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Supplementary Table 2 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

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Supplementary Table 1 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

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Epidermal growth factor receptor (Searches were conducted in PubMed and supplemented with recent conference proceedings in November 30th, 2021.Several novel emerging therapies showed favorable safety profile and promising anti-tumor activity in NSCLC patients with EGFR ex20ins in recent several clinical trials.There is still room for improvement in the treatment results of NSCLC harboring EGFR ex20ins. Future research should focus on the molecular heterogeneity in the size and location of distinct EGFR ex20ins, the mechanisms of acquired resistance to novel EGFR inhibitors, effective treatment that have good central nervous system penetrance, and the potential role of combination strategy.

Fenbendazole is a benzimidazole anthelmintic agent, with a broad antiparasitic range in animals such as dogs and pigs. The agent is also reported to exert antitumor effects and inhibit microtubule-associated tubulin polymerization, but its safety and tolerability profile in humans remains unclear. An 80-year-old female patient with advanced nonsmall cell lung cancer (NSCLC) was started on pembrolizumab monotherapy. The patient experienced severe liver injury 9 months later. An interview with her and her family revealed that she had been taking fenbendazole for a month, solely based on social media reports suggesting its effectiveness against cancer. After discontinuation of the self-administration of fenbendazole, the patient’s liver dysfunction spontaneously resolved. The antitumor inhibitory effects of fenbendazole have been reported; however, she did not experience tumor shrinkage. This is the first case report of a patient with advanced NSCLC who self-administered the anthelmintic, fenbendazole. Twitter and Facebook are online social media platforms which have been constructively used to exchange information among cancer patients. However, sources of medical information on these platforms are often unproven, and it is difficult for nonmedical professionals to accurately select and filter complex medical information. Physicians should enquire patients about self-administration of orally ingested products, including dietary supplements, herbs, or bioactive compounds, in cases of unexpected adverse reactions.

Objectives The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation. Methods A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens. Results Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs. Conclusions The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

Background/aim The Archer FusionPlex platform is widely used for comprehensive fusion-gene detection in cancer tissues. This platform separately displays results for strong-evidence and weak-evidence fusion candidates (WEFCs). Distinctive fusion patterns are frequently found in the weak-evidence category and information about the patterns is clinically essential. Patients and methods We describe the type and frequency of WEFCs observed using the FusionPlex Sarcoma Panel (S Panel) and the FusionPlex ALK, RET, and ROS1 ver2 Panel (ARR Panel). Results A total of 97 specimens were examined and 620 candidates were detected and categorized as WEFCs. A median of five WEFCs were detected per sample. In the S Panel group, there were 13 WEFCs with a frequency of more than 1%. In the ARR Panel group, a total of 16 WEFCs were detected with a frequency of more than 1%. Conclusion Specific WEFCs were detected according to the panel selected.

Background RNA‐based sequencing is considered ideal for detecting pathogenic fusion‐genes compared to DNA‐based assays and provides valuable information about the relative expression of driver genes. However, RNA from formalin‐fixed paraffin‐embedded tissue has issues with both quantity and quality, making RNA‐based sequencing difficult in clinical practice. Analyzing stamp‐derived RNA with next‐generation sequencing (NGS) can address the above‐mentioned obstacles. In this study, we validated the analytical specifications and clinical performance of our custom panel for RNA‐based assays on the Ion Torrent platform. Methods To evaluate our custom RNA lung panel, we first examined the gene sequences of RNA derived from 35 NSCLC tissues with diverse backgrounds by conventional methods and NGS. Next, we moved to the clinical phase, where clinical samples (all stamp‐derived RNA) were used to examine variants. In the clinical phase we conducted an NGS analysis while simultaneously applying conventional approaches to assess the feasibility and validity of the panel in clinical practice. Results In the prerun phase, all of the variants confirmed with conventional methods were detected by NGS. In the clinical phase, a total of 80 patients were enrolled and 80 tumor specimens were sequenced from February 2018 to December 2018. There were 66 cases in which the RNA concentration was too low to be measured, but sequencing was successful in the vast majority of cases. The concordance between NGS and conventional methods was 95.0%. Conclusions RNA extraction using stamp specimens and panel sequencing by NGS were considered applicable in clinical settings. Key points Significant findings of the study Next‐generation sequencing using RNA from stamp specimens was able to detect driver gene changes in non‐small cell lung cancer including fusion genes with the same accuracy as conventional methods. What this study adds Using RNA from stamp specimens obtained from biopsy increases the number of candidate cases for RNA sequencing in clinical settings.

