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Although recent reports have revealed the importance of the inactivation of both RB1 and TP53 in the transformation from lung adenocarcinoma into neuroendocrine carcinoma (NEC), the requirements for complete transformation into NEC have not been elucidated. To investigate alterations in the characteristics associated with the inactivation of RB1/TP53 and define the requirements for transformation into NEC cells, RB1/TP53 double-knockout A549 lung adenocarcinoma cells were established, and additional knockout of REST and transfection of ASCL1 and POU class 3 homeobox transcription factors (TFs) was conducted. More than 60 genes that are abundantly expressed in neural cells and several genes associated with epithelial-to-mesenchymal transition were up-regulated in RB1/TP53 double-knockout A549 cells. Although the expression of chromogranin A and synaptophysin was induced by additional knockout of REST (which mimics the status of most NECs), the expression of another neuroendocrine marker, CD56, and proneural TFs was not induced. However, coexpression of ASCL1 and POU3F4 in RB1/TP53/REST triple-knockout A549 cells induced the expression of not only CD56 but also other proneural TFs (NEUROD1 and insulinoma-associated 1) and induced NEC-like morphology. These findings suggest that the inactivation of RB1 and TP53 induces a state necessary for the transformation of lung adenocarcinoma into NEC and that further inactivation of REST and coexpression of ASCL1 and POU3F4 are the triggers for complete transformation into NEC.

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-β1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-β1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-β1. Knockdown of PISD alone without TGF-β1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.

Supplemental Experimental Procedures

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Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

Supplementary Table 1- List of the 244 cancer related genes of the target capturing panel Supplementary Table 2 - The coverage statistics for each sample of large cell neuroendocrine carcinoma (LCNEC) Supplementary Table 3 - The coverage statistics for each sample of advanced small cell lung cancer (SCLC) Supplementary Table 4 - Validation of the mutations detected in this study using the Oncomine® Cancer Research Panel (OCP) Supplementary Table 5- Primer Sequences: Sanger Sequencing Supplementary Table 6 - Antibody for immunohistochemical staining Supplementary Table 7 - Candidate somatic mutations of large cell neuroendocrine carcinoma (LCNEC) Supplementary Table 8 - Candidate somatic mutations in advanced small cell lung cancer (SCLC) Supplementary table 9 - Hotspot mutations detected in small cell lung cancer (SCLC) Supplementary Table 10- Variant frequency of candidate somatic mutations of large cell neuroendocrine carcinoma (LCNEC) combined with non-small cell lung cancer (NSCLC) Supplementary Table 11- Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis for the top six most frequently mutated genes in large cell neuroendocrine carcinoma (LCNEC)

Supplementary figure legends

Supplementary Fig. S1. The mean baseline Levels of PIP3 (38:4) per mg tissue in xenograft models transplanted with SCLC cells Supplementary Fig. S2. Metabolic alteration in SCLC cells treated with gedatolisib in vitro and in vivo Supplementary Fig. S3. Comparative metabolic profiling in LAD and SCLC cell lines Supplementary Fig. S4. Gene expression alteration after treatment with PI3K/mTOR inhibitor Supplementary Fig. S5. Schematic diagram of metabolic linkage Supplementary Fig. S6. Addition of 5''-deoxy-5''-(methylthio)-adenosine (MTA) reversed drug sensitivity from a resistant to a sensitive phenotype Supplementary Fig. S7. HPRT1 expression was downregulated by an HPRT1-specific siRNA in SCLC cells

Supplementary Table S1. The pathway classification of metabolites used for the MSEA Supplementary Table S2. Genetic profiles in 42 SCLC cell lines Supplementary Table S3. Quantitative phospho-peptide analysis in H1048 cells with or without Gedatolisib treatment Supplementary Table S4. Quantitative phosphatidyl lipids analysis in SCLC cell Supplementary Table S5. Quantitative phosphatidyl lipids analysis in H1048 cells Supplementary Table S6. 116 metabolites in SCLC cells with or without Gedatolisib treatment Supplementary Table S7. 116 metabolites in H1048 and SBC5 with or without Gedatolisib treatment Supplementary Table S8. Metabolite set enrichment analysis (MSEA) to identify significantly enriched metabolic pathways related to gedatolisib Supplementary Table S9. Amount of 116 metabolites in SCLC tissues

