude in the MLBI group was significantly lower than that in the nMLBI group. The mediolateral movement trajectory amplitude was significantly correlated with the fall score., Conclusions: The current results suggest that PD patients with mediolateral balance impairments showed mediolateral postural sway during gait compared with PD patients without mediolateral balance impairments. It is necessary to focus on the instabilities in the mediolateral direction to avoid falls in PD patients., Competing Interests: CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare., (2022 The Japanese Association of Rehabilitation Medicine.)