BRAF mutations are rare driver mutations in non-small cell lung cancer (NSCLC), accounting for 1%-2% of the driver mutations, and the mutation spectrum has a wide range in contrast to other tumors. While V600E is a dominant mutation in melanoma, more than half of the mutations in NSCLCs are non-V600E. However, treatment with dabrafenib plus trametinib targets the BRAF V600E mutation exclusively. Therefore, distinguishing between V600E and non-V600E mutations is crucial for biomarker testing in NSCLC in order to determine treatment of choice. Immunohistochemistry (IHC) using the BRAF V600E mutation-specific antibody is clinically used in melanoma patients, but little is known about its application in NSCLC, particularly with regard to the assay performance for non-V600E mutations. In the present study, we examined 117 tumors with BRAF mutations, including 30 with non-V600E mutations, using BRAF mutation-specific IHC. None of the tumors with non-V600E mutations, including two compound mutations, showed a positive reaction. Furthermore, all V600E mutations were positive except for one case with combined BRAF V600E and K601_W604 deletion. Our findings confirmed that the BRAF V600E mutation-specific IHC is specific without any cross-reactions to non-V600E mutations, suggesting that this assay can be a useful screening tool in clinical practice.

Background Although patients with advanced cancer often have poor prognostic awareness, the most effective communication approach for improving prognostic awareness is unclear. In addition, the association between prognostic awareness and preferences for future medical treatment remains unexplored. Materials and Methods We performed a prospective observational study of consecutive patients with advanced or post-operative recurrent non-small cell lung cancer whose disease had progressed after first–line chemotherapy, and their caregivers. We evaluated patterns of clinical discussions about incurability, prognostic awareness, and preference for future medical treatment at baseline and 3 months later. Results We obtained 200 valid responses to the questionnaires at baseline and 147 valid responses 3 months later. In addition, 180 caregivers returned valid responses. A total of 54% of patients and 51% of caregivers had accurate awareness at baseline, and 52% of patients had accurate awareness 3 months later. Multiple logistic regression analysis revealed that patients who were informed about incurability in recent and past discussions were significantly more likely to have accurate awareness 3 months later, compared with those who were only informed recently (adjusted odds ratio 5.08; 95% CI, 1.31-19.78; P = .019). Accurate awareness at 3 months was significantly negatively associated with preference for life-prolonging treatment at 3 months after adjusting for covariates (adjusted odds ratio 0.39; 95% CI, 0.17-0.90; P = .028). Conclusion Patients with advanced cancer who had both recent and past discussions about incurability with their oncologists have more accurate prognostic awareness. Improving prognostic awareness could reduce the preference for life-prolonging treatment.

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Aims Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs. Methods and results We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib. Conclusions Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript.

The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation.We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer.One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect.The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

Background Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, has shown survival benefit in clinical trials of various malignant tumors. Nivolumab-induced pneumonitis is major immune-related adverse event (irAE) that is occasionally serious and life-threatening. The aim of this study was to examine the association between pre-existing interstitial lung disease (ILD) on chest computed tomography (CT) and nivolumab-induced pneumonitis among different types of solid tumors. Methods We retrospectively collected the clinical data of 311 patients who were diagnosed with non-small cell lung cancer (NSCLC), head and neck cancer (HNC), or gastric cancer (GC), and treated with nivolumab monotherapy. Patients who underwent chest CT immediately before starting nivolumab without previous thoracic radiotherapy or other immune checkpoint inhibitors were eligible. We collected baseline patient characteristics and assessed pre-existing ILD on baseline chest CT. Results Finally, 188 patients were included in the analysis: 96 patients with NSCLC, 43 patients with HNC, and 49 patients with GC. NSCLC patients had a significantly higher rate of pre-existing ILD compared with HNC/GC patients (P = 0.047). Nivolumab-induced pneumonitis occurred in 11.7% (22 of 188), including 14.6% (14 of 96) of NSCLC, and 8.7% (8 of 92) of HNC/GC. Univariate and multivariate logistic regression analyses revealed that pre-existing ILD (odds ratio, 5.92; 95% confidence interval (CI), 2.07–18.54, P = 0.0008) and male sex (odds ratio, 5.58; 95% CI, 1.01–104.40, P = 0.049) significantly increased the risk of nivolumab-induced pneumonitis. Conclusion Our results indicated that pre-existing ILD and male sex are risk factors for nivolumab-induced pneumonitis in solid tumors.

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non‐small‐cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD‐1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty‐eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option., This study showed the efficacy of local therapy for oligoprogressive disease after PD‐1 blockade in advanced non‐small‐cell lung cancer.

