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

Supplementary Table 1: Patient characteristics; Supplementary Table 2: Primers for amplifying MET gene; Supplementary Figure 1: PC-9/LMC-GR did not express HGF or possess MET mutations; Supplementary Figure 2: Acquired gefitinib resistance of HCC827/luc cells in LMC model was associated with MET copy number gain; Supplementary Figure 3: Subcutaneous tumors with PC-9/LMC-GR cells are sensitive to gefitinib treatment.

Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P < 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with the EGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). Although EGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related to MET copy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs. Mol Cancer Ther; 16(3); 506–15. ©2017 AACR.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738., This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.

Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB–IIIA NSCLC. Patients with completely resected p-stage IB–IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73–1.23; P = 0.69). Although GEM-based adjuvant therapy for patients with completely resected stage IB–IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.

This pilot study evaluated the pharmacokinetics and clinical outcome of nivolumab, administered every 4 weeks to patients with advanced non-small-cell lung cancer. The interval of nivolumab administration was changed from 2 to 4 weeks in four patients in whom tumor growth had been controlled for more than 6 months. Pharmacokinetics and clinical outcomes of nivolumab were prospectively investigated. The estimated steady-state nivolumab mean plasma concentration (±standard deviation) of each interval in the four patients was 53.1 (±15.0) at 4 weeks and 105.2 (±29.5) μg/mL at 2 weeks. No disease progression was observed in three patients for at least 1 year after the interval change; however, one patient developed interstitial lung disease within 5.6 months after the change. In conclusion, the pharmacological effects of nivolumab continued with doses administered less frequently than the standard schedule. Nevertheless, further research on nivolumab administration intervals is necessary.

Background/aim To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma. Patients and methods Six advanced lung adenocarcinoma patients with EGFR mutation were treated with osimertinib 80 mg/day plus ramucirumab 10 mg/kg, every two weeks. Defined dose-limiting toxicity (DLT) was assessed within the first two treatment cycles. Results Of those enrolled, five patients had both EGFR exon 20 T790M mutation and sensitizing mutation. DLT was observed in one patient (grade 3 appetite loss). During the entire period, no other severe adverse event was observed. Five patients showed partial response and one disease progression. Median progression-free survival for patients with EGFR T790M was 9.2 months. In an exploratory analysis, changes of cell-free DNA at 2 weeks predicted radiological tumor responses. Conclusion The safety results of osimertinib plus ramucirumab in Japanese lung adenocarcinoma patients with EGFR mutation will lead to further efficacy investigation.

Background Nivolumab is a programmed cell death 1 (PD‐1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non‐squamous (non‐SQ) non‐small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO‐4538‐05) and non‐SQ (ONO‐4538‐06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2‐42.1) and 22.4% (14.5‐32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long‐term safety and efficacy in patients with SQ and non‐SQ NSCLC by pooling data from these two trials. Methods SQ (N = 35) and non‐SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan–Meier method. A pooled analysis of SQ and non‐SQ patients was also performed. Results In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4‐25.2), and the estimated 1‐year, 2‐year, and 3‐year survival rates were 71.4% (53.4‐83.5), 37.1% (21.6‐52.7), and 20.0% (8.8‐34.4), respectively. In non‐SQ NSCLC patients, median OS was 17.1 months (13.3‐23.0), and the estimated 1‐, 2‐, and 3‐year survival rates were 68.0% (56.2‐77.3), 37.4% (26.5‐48.1), and 31.9% (21.7‐42.5), respectively. When SQ NSCLC and non‐SQ NSCLC data were pooled, the median OS was 17.1 months (14.2‐20.6), and the estimated 1‐, 2‐, and 3‐year survival rates were 69.1% (59.6‐76.8), 37.3% (28.3‐46.2), and 28.1% (20.0‐36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. Conclusion Treatment with nivolumab improved long‐term survival and was well tolerated in patients with SQ and non‐SQ NSCLC. Trial registration JapicCTI‐132072; JapicCTI‐132073.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

