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Introduction: The effect of polypharmacy on older patients with cancer is unclear. This study aimed to explore the effect of polypharmacy on the outcomes of treatment in older patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors., Materials and Methods: We retrospectively reviewed the records of older patients (aged ≥65 years) with advanced NSCLC who received PD-1/PD-L1 inhibitors with or without platinum-based chemotherapy as first-line treatment from March 2016 to December 2020. Patients with driver oncogenes or Eastern Cooperative Oncology Group performance status (PS) ≥2 were excluded. Polypharmacy was defined as receiving five or more oral or inhaled medications at baseline. We compared the progression-free survival (PFS), overall survival (OS), and mean cumulative length of hospital stays between the polypharmacy and non-polypharmacy groups., Results: A total of 122 patients, with a median age of 72 years (range, 65-89 years), were included in the analysis. Of the patients, 34 (27.8%) had a PS of 0 and 68 (55.7%) had a PD-L1 tumor proportion score (TPS) of ≥50%. The median number of oral or inhaled medications was 4 (range, 0-12), and 60 (49.1%) patients were taking ≥5 medications (polypharmacy). Age and Charlson Comorbidity Index score were significantly higher in the polypharmacy group (P = 0.01 and P < 0.001, respectively). Compared with the non-polypharmacy group, the polypharmacy group had a similar median PFS (6.7 vs. 8.5 months, P = 0.94) and a shorter median OS (17.3 vs. 26.0 months, P = 0.04). In the polypharmacy group, the adjusted hazard ratio for OS (adjusted for age, PS, and PD-L1 TPS) was 1.65 (95% confidence interval, 1.04-2.86, P = 0.03). Patients in the polypharmacy group had longer hospital stays (46.3 ± 7.5 vs. 27.7 ± 4.1 days/person, P < 0.05) and more emergency hospitalizations (1.6 ± 0.3 vs. 0.8 ± 0.1 times/person, P < 0.05) during the first year., Discussion: Polypharmacy was associated with shorter survival time and longer hospitalization in older patients with advanced NSCLC receiving first-line immunotherapy with or without chemotherapy., Competing Interests: Declaration of Competing Interest None of the authors has any financial or personal relationships with other individuals or organizations that could inappropriately influence this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction/background: The proper duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains unclear. Previously, sponsor-initiated clinical trials have more often used either a maximum 2-year fixed duration of ICI treatment or continuous treatment until documented disease progression. The study aimed to evaluate the association between ICI treatment duration (2-year fixed or continuous) and prognosis in patients with advanced NSCLC., Patients and Methods: The medical records of 425 patients with NSCLC who received ICI before August 31, 2019 were retrospectively reviewed., Results: No differences in time to treatment failure > 24 months (TTF-24) were detected between patients who underwent ICI treatment for > 2 years and patients who stopped ICI treatment at 2 years. Treatment-related adverse events tended to be higher in the patients with ICI treatment > 2 years., Conclusion: ICI treatment > 2 years did not significantly prolong the TTF compared with ICI treatment = 2 years, but it did increase the incidence of treatment-related adverse events., Competing Interests: Competing Interest Haruki Kobayashi reports personal fees from Eli Lilly, Novartis, Taiho Pharmaceutical, Chugai pharma, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb Japan, outside the submitted work. Kazushige Wakuda reports grants from AstraZeneca, Chugai pharma, Novartis, Abbvie, AMGEN, Daiichi Sankyo, Dizal Pharma; personal fees from Chugai pharma, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly, MSD, Ono Pharmaceutical, Daiichi Sankyo, Jassen Pharmaceutial, Takeda, Nippon Kayaku, outside the submitted work. Tateaki Naito reports grants from Otsuka Pharmaceutical; personal fees from Ono Pharmaceutical, HELSINN SA, outside the submitted work. Nobuaki Mamesaya reports grants from Boehringer Ingelheim; personal fees from Chugai pharma, AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, MSD, Ono Pharmaceutical, outside the submitted work. Ryo Ko reports grants from MSD, AstraZeneca; personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Takeda, MSD, outside the submitted work. Akira Ono reports personal fees from Chugai pharma, AstraZeneca, Ono Pharmaceutical, outside the submitted work. Hirotsugu Kenmotsu reports grants from Ono Pharmaceutical, Novartis, Eli Lilly, AstraZeneca, Loxo Oncology; personal fees from AMGEN, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai pharma, Daiichi Sankyo, Eli Lilly, Kyowa Hakko