Supplementary methods for Sanger sequencing, copy number analysis with quantitative PCR, and Immunohistochemical staining

Supplemental Tables 1-4. Supplemental Table 1: Characteristics of primary adenocarcinoma from which CAFs were obtained. Supplemental Table 2: Primary tumor characteristics(N=106). Supplemental Table 3: Impact of predictive factors on progression free survival of EGFR-TKI in patients with EGFR activating mutation by univariate and multivariate analysis (n=106). Supplemental Table 4: The correlation between PDPN expression status and clinical response to EGFR-TKIs in patients with EGFR common mutations, exon 19 deletion and L858R (N=102).

Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179–90. ©2018 AACR.

Supplemental Figures 1-6. Supplemental Figure 1: Fluorescence microscopy showing mRFP-labeled PC-9 (red) and Venus-labeled CAFs (green) with or without gefitinib treatment. Supplemental Figure 2: mRNA levels of podoplanin (PDPN) in CAF-Ctrl and CAF PDPN-WT. Supplemental Figure 3: Co-culture with other CAFs induces gefitinib resistance. mRFP-labeled PC-9 and HCC-827 cells were co-cultured with CAFs (CAF-Ctrl, PDPN-WT, or CAF-PDPN-Del.IC) in the presence or absence of gefitinib treatment. The total cell numbers of PC-9 or HCC-827 cells treated for 72 hours with gefitinib in the presence or absence of Venus-labeled CAF-Ctrl, PDPN-WT, or CAF-PDPN-Del.IC are shown. Supplemental Figure 4: The number of the cases according to the PDPN-positive CAF area/stromal area (%). Supplemental Figure 5: PFS according to podoplanin expression in patients with EGFR common mutations (exon 19 deletion and L858R). Supplemental Figure 6: mRNA levels of HGF in CAF-Ctrl and CAF PDPN-WT.

Supplementary Figure 1: Representative example of tissue microarray (TMA) punched out from a combined large-cell neuroendocrine carcinoma (LCNEC) with adenocarcinoma. Supplementary Figure 2: Validation of five mutations on the PI3K/AKT/mTOR pathway by Sanger sequencing (LCNEC 68c: PIK3CA E545K, LCNEC 9c: PTEN K342*, LCNEC 13c: PTEN S59*, LCNEC 4c: RICTOR R910H, LCNEC 11p: MTOR E2419K). Supplementary Figure 3: Correlation of gene copy number, calculated using the total depth on the covered region of each of 244 targeted genes and those obtained from the Oncomine® Cancer Research Panel (OCP). Supplementary Figure 4: Validation of the copy number gains or amplifications of 13 samples (8 LCNEC samples, 1 SCLC biopsy samples and 4 SCLC surgically resected cases) for MYCL1, MYC and FGFR1 by a quantitative real-time polymerase chain reaction (qPCR). Supplementary Figure 5: Overview of the key driver alterations and other activating alterations in small cell lung cancer (SCLC). Genetic alterations in the PI3K/AKT/mTOR pathway were detected in 24 (17%) of the tumors: PIK3CA (4%), PTEN (6%), AKT2 (2%) and RICTOR (6%). Copy number gains of each MYC family member were mutually exclusive. Supplementary Figure 6: Relationship between RB1 mutation and IHC staining of RB and p16. The mutual exclusivity of the protein expression between RB and p16 was distinct. Supplementary Figure 7: Relationship between genetic alteration and protein expression in large-cell neuroendocrine carcinoma (LCNEC) of the lung. Comparison of the over expression of receptor tyrosine kinases (RTKs) with the genetic alterations in resected LCNEC specimens (51 of 65 resected cases) revealed no significant relationship between strongly positive RTKs (KIT, EGFR, IGF1R, KDR, ERBB2) expression and genetic alterations.