Objectives Pneumonitis related to the use of anti-programmed death 1 (PD-1) antibodies is a common immune-related adverse event that can be life-threatening. However, the relationship between pulmonary fibrosis/emphysema and the incidence of anti-PD-1-related pneumonitis is unclear. Materials and methods We retrospectively reviewed data from 123 patients who were diagnosed with non-small-cell lung cancer and treated with anti-PD-1 antibodies (nivolumab or pembrolizumab) at the Aichi Cancer Center Hospital, Japan, between December 17, 2015, and November 30, 2017. Patients who previously received thoracic radiotherapy to the primary lesion, mediastinum, spinal, or rib metastases were excluded from the analysis. Fibrosis score (0–5) and emphysema score (0–4) on baseline chest computed tomography (CT) were determined by two diagnostic radiologists. Results Eighteen patients (14.6%) experienced anti-PD-1-related pneumonitis, of which four (3.3%) were grade ≥3. The median onset time of pneumonitis after starting anti-PD-1 therapy was 60 days (range, 6–634 days). According to the analysis of fibrosis score, pneumonitis occurred in 13 (35.1%) of the 37 patients with a fibrosis score ≥1 and in 5 (5.8%) of 86 patients with a fibrosis score of 0. Univariate and multivariate logistic regression analysis revealed that fibrosis score ≥1 was the only risk factor for anti-PD-1-related pneumonitis (p = 0.0008). Conclusion Our results indicate that pre-existing pulmonary fibrosis significantly increases the risk of anti-PD-1-related pneumonitis. Further studies are needed to identify predictive factors of anti-PD-1-related pneumonitis in patients with fibrotic changes on CT findings.

BACKGROUND/AIM The aim of this study was to evaluate the safety and efficacy of osimertinib for elderly patients, since the data remain limited. PATIENTS AND METHODS A total of 77 patients with advanced non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation and treated with osimertinib were reviewed. Efficacy and safety indicators, such as EGFR-tyrosine kinase inhibitor (TKI)-related adverse events (AEs) and osimertinib-associated hematotoxicity, were evaluated in elderly patients (elderly group, EG; age, ≥75 years) by comparing them with younger patients (non-EG; aged

Background The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models. Methods In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated. Results Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2). Conclusion A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level. Clinical trial registration ID ClinicalTrials.gov number, NCT01095302.

This report presents an unusual case of life-threatening massive bleeding in the pulmonary trunk adjacent to the right ventricular outflow tract during resection of a large primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) in the absence of cardiovascular surgeons. The patient was a 21-year-old male whose large mediastinal tumor was diagnosed as an extragonadal PMNSGCT, which was a mixture of a yolk sac tumor and an immature teratoma. Generally, chemotherapy causes extensive peripheral tumor necrosis of PMNSGCTs, thus enabling their complete resection. In this case, surgeons considered the resection as possible by dissecting the peripheral necrotic tissue, and cardiovascular surgeons were thus not consulted. Enlarged modified left hemi-clamshell thoracotomy (HCST) was applied. While dissecting around the pulmonary trunk, the assistant-held forceps accidentally touched the tensed pulmonary trunk, which caused bleeding. We immediately contacted the collaborating cardiac surgery department at another hospital for assistance. Meanwhile, massive bleeding occurred, leading to hemorrhagic shock, and thus direct cardiac massage was required. Our team managed to establish a venoarterial (VA) extracorporeal membrane oxygenation (ECMO). After the arrival of cardiac surgeons, a suction circuit was added, and bleeding was stopped using sutures. Finally, complete resection of the tumor was achieved, and the patient awoke the following day without any brain dysfunction. After discussions with all the members involved in the surgery, we developed an in-hospital consensus on how to perform surgeries for large thoracic tumors safely at our cancer center without the cardiovascular surgery department. We herein present the case and consensus and discuss the relevant issues.

// Yuko Oya 1 , Tatsuya Yoshida 1 , Hiroaki Kuroda 2 , Masashi Mikubo 3 , Chiaki Kondo 1 , Junichi Shimizu 1 , Yoshitsugu Horio 1 , Yukinori Sakao 2 , Toyoaki Hida 1 and Yasushi Yatabe 3 1 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 2 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan 3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan Correspondence to: Tatsuya Yoshida, email: t.yoshida@aichi-cc.jp Keywords: nivolumab, non-small cell lung cancer, programmed cell death-1(PD-1), programmed cell death-ligand 1 (PD-L1) Received: June 27, 2017 Accepted: September 21, 2017 Published: October 07, 2017 ABSTRACT Background: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients. Results: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (≥ 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab. Materials and Methods: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated. Conclusions: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab.

Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP.

Purpose Anaplastic lymphoma kinase (ALK) rearrangement–positive non–small-cell lung cancers can be effectively treated with an ALK tyrosine kinase inhibitor (TKI) such as crizotinib, but the response magnitude and duration are heterogeneous. Several ALK variants have been identified, but few studies have focused on the effects of different ALK variants on the efficacy of crizotinib. Patients and Methods Among 55 patients treated with crizotinib as the initial ALK-TKI between January 2007 and December 2014, we identified 35 patients with tumor specimens that could be evaluated for ALK variants by reverse transcription polymerase chain reaction. We retrospectively evaluated the efficacy of crizotinib on the basis of the objective response rate and progression-free survival (PFS) according to the ALK variants. Results The most frequent ALK variant was variant 1 in 19 patients (54%), followed by variant 2 in five patients (14%), variant 3a/3b in four patients (12%), and other variants in seven patients (20%). Objective response rate was 69% in all patients, whereas it was 74% and 63% in the variant 1 and non–variant 1 groups, respectively. The median PFS time was significantly longer in patients with variant 1 than in those with non–variant 1 (median PFS, 11.0 months [95% CI, 6.5 to 43.0 months] v 4.2 months [95% CI, 1.6 to 10.2 months], respectively; P < .05). Multivariable analysis identified two significant factors associated with PFS duration, ALK variant 1 (hazard ratio, 0.350; 95% CI, 0.128 to 0.929; P < .05) and advanced stage (hazard ratio, 4.646; 95% CI, 1.381 to 21.750; P < .05). Conclusion Our results indicate the better efficacy of crizotinib in patients with ALK variant 1 versus non–variant 1. The ALK variant status might affect the efficacy of ALK-TKIs.

Aim To investigate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for patients receiving cisplatin (≥50 mg/m2), because this antiemetic therapy has not been sufficiently examined in patients receiving cisplatin. Methods We conducted a phase II study to evaluate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for chemotherapy naive patients receiving cisplatin (≥50 mg/m2). Patients received prophylactic dexamethasone (20 mg IV, day 1), palonosetron (0.75 mg IV, day 1), and olanzapine (10 mg, days 1–4). The patients were monitored for emesis and nausea for 120 h after chemotherapy. The primary endpoint was the complete response (CR) rate, which was defined as no vomiting episodes and no use of rescue medication for the overall period. CR rates of 65% and 45% would indicate the potential usefulness and the lower limit of interest, respectively. Results Fifty-one patients, including 37 esophageal cancer patients were enrolled, of whom 41 (80%) completed the treatment protocol as planned. The complete response rate for the overall period was 43% (95% confidence interval: 29–58); the primary endpoint was not met. Vomiting was frequently observed, with the overall rate of 51%. Most events occurred during 24–72 h after chemotherapy. Somnolence was observed in 73% of the patients, but it was well tolerated in most cases. Conclusions Olanzapine combined with palonosetron and dexamethasone did not prevent chemotherapy-induced nausea and vomiting induced by cisplatin as expected. The safety of this antiemetic therapy was confirmed.

Background Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor ( EGFR ) mutation on CRT efficacy. Methods From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. Results Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR -mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6–19.0] versus 16.5 [95% CI: 11.8–19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR -mutant and wild-type patients, respectively ( p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR -mutant patients (35%). However, locoregional recurrence was less common in EGFR -mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR -mutant and wild-type patients (51.1 [95% CI: 28.2–70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras -mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). Conclusion Concurrent CRT resulted in shorter progression-free survival in EGFR -mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR -mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed.

Anti-PD-1 therapy has been the standard treatment for advanced NSCLC patients. Some patients show durable response, while there are cases that show rapid progression after initiation of ICI treatment, which leads to early death. Therefore, we need a clear biomarker that identifies for early death after initiation of ICI treatment. We reported that CRP is a predictive marker for the efficacy of nivolumab for advanced NSCLC. Among pro-inflammatory cytokines, IL 6 and IL-1β are reported as a poor prognostic factor of cancer patients, and TNFα and INF-γ are reported to be one of the predictors of ICI efficacy.The aim of this study is to investigate the relationship between serum pro-inflammatory cytokines levels and the efficacy of ICI treatment and early death after ICI treatment. Methods: We retrospectively reviewed the predictive factors of efficacy and early death (death within 3 months after initiation of treatment) in anti-PD-1 monotherapy in all cohort (N=307). Based on the results in all cohort, we investigated the relationship of proinflammatory cytokines (IL-1β, IL6, IL10, INFγ) level in serum before pre-anti PD-1 therapy by Luminex® system and the clinical outcome of anti-PD-1 treatment in cytokine cohort (N=67). Patients with advanced or postoperative recurrence NSCLC who received 1≤ dose of ICI from December 2015 to September 2018 in our institute were included. Results: Among 307 patients, 45 patients (14.6%) died within 3 months after the initiation of anti-PD-1 therapy in all cohort. The median PFS of ICI treatment was 3.1months (95%CI: 2.5-4.1). EGFR or ALK mutation, poor PS (2≤), PD-L1 negative, high CRP(1.0 mg/dl≤) were identified as predictive factors for shorter PFS using Cox proportional model. Poor PS, high lung immune prognostic index (2≤), low albumin ( Conclusions:This analysis demonstrated that serum high IL6 level at baseline associated with the early death after initiation anti-PD-1 treatment and shorter PFS in advanced NSCLC. Citation Format: Yuko Oya, Tatsuya Yoshida, Teppei Yamaguchi, Hiroaki Kuroda, Junichi Shimizu, Yoshitsugu Horio, Hirokazu Matsushita, Toyoaki Hida. High serum interleukin 6 level associates with early death after initiation of treatment with PD-1 inhibitor in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5390.

9524 Background: At present, platinum-doublet chemotherapy or in combination with an immune check point inhibitor are standard treatment for patients with metastatic or recurrent NSCLC which lacks somatic gene alterations. Although CbP is one of the commonly used treatment options for NS-NSCLC, its clinical utility is limited due to lack of optimal biomarkers. Methods: Chemotherapy-naïve patients with pathologically proven advanced or recurrent NS-NSCLC received carboplatin (area under the curve = 5-6, at investigator’s discretion) plus pemetrexed (500 mg/m2) every 3 weeks followed by maintenance pemetrexed until disease progression. Blood samples were collected before treatment for proteomic analysis using mass spectrometry (MS). A classifier was constructed based on both an objective response assessed by radiologist independent of attending physicians in accordance with RECIST v1.1 and expression profiles of protein in a training cohort. The constructed classifier was then assessed with a validation cohort evaluating prediction accuracy of good responder, progression free survival (PFS) and overall survival (OS). Results: Of 244 patients with NS-NSCLC in a training cohort, proteomic profiles in blood from 96 patients who responded or progressed after treatment with CbP were analyzed to develop a classifier based on weighted voting. Details of the classifier will be presented at the 2020 ASCO Annual Meeting. The classifier was then applied to validation cohort (n = 94), and we successfully identified patients who benefit from the treatment (55 in good MS group) or not (39 in poor MS group). The objective response rate of the good MS group was significantly higher than that of the poor MS group (30.9% vs. 5.1%; p = 0.0018). The good MS group showed a significantly improved survival compared to the poor MS group (median PFS, 6.0 m vs. 2.3 m; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.09-0.27; p < 0.001; median OS, 25.7 m vs. 5.1 m; HR, 0.18; 95% CI, 0.1-0.34; p < 0.001). Conclusions: In the present study, we successfully developed and validated a predictive classifier using proteomic analyses with blood samples collected from patients before treatment with CbP, suggesting the clinical utility of the classifier in selecting NS-NSCLC patients for treatment with CbP. Clinical trial information: UMIN000008476 .

The aim of this study was to evaluate the safety and efficacy of osimertinib for elderly patients, since the data remain limited.A total of 77 patients with advanced non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation and treated with osimertinib were reviewed. Efficacy and safety indicators, such as EGFR-tyrosine kinase inhibitor (TKI)-related adverse events (AEs) and osimertinib-associated hematotoxicity, were evaluated in elderly patients (elderly group, EG; age, ≥75 years) by comparing them with younger patients (non-EG; aged75 years). The frequency of AEs associated with osimertinib was compared with the initial EGFR-TKI treatment before osimertinib administration in the same patient cohort.Of the total 77 patients, 18 (23%) were assigned to the EG, whereas 59 (77%) were assigned to the non-EG. There were no significant differences in overall response rate and progression-free survival between the two groups. Regarding the safety of osimertinib, the EG had significantly more grade ≥2 paronychia than the non-EG (16.6% vs. 1.6%, p=0.04). Additionally, the maximum grade of EGFR-TKI-related AEs associated with osimertinib in the EG was significantly lower than that of the initial EGFR-TKI treatment (p=0.03).Osimertinib is a safe and effective treatment option for elderly patients with advanced NSCLC who harbor the EGFR mutation.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.