Kirin, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, outside the submitted work. Haruyasu Murakami reports grants from AstraZeneca, Chugai pharma, Takeda, Abbvie, Daiichi Sankyo, IQvia; personal fees from AstraZeneca, Chugai pharma, Takeda, Abbvie, Daiichi Sankyo, MSD, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Pfizer, Novartis, Eli Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, Eisai, Nippon Kayaku, outside the submitted work. Tetsuo Shimizu reports personal fees from Eli Lilly, Taiho Pharmaceutical, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Takeda, outside the submitted work. Yasuhiro Gon reports personal fees from Chugai pharma, outside the submitted work. Toshiaki Takahashi reports grants from AstraZeneca, Chugai Pharma, Eli Lilly Japan, Ono Pharmaceutical, MSD, Pfizer, AMGEN, Boehringer Ingelheim, Merck Biopharma; personal fees from AstraZeneca, Chugai Pharma, Eli Lilly Japan, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Roche Diagnostics, Takeda, Yakult, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations., Methods: We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review., Results: Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700-1.060, 95% confidence interval: 0.531-1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm., Conclusions: This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC., Methods: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA., Results: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively., Conclusions: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear., Patients and Methods: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses., Results: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001)., Conclusions: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib., Competing Interests: Disclosure KI reports personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merk Sharp & Dohme (MSD), Ono Pharmaceutical, and Taiho Pharmaceutical. MM reports grants from Boehringer Ingelheim, Eli Lilly; personal fees from Eli Lilly, Chugai, Astra Zeneca, Ono, Pfizer, MSD; nonfinancial support from F. Hoffmann-La Roche; others from Chugai, Astra Zeneca, Pfizer, Merk Serono, Kissei, Taiho, and Novartis. KW reports grants from Chugai Pharmaceutical Co., Ltd, AstraZeneca, Novartis, and Abbie; receiving personal fees from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K., Ono Pharmaceutical, MSD, and AstraZeneca. OH reports grants from AstraZeneca, Novartis, Boehringer Ingelheim, Byer, Daiichi Sankyo, GlaxoSmithKline; personal fees from AstraZeneca, Novartis, and Boehringer Ingelheim. TS has patents pending with AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, and Takeda. KT reports personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, MSD, Taiho, and Novartis. NF reports personal fees from Eli Lilly Japan, Chugai, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim Japan, Taiho, Ono, and Pfizer Japan. TK reports personal fees from Boehringer Ingelheim and AstraZeneca. SI reports grants from AstraZeneca and Chugai; personal fees from AstraZeneca, Boehringer Ingelheim, Ono, Taiho, Bristol Myers Squibb, Eli Lilly Japan, Pfizer, and Chugai. YK reports grants from MSD; personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. HY reports personal fees from Boehringer Ingelheim, AstraZeneca, Chugai pharmaceutical, Eli Lilly, Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, MSD KK, Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Delta-Fly Pharma, Nippon Kayaku, and Taiho Pharmaceutical. MK reports grants from Eli Lilly; receiving personal fees from Eli Lilly, CHUGAI PHARMACEUTICAL CO, AstraZeneca, MSD, ONO PHARMACEUTICAL CO, Bristol Myers Squibb, Takeda Pharmaceutical Company, and Boehringer Ingelheim. HS reports grants from AstraZeneca, MSD (Merk), Ono Pharmaceutical, Eli Lilly Japan, Chugai Pharmaceutical, Bristol Myers Squibb, Quintiles Transnational Japan, Chugai Pharmaceutical, Beyer Pharmaceuticals, Olympus, Boehringer Ingelheim Japan, West Japan Oncology Group, AC Medical, Novartis Pharma, Japan Blood Products Organization, CMIC HOLDINGS, Takeda, A2 Healthcare, Otsuka, Pfizer, Parexel International, Boston Scientific, Harada, Nobelpharma, Taisho Toyama Pham; personal fees from AstraZeneca, MSD (Merk), Ono Pharmaceutical, Eli Lilly Japan, Covidien Japan, Taiho Pharmaceutical, Becton, Dickinson and Company, AMCO Inc., Kyowa Hakko Kirin, KYORIN Pharmaceutical, Chugai Pharmaceutical, Olympus, Boehringer Ingelheim Japan, Novartis Pharma, Pfizer, Parexel International, and Boston Scientific. All other authors have declared no conflicts of interest. Role of the funder/sponsor The funding sources from CJLSG had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Programmed cell death 1 (PD-1) inhibitors have become a standard treatment, albeit not completely effective, for