Supplemental Figure legends

Purpose: The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs.Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106).Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P < 0.01).Conclusions: Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs. Clin Cancer Res; 21(3); 642–51. ©2014 AACR.

Background: bronchoscopy is a relatively invasive procedure, and standard anesthesia is often inadequate. The recently introduced transcutaneous carbon dioxide (tcpCO2) monitoring has become a convenient surrogate method for continuous monitoring of the partial pressure of arterial carbon dioxide (PaCO2). The objective of this study was to evaluate the safety of additional use of propofol during bronchoscopy by transcutaneous blood gas monitoring. Methods: patients in whom transcutaneous gas monitoring was performed during bronchoscopy were included in this study. The study subjects were divided into two groups: 1) the midazolam + fentanyl group (MF group), and 2) the group in which midazolam was switched to propofol because of inadequate sedation with midazolam + fentanyl (MFP group). We conducted a retrospective analysis of the transcutaneous gas measurement data obtained during bronchoscopy. Results: data of a total of 61 patients (MF group, n=41; MFP group, n=20) were analyzed. The duration over which the tcpCO2 remained over 50 mm Hg was longer in the MFP group (MF 0.0 min vs. MFP 7.8 min, p=0.042). The percentage of patients in whom the tcpCO2 rose to over 50 mm Hg was also higher in the MFP group (MF group, 14.6% vs. MFP group, 65.0%). None of the patients required discontinuation of the bronchoscopic procedure due to inadequate sedation. Conclusions: while the addition of propofol improved the tolerability of the procedure in difficult-to-sedate patients, it was also associated with a higher risk of ventilatory failure and hypoxemia. Thus, in order to ensure safety, additional propofol should be used with caution under continuous pCO2 monitoring, such as by transcutaneous measurement. Trial registration: this study was conducted with the approval of the Clinical Research Management Division of Dokkyo Medical University (Approval No.: R-15-5J) under the supervision of a well-trained bronchoscopist. The contents of the study were disclosed in an opt-out format.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25–40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1–LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1–LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1–LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1–LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1–LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1–LTK fusion as a target in NSCLC that could be treated with lorlatinib. Whole-transcriptome sequencing of a subset of 75 non-small-cell lung cancer specimens in a multi-institutional genome screening study identified a fusion of the CLIP1 and LTK genes with transformational potential due to constitutive LTK kinase activity.

Background It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs. Methods We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS). Results A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007). Conclusions The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance., Concomitant medication had no significant effect on the efficacy and safety of immune checkpoint inhibitors. Opioid use was associated with shorter overall survival and further study of this possible effect is required. This study is the first to demonstrate the impact of angiotensin receptor blockers or vitamin D on ICI treatment in patients with non‐small cell lung cancer.

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

To date, no clinical trials on the use of induction therapy before surgery have focused solely on lung squamous cell carcinoma (LSCC). We report the results of the Personalized Induction Therapy-2 (PIT-2) trial, a multicenter phase II study, performed to investigate the efficacy and safety of S-1 + cisplatin with concurrent thoracic radiotherapy (TRT) followed by surgery in patients with stage IIIA (N2) LSCC.Patients with pathologically proven stage IIIA (N2) LSCC received induction therapy comprising three cycles of S-1 + cisplatin with concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at a dose of 40 mg/mOf 45 registered patients, 43 underwent induction therapy. Of the 43 patients, 39 (91%) underwent surgery (35 lobectomies, 3 pneumonectomies, and 1 wedge resection). The 2-year PFS, 2-year overall survival, objective response rate, and pathological complete response rates were 67% (90% confidence interval [CI] 54-78%), 70% (95% CI 53-81%), 86% (95% CI 76-96%), and 39% (95% CI 23-54%), respectively. No new treatment-related adverse events occurred during the induction therapy. One case of 90-day postoperative mortality involving a patient who underwent right pneumonectomy and developed pneumonia after discharge occurred.Induction therapy using S-1 + cisplatin with concurrent TRT followed by surgery is a feasible and promising treatment approach for stage IIIA (N2) LSCC.

PURPOSE To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.

The usefulness of the histopathology of biopsy samples for predicting the efficacy of immunotherapy in non-squamous, non-small cell lung cancer (NSq NSCLC) patients remains unclear. We retrospectively investigated the associations between the histopathological features in biopsy samples and survival outcomes in advanced NSq NSCLC patients receiving pembrolizumab. NSq NSCLC was classified histopathologically as morphological adenocarcinoma or non-small cell carcinoma (NSCC: absence of definitive features of either adenocarcinoma or a squamous morphology). We investigated the association between the tumor morphological features and immune/genetic features by examining the tumor PD-L1 expression and tumor mutation burden (TMB). Among 33 advanced NSq NSCLC patients with tumor PD-L1 scores ≥ 50% receiving pembrolizumab as first-line therapy, a biopsy diagnosis of NSCC was associated with a significantly longer progression-free survival [median 16.8 vs. 2.3 months; hazard ratio (HR) 0.26; 95% CI 0.10–0.62, P = 0.01] and overall survival (median NR vs. 10.1 months; HR 0.35; 0.12–0.97, P = 0.04) as compared to that of morphological adenocarcinoma. In an analysis of 367 biopsy samples, the NSCC group showed a higher percentage of samples with PD-L1 scores ≥ 50% than the morphological adenocarcinoma group (35% vs. 10%). The NSCC group (n = 8) also showed a significantly higher TMB than the morphological adenocarcinoma group (n = 7) (median 236 vs. 25 mutations/whole exome, P = 0.01). Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.

Lorlatinib is a potent, brain‐penetrant, third‐generation anaplastic lymphoma kinase (ALK)/ROS proto‐oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK‐rearranged/ROS1‐rearranged advanced non–small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC‐ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK‐rearranged/ROS1‐rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty‐one ALK‐rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC‐ORR. The ORR and the IC‐ORR for Japanese patients in EXP2‐5 were 54.8% (95% confidence interval [CI]: 36.0‐72.7) and 46.7% (95% CI: 21.3‐73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9‐81.6). The most common treatment‐related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single‐dose and multiple‐dose pharmacokinetic profiles among Japanese patients were similar to those in non–Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK‐rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated., Lorlatinib showed clinically meaningful responses (54.8%; 95% CI: 36.0‐72.7) and intracranial responses (46.7%; 95% CI: 21.3‐73.4) among ALK‐rearranged Japanese patients with non–small cell lung cancer who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only (42.9%; 95% CI: 9.9‐81.6). Lorlatinib was generally well tolerated, with a similar adverse event profile among Japanese patients to that among the overall population.

Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed death‐ligand 1 (PD‐L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single‐center, prospective single‐arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% [90% confidence interval: 2%‐9%]) was significantly lower than the expected rate (20% with 30% threshold, P 1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer., In this study, cryoprobe biopsy was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events was 4%. Compared with forceps biopsy samples, cryoprobe biopsy samples were larger and resulted in a larger proportion of definite histomorphological diagnoses and larger amounts of DNA/RNA extracted from samples.

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first‐line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28‐d cycles, in patients with EGFR‐activating mutation–positive (EGFR‐positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non‐small cell lung cancer (NSCLC). The primary endpoint was progression‐free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307‐0.961]; 2‐sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0‐31.3] mo, 9.3 [95% CI, 7.4‐14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first‐line dacomitinib in Japanese patients with EGFR‐positive advanced NSCLC., We evaluated the efficacy and safety of first‐line dacomitinib compared with gefitinib in a subgroup of Japanese patients with EGFR‐activating mutation–positive advanced non‐small cell lung cancer who were enrolled in the ARCHER 1050 randomized phase 3 trial. Results for the primary efficacy endpoint in the Japanese patients (n = 81) were consistent with the results in the overall ARCHER 1050 population; there was a clinically meaningful prolongation of median PFS by 8.9 mo favoring dacomitinib. The safety profile of dacomitinib was manageable by dose reduction or temporary dose interruption and no new safety signals were observed in the population of Japanese patients compared with the overall ARCHER 1050 study population.

