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Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p

Background KRAS-mutated non-small cell lung cancer (NSCLC) accounts for 23–35% and 13–20% of all NSCLCs in white patients and East Asians, respectively, and is therefore regarded as a major therapeutic target. However, its epidemiology and clinical characteristics have not been fully elucidated because of its wide variety of mutational subtypes. Here, we focused on two distinct base substitution types: transversion mutations and transition mutations, as well as their association with environmental factors and clinical outcome. Methods Dataset from the Japan Molecular Epidemiology Study, which is a prospective, multicenter, and molecular study epidemiology cohort study involving 957 NSCLC patients who underwent surgery, was used for this study. Questionnaire-based detailed information on clinical background and lifestyles was also used to assess their association with mutational subtypes. Somatic mutations in 72 cancer-related genes were analyzed by next-generation sequencing, and KRAS mutations were classified into three categories: transversions (G > C or G > T; G12A, G12C, G12R, G12V), transitions (G > A; G12D, G12S, G13D), and wild-type (WT). Clinical correlations between these subtypes have been investigated, and recurrence-free survival (RFS) and overall survival (OS) were evaluated. Results Of the 957 patients, KRAS mutations were detected in 80 (8.4%). Of these, 61 were transversions and 19 were transitions mutations. Both pack-years of smoking and smoking duration had significant positive correlation with the occurrence of transversion mutations (p = 0.03 and p = 0.01). Patients with KRAS transitions had the shortest RFS and OS compared to KRAS transversions and WT. Multivariate analysis revealed that KRAS transitions, along with age and stage, were significant predictors of shorter RFS and OS (HR 2.15, p = 0.01; and HR 2.84, p Conclusions Smoking exposure positively correlated with transversions occurrence in a dose-dependent manner. However, vegetable intake negatively correlated with transitions. Overall, KRAS transition mutations are significantly poor prognostic factors among resected NSCLC patients.

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m2, day1, 8) every 3 weeks followed by Bev (15 mg/kg, day1) plus nab-PTX (100 mg/m2, day1, 8) every 3 weeks without disease progression or unacceptable severe toxicities. The primary endpoint was objective response rate (ORR). Results The study enrollment was ceased because of suspension of the registration period (as scheduled) after 12 of 20 planned patients were treated successfully between March 2014 and February 2018. The ORR was 58.3 % (95 % CI, 27.7–84.8 %), and the disease control rate was 100 % (95 % CI, 73.5–100 %). Eight patients received maintenance therapy. Median progression-free and overall survival times were 14.4 and 26.9 months, respectively. Most patients experienced hematological toxicities, including ≥ grade 3 neutropenia and anemia; none experienced severe bleeding events and grade 5 toxicities. Conclusion The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-naive non-SQ NSCLC patients with MPE. Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39–91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0–1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50–74%, 75–89%, and 90–100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0–1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05–2.72; p = 0.03138), CRP/Alb (

Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I ‘Quartet Trial’ to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).

No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy.The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area1.25 m(2), 100 mg/day for those with a body surface area of 1.25-1.5 m(2), and 120 mg/day for those with a body surface areaor = 1.5 m(2).Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1-9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days.S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC.

The online version of the original article can be found underdoi:10.1007/s10147-010-0034-0.A. Ono T. Naito H. Murakami T. Takahashi Y. Nakamura A. Tsuya K. Kaira S. Igawa T. Shukuya A. Tamiya R. Kaira N. Yamamoto (&)Division of Thoracic Oncology, Shizuoka Cancer Center,1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun,Shizuoka 411-8777, Japane-mail: n.yamamoto@scchr.jpM. EndoDivision of Diagnostic Radiology, Shizuoka Cancer Center,1007 Nagaizumi-cho, Shizuoka 411-8777, Japan