patients with advanced non-small-cell lung cancer (NSCLC). Previous studies of advanced melanoma have revealed that the tumor burden predicted the response to PD-1 inhibitors, although this relationship has remained unclear for NSCLC., Patients and Methods: The present single-center retrospective study evaluated 163 patients with advanced NSCLC who had received PD-1/programmed cell death ligand 1 (PD-L1) inhibitor monotherapy from December 2015 to December 2018. The clinical tumor burden was estimated using the baseline sum of the target lesions' longest diameters (BSLDs), measured according to the Response Evaluation Criteria for Solid Tumors, and the baseline number of metastatic lesions (BNMLs)., Results: The optimal cutoff values for predicting progression-free survival (PFS) were 5 for the BNMLs and 76 mm for the BSLDs, using the minimum P value method. The low-BNML group included 73 patients (44.8%). The median PFS was 12.2 months in the low-BNML group and 2.8 months in the high-BNML group (hazard ratio, 0.51; P = .0005). The low-BSLD group included 92 patients (56.4%). The median PFS was 9.6 months in the low-BSLD group and 3.4 months in the high-BSLD group (hazard ratio, 0.52; P = .0006). Multivariable analysis revealed that low-BSLD, low-BNML, nonsquamous histologic type and a PD-L1 tumor proportion score of ≥ 50% were independently associated with prolonged PFS., Conclusions: PD-L1 expression and the clinical tumor burden can predict the efficacy of PD-1/PD-L1 inhibitor monotherapy for NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs). To facilitate the use of third-generation EGFR-TKIs to potentially overcome T790M-mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation., Patients and Methods: We retrospectively screened patients with non-small-cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016. Factors influencing T790M status were evaluated by univariate and multivariate analysis., Results: Among 131 rebiopsied patients for whom EGFR mutation status was available, 58 (44%) had T790M mutations. Patient characteristics at rebiopsy were not significantly different between T790M-positive and -negative groups, except for surgical history (postsurgery recurrence). Total duration of EGFR-TKI treatment before rebiopsy, TKI-free interval, EGFR-TKI treatment history immediately before rebiopsy, continuation of initial EGFR-TKI beyond progressive disease, progression-free survival after initial TKI treatment, and rebiopsy site (other than fluid samples) significantly influenced T790M status. The incidence of T790M mutation was shown by multivariate analysis to be significantly higher in patients with postsurgery recurrence and total duration of EGFR-TKI treatment ≥ 1 year before rebiopsy (odds ratio, 4.2; 95% confidence interval, 1.3-15.7 and odds ratio, 4.4; 95% confidence interval, 1.1-19.8, respectively)., Conclusion: Postsurgery recurrence and longer total duration of EGFR-TKI treatment before rebiopsy may represent useful predictive markers for T790M detection. In patients with these clinical factors, rebiopsies are more recommended to detect T790M mutation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Amplicon-based massively parallel sequencing (MPS) is an effective platform for identifying clinically actionable mutations across many genes in limited amounts of tissue. Most lung cancers are diagnosed and staged using small tissue samples obtained by transbronchial biopsy (TBB). To determine whether the mutations in TBB specimens detected by amplicon-based MPS reflect those present in the tumors, we compared the mutational profiles of preoperative TBB specimens and corresponding surgically resected specimens., Patients and Methods: Fresh-frozen primary tumor specimens from non-small-cell lung cancer patients (n = 46) obtained preoperatively by TBB and during surgical resection were analyzed. The concordance of mutations detected by amplicon-based MPS in the 2 sample types was investigated, and the allele frequency of the mutations common to both specimens from the same patient was determined., Results: An initial assessment of DNA quantity revealed that 46% of the TBB specimens (21 of 46) had less than the lower limit for amplicon-based MPS. These 21 TBB specimens were consequently omitted from the analysis. Of the 29 mutations detected in the TBB and/or surgically resected specimens from 25 patients, 23 were present in both samples, for a concordance rate of 79%., Conclusion: Amplicon-based MPS with TBB specimens approximately reflects clinically relevant tumor mutation profiles. However, the rate of TBB specimens with sufficient DNA quantity for amplicon-based MPS was only around 50%. Therefore, surgically resected specimens have a valuable role in exploratory and comprehensive genomic profiling., (Copyright © 2016 Elsevier Inc. All rights reserved.)