9111 Background: DFP-14323(INN: ubenimex) was developed as a biological response modifier and has been approved for maintenance therapy of AML in Japan. Ubenimex is an inhibitor of aminopeptidase N (APN), originated from Streptomyces olivoreticuli. APN is well known as one of the prognostic factors for several cancer types, including non-small-cell lung cancer (NSCLC). Meanwhile, afatinib is one of the standard treatments in NSCLC with EGFR mutation, but the toxicities often require dose reduction. Recently, it is suggested that reducing afatinib doses can decrease treatment-related adverse events without affecting efficacy. We aimed to examine efficacy of DFP-14323 with low-dose afatinib by conducting phase II study in patients with metastatic NSCLC harboring EGFR mutation. Methods: The study was a multi-center, single-arm, open-label phase II trial. Stage III/IV and treatment-naïve patients with common EGFR mutation-positive (L858R/19del) NSCLC were treated with DFP-14323 at a fixed dose of 10mg/day and afatinib at a starting dose of 20 mg/day until disease progression or intolerable toxicity. The primary endpoint was disease control rate (DCR), defined by sum the CR, PR and SD. The secondary endpoints were progression-free survival(PFS), overall response rate(ORR), N/L ratio, and safety. A sample size of 26 patients was determined, assuming a threshold DCR 70% and an expected DCR 90% with a two sided α error of 0.05 and a β error of 0.20, based on the Simon’s two stage design. Results: From July 2018 to March 2020, 26 patients were enrolled. A median age was 72 years (range, 53-82), 21(81%) were female, and 16 (62%) were never-smokers. Half of patients had Del-19 and other half had L858R. An efficacy analysis provided a DCR of 100% (previously reported) with 18 responders (ORR : 69%). Independent imaging evaluation at 72 weeks provided a median PFS was confirmed to be 16.6mts (95% CI 10.2, 22.9, median follow-up time for censored cases: 16.3mts). According to updated exploratory follow-up by physicians, as of the data cut-off of Dec 2021, median PFS was calculated 20.6 mts (95% CI, 12.6, 28.5, median follow-up time for censored case: 20.9mts). Seven Grade 3 adverse events were observed in 6patient(23%), and paronychias in 3 patients and diarrhea, stomatitis, dermatitis, and lymphocytopenia in 1 patient each. One paronychia was considered to be related to DFP-14323 and the other events to afatinib. No grade 4 or 5 adverse events were observed. One Grade 1 ILD was observed but recovered soon without treatment. Conclusions: Combination of DFP-14323 and low-dose afatinib has shown comparable potential as a first-line treatment for EGFR mutation positive NSCLC with feasible efficacy and good safety profile. We are planning a phase III study to evaluate this combination therapy as compared with other EGFR-TKIs. Clinical trial information: UMIN000033062.

Background Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1-mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring. Methods Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The ASGITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6→661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non-small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab. Results Nivolumab was selectively detected in human plasma and the linear range was 5-200 mcg/mL (R = 0.99). The accuracy and intraday and interday imprecision were within ±15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach. Conclusions An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.

Importance Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients withEGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. Objective To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma withEGFRT790M mutation. Design, Setting, and Participants Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquiredEGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. Interventions The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. Results From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08;P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months;P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months;P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). Conclusions and Relevance In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma withEGFR T790M mutation. Trial Registration UMIN Clinical Trials Registry Identifier:UMIN000023761

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

Background Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. Methods Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. Results A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4–25.2) months and 14.3% in squamous patients, 17.1 (13.3–23.0) months and 19.4% in non-squamous patients and 17.1 (14.2–20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of, This long-term follow-up demonstrated ongoing efficacy and safety of nivolumab over ≥5 years in patients with squamous or non-squamous non-small cell lung cancer in Japan.

An oesophageal fully covered self‐expanding metallic stent (SEMS) was placed in a 54‐year‐old Japanese man to relieve dysphagia owing to a stage cT1bN3M1c lung adenocarcinoma. High expression of programmed cell death‐ligand 1 was microscopically confirmed, and pembrolizumab was subsequently administered. Several days later, the patient was hospitalized with septic shock, and severe mediastinitis and pneumonia caused by oesophageal SEMS‐induced oesophageal and bronchial perforations were observed. Thoracoscopic surgery was performed to drain the mediastinal abscess, and an additional oesophageal SEMS was placed to close the oesophageal perforation. The patient gradually recovered from the potentially fatal infection, and the SEMS was retrieved after confirming perforation closure. We re‐initiated pembrolizumab administration, and the patient responded well. The present report reveals the potential risk and effectiveness of SEMS, especially when administered with immune checkpoint inhibitors., An oesophageal fully covered self‐expanding metallic stent was inserted in a patient with advanced lung adenocarcinoma. After administration of pembrolizumab, he was hospitalized with septic shock caused by oesophagobronchial perforations. Owing to a drainage surgery and insertion of additional stents, he was recovered and pembrolizumab administration was re‐initiated with complete resolution.