Objectives SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study. Materials and methods Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m2 on day 1 and S-1 80 mg/m2 on days 1–14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients. Results A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73–1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5–49.6)/32.1 % (95 %CI, 18.9–45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58–1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7–81.8)/66.4 % (95 %CI, 53.0–79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients). Conclusion The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.

Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study ( ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.

BackgroundPD-L1 expression on tumor cells is a marker of PD-1/PD-L1 antibody treatment efficacy for advanced non-small cell lung cancer (NSCLC). PD-L1 antibody (atezolizumab) prolongs overall survival (OS) compared with platinum doublet as first-line treatment for NSCLC with high PD-L1 expression. Bevacizumab enhanced cytotoxic agent and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor efficacy in non-squamous (NS)-NSCLC, and PD-1/PD-L1 antibodies in preclinical models.MethodsThis single-arm phase II study investigated clinical benefits of adding bevacizumab 15 mg/kg to atezolizumab 1200 mg fixed dose in a first-line setting for advanced NS-NSCLC patients with PD-L1 expression ≥50% without EGFR/ALK/ROS1 alterations. Primary endpoint was objective response rate (ORR) assessed by central review committee. Secondary endpoints were progression-free survival (PFS), duration of response (DOR), OS, and safety.ResultsOf 39 enrolled patients, 33 (84.6%) had stage IV NSCLC and 36 (92.3%) had smoking history. As of March 31, 2020, no patient had a complete response and 25 patients had a partial response (ORR=64.1%, 95% CI 47.18 to 78.80). Twelve-month PFS and OS rates were 54.9% (35.65 to 70.60) and 70.6% (50.53 to 83.74), respectively. The median DOR in 25 responders was 10.4 months (4.63–not reached). The median treatment cycle was 12 (1 to 27). Nineteen patients discontinued study treatment because of disease progression (N=17) or immune-related adverse events (AEs) (N=2) (sclerosing cholangitis or encephalopathy). There were 23 serious AEs in 12 patients, but no grade 4/5 toxicity.ConclusionsAtezolizumab with bevacizumab is a potential treatment for NS-NSCLC with high PD-L1 expression.Trial registration numberJapicCTI-184038.

ObjectiveWe aimed to determine antibody titres at 6 months and their rate of change during 3-6 months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) and to explore clinical variables associated with titres in Japan.MethodsWe enrolled 365 healthcare workers (250 women, 115 men) whose 3-month antibody titres were analyzed in our previous study and whose blood samples were collected 183 ± 15 days after the second dose. Participant characteristics collected previously were used. The relationships of these factors with antibody titres at 6 months and rates of change in antibody titres during 3-6 months were analyzed.ResultsMedian age was 44 years. Median antibody titre at 6 months was 539 U/mL. Older participants had significantly lower antibody titres (20s, 752 U/mL; 60s–70s, 365 U/mL). In age-adjusted analysis, smoking was the only factor associated with lower antibody titres. Median rate of change in antibody titres during 3-6 months was −29.4%. The only factor significantly associated with the rate of change in Ab titres was not age or smoking, but sex (women, −31.6%; men, −25.1%).ConclusionThe most important factors associated with lower antibody titres at 6 months were age and smoking, as at 3 months, probably reflecting their effect on peak antibody titres. However, antibody titres significantly attenuated during 3-6 months in women alone, which reduced the sex difference in antibody titres seen during the first 3 months. Antibody titres may be affected by different factors at different time points.