The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies.In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires.Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL.Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Background Immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic agents in non-small cell lung cancer (NSCLC). However, the duration for which ICIs should be continued remains a clinical problem. Methods We examined the efficacy of anti-PD-1/PD-L1 inhibitors after the discontinuation of antibodies due to adverse events (AEs) in patients with NSCLC. This was a multicenter retrospective study that analyzed NSCLC patients who were treated with PD-1/PD-L1 inhibitors by August 2016. Results The patients with NSCLC were 18 males and 1 female at a median 67 years of age (range: 49–80 years). Eighteen of 19 patients were treated with nivolumab, one was with atezolizumab. Approximately half of AEs were interstitial pneumonia. Fourteen patients (73.7%) were treated with steroid therapy. The median number of treatment cycles was 7 (range, 1–70), and the median duration of treatment was 2.8 months (range, 1 day-32.9 months). The overall response rate with confirmation during treatment was 21.1%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI] = 3.2–17.1 months) and 5.6 months (95% CI = 0–12.2 months) from the initiation and the discontinuation of PD-1/PD-L1 treatment, respectively. The median PFS after discontinuation according to the confirmed response during administration was not reached for partial response (PR) and 4.9 months (95% CI, 3.7–6.0) for stable disease (SD) patients (P = 0.02). Conclusion The PFS of the PR patients was completely different from that of the SD patients. The cases with PR prior to the onset of AE tended to show a durable response after the discontinuation of PD-1/PD-L1 inhibitors. Electronic supplementary material The online version of this article (10.1186/s12885-018-4819-2) contains supplementary material, which is available to authorized users.

Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial. However, various clinical trials have suggested that EGFR-TKI beyond PD plus single-agent chemotherapy may be a possible treatment strategy. Materials and Methods This study was a single-arm phase II trial. Patients with EGFR-activating mutations (del19 and L858R) that progressed using first-line gefitinib treatment were enrolled and treated with gefitinib beyond PD plus pemetrexed 500 mg/m2 q3w. The primary endpoint was progression-free survival (PFS). Mutation-biased polymerase chain reaction quenching probe, which is the original method for detecting T790M mutations in cell-free plasma DNA, was used prior to treatment. Results Thirty-six patients were enrolled between May 1, 2013, and March 31, 2016. One patient was excluded before starting the treatment. Among the 35 patients, 15 patients had del19 mutations, and 20 patients had L858R mutations; 33 patients were evaluable for response by using radiographic findings. The median PFS was 6.7 months (95% confidence interval: 4.4–7.7 months). Nineteen patients were T790M positive. No significant difference in PFS was found in a subgroup analysis of EGFR mutation status and T790M positivity. All toxicities were tolerable. Conclusion Gefitinib plus pemetrexed treatment following relapse using gefitinib in patients with Non-small cell lung cancer harboring EGFR mutations demonstrated preferable PFS with mild toxicity. This combination therapy may be considered for platinum-unfit patients without T790M with disease progression using first-line gefitinib. (This clinical trial was registered in UMIN-CTGR as UMIN000010709).

BACKGROUND Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer., Treatment of EGFR mutant non-small cell lung cancer (NSCLC) often develops resistance to EGFR TKIs. In this study, the authors discover a non-canonical activation of β-catenin signaling through Notch3 as a mechanism of adaptation to and resistance to EGFR TKI treatment in NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with EGFR mutant non-small-cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third-generation EGFR-TKI that can inhibit the kinase even when the common resistance-conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first-line EGFR-TKI treatment. AURA3 was a randomized (2:1), open-label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum-based therapy plus pemetrexed (500 mg/m2 ) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first-line EGFR-TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end-point was progression-free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum-pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13-0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum-pemetrexed groups, respectively. Grade ≥3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum-pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation-positive NSCLC whose disease has progressed following first-line EGFR-TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.).

Background Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. Method Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. Result Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin–irinotecan–leucovorin–5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin–irinotecan–leucovorin–5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. Conclusion CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.

Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for EGFR‑TKI sensitizing (EGFRm) and T790M resistance mutations. The primary objective of the cytology cohort in the AURA study was to investigate safety and efficacy of osimertinib in pretreated Japanese patients with EGFR T790M mutation‐positive non‐small cell lung cancer (NSCLC), with screening EGFR T790M mutation status determined from cytology samples. The cytology cohort was included in the Phase I dose expansion component of the AURA study. Patients were enrolled based on a positive result of T790M by using cytology samples, and received osimertinib 80 mg in tablet form once daily until disease progression or until clinical benefit was no longer observed at the discretion of the investigator. Primary endpoint for efficacy was objective response rate (ORR) by investigator assessment. Twenty‐eight Japanese patients were enrolled into the cytology cohort. At data cut‐off (February 1, 2016), 12 (43%) were on treatment. Investigator‐assessed ORR was 75% (95% confidence interval [CI] 55, 89) and median duration of response was 9.7 months (95% CI 3.8, not calculable [NC]). Median progression‐free survival was 8.3 months (95% CI 4.2, NC) and disease control rate was 96% (95% CI 82, 100). The most common all‐causality adverse events were paronychia (46%), dry skin (46%), diarrhea (36%) and rash (36%). Osimertinib provided clinical benefit with a manageable safety profile in patients with pretreated EGFR T790M mutation‐positive NSCLC whose screening EGFR T790M mutation‐positive status was determined from cytology samples. (ClinicalTrials.gov number NCT01802632).

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.

Objective: The aim of this study was to evaluate the effectiveness of a rash team management intervention designed by certified nurses, medical physicians, and certified pharmacists. The quality of life (QOL) of patients administered epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) was assessed using the dermatology life quality index (DLQI) and Skindex-29 QOL questionnaires. Methods: A total of 51 patients with nonsmall cell lung cancer who were treated using EGFR-TKIs were examined between November 1, 2014, and October 31, 2015, at the Institute of Biomedical Research and Innovation in Kobe city, Japan. All the patients were treated daily with erlotinib, gefitinib, or afatinib. The common terminology criteria for adverse events (version 4.0) system were used to grade treatment-induced toxicity events. The multimodality rash management team included nurses, pharmacists, and physicians. The team intervened before the initiation of treatment with EGFR-TKIs and at every visit. Patient QOL characteristics were evaluated using the DLQI and Skindex-29 assessment tools. Results: The number of patients with high-grade toxicity decreased when the multimodal approach was used. No grade 3 skin toxicities were recorded in the postintervention cohort. QOL scores for symptoms and feelings (emotions) were impaired in patients who were treated with EGFR-TKIs. Conclusions: The rash team management approach may be useful for patients treated with EGFR-TKIs. Specific QOL evaluation tools for the assessment of the effects of a team approach for rash management should be developed.

Purpose: The purpose of the study was to evaluate the site of paronychia in patients with non-small cell lung cancer harboring an epidermal growth factor receptor (EGFR) gene activating mutation who were treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Patients and Methods: The study included 55 patients with non-small-cell lung cancer who were treated with an EGFR TKIs. Resulting all toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0 system. Drug concentrations were determined with use of a quantum triple-quadrupole mass spectrometer and dried blood spots testing. Results: Paronychia most commonly occurred in the thumb and the big toe. There was no correlation between the severity of paronychia and the drug concentration of each EGFR TKI at the site of paronychia. The mean penetration rates of the drug from plasma to the tip of the finger and toe were 74.1% (erlotinib), 82.2% (gefitinib), and 99.9% (afatinib). Conclusions: High concentrations of an EGFR TKI at the affected site did not play a role in the onset mechanism of paronychia. Therefore, educating patients about ways to avoid compression may be a better approach to managing this adverse event than reducing the dose of the EGFR-TKI or stopping treatment.

BACKGROUND Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia. METHODS This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results. RESULTS The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and -0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively (P

// Akito Hata 1 , Nobuyuki Katakami 1 , Shigeki Nanjo 1 , Chiyuki Okuda 1 , Reiko Kaji 1 , Katsuhiro Masago 1 , Shiro Fujita 1 , Hiroshi Yoshida 2 , Kota Zama 2 , Yukihiro Imai 3 and Yukio Hirata 1 1 Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan 2 Department of Contract Research for Clinical Pathology, GeneticLab Co. Ltd., Sapporo, Japan 3 Department of Clinical Pathology, Kobe City Medical Center, General Hospital, Kobe, Japan Correspondence to: Akito Hata, email: a-hata@fbri.org Keywords: PD-L1; EGFR mutation; non-small cell lung cancer; PD-L1 IHC; PD-L1 antibody Received: April 12, 2017 Accepted: November 11, 2017 Published: December 01, 2017 ABSTRACT Background: Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR ) mutations, implying lower PD-L1 expression in EGFR -mutant NSCLC than in EGFR -wild type. Methods: We retrospectively analyzed correlation between PD-L1 expression and EGFR status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+. Results: We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in EGFR -mutant samples (n=65) was 3 (range, 0-150), whereas EGFR -wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in EGFR -mutant vs. EGFR -wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and EGFR mutation status (p=0.0490) as significant factors. Multivariate analysis identified EGFR mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients. Conclusions: PD-L1 expression was significantly lower in EGFR -mutant NSCLC samples than in EGFR wild-type samples. Its expression could be dynamic and affected by age of sample.

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids—common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.

Background Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician’s choice (TPC). Patients and methods Patients with advanced NSCLC who had received ≥2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate. Results Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95–1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90–1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side-effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%). Conclusion This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC. Trial registration ID www.ClinicalTrials.gov ; NCT01454934.

Purpose This randomized, double-blind, multicenter study aimed to determine the dose of naldemedine, a peripherally-acting μ-opioid receptor antagonist, for future trials by comparing the efficacy and safety of three doses of naldemedine versus placebo in patients with cancer and opioid-induced constipation. Methods Patients ≥ 18 years old with cancer, an Eastern Cooperative Oncology Group performance status ≤ 2, who had been receiving a stable regimen of opioid analgesics for ≥ 2 weeks, had at least one constipation symptom despite laxative use, and no more than five spontaneous bowel movements (SBMs) during the past 14 days, were randomly assigned (1:1:1:1) to oral, once-daily naldemedine 0.1, 0.2, or 0.4 mg, or placebo, for 14 days. The primary end point was change in SBM frequency per week from baseline during the treatment period. Secondary end points included SBM responder rates, change from baseline in the frequency of SBM without straining, and complete SBM. Safety was also assessed. Results Of 227 patients who were randomly assigned, 225 were assessed for efficacy (naldemedine 0.1 mg, n = 55; 0.2 mg, n = 58; 0.4 mg, n = 56; placebo, n = 56) and 226 for safety. Change in SBM frequency (primary end point) was higher with all naldemedine doses versus placebo ( P < .05 for all comparisons), as were SBM responder rates and change in complete SBM frequency. Change in SBM frequency without straining was significantly improved with naldemedine 0.2 and 0.4 (but not 0.1) mg versus placebo (at least P < .05). Treatment-emergent adverse events were more common with naldemedine (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than placebo (51.8%); the most common treatment-emergent adverse event was diarrhea. Conclusion Fourteen-day treatment with naldemedine significantly improved opioid-induced constipation in patients with cancer and was generally well tolerated. Naldemedine 0.2 mg was selected for phase III studies.

Errors in sequencing are a major obstacle in the interpretation of next-generation sequencing (NGS) results. In the present study, sequencing errors identified from analysis of single nucleotide variants (SNVs) identified during exome sequencing of human germline DNA were studied using the Thermo Fisher Ion Proton System. Two consanguineous cases were selected for sequencing using the AmpliSeq Exome capture kit, and SNVs found in both cases were validated using Sanger sequencing. A total of 98 SNVs detected by NGS were randomly selected for further analysis. Nine of the analyzed SNVs were shown to be false positives when confirmed by Sanger sequencing. All but one SNV were considered to be homopolymer regions, mainly through the insertion or deletion of nucleotides. The remaining error was considered to be related to the primer. The present results revealed that the majority of the SNV sequencing errors originated from homopolymer insertion/deletion errors, which are commonly observed when using the Ion Torrent system.

Aim The aim of this study was to evaluate whether irradiation induces the expression of tumor programed cell death ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC). Patients and methods Seventeen patients with NSCLC who received chemoradiotherapy and underwent tumor resection and six patients whose pre-treatment biopsy specimens were available, were analyzed by immunohistochemistry for PD-L1 expression between September 2011 and June 2016 at the Institute of Biomedical Research and Innovation Hospital. Results Among six patients for which pre-irradiation biopsy samples were available, the H-score for PD-L1 was reduced after irradiation following staining with two different antibody clones (SP28-8 and SP142). A PD-L1 H-score >5 with SP28-8 antibody (hazard ratio=6.46; 95% confidence interval=1.209-34.53; p=0.029) was a significant negative factor for duration of progression-free survival after curative operation or chemoradiation. Conclusion We showed that tumor PD-L1 expression decreased in patients with NSCLC who received chemoradiotherapy and radiation resistance might be due to pre-treatment PD-L1 expression.

Objectives Unresectable stage III NSCLC (non–small cell lung cancer) confers a poor prognosis and interest is growing in the use of immunotherapy to improve outcomes for patients with this disease. We investigated the safety and efficacy of maintenance tecemotide, a mucin 1 (MUC1)-specific agent that induces T-cell responses to MUC1, versus placebo in Japanese patients with stage III unresectable NSCLC and no disease progression after primary chemoradiotherapy. Materials and methods Patients aged ≥20 years with unresectable stage III NSCLC, stable disease or clinical response after primary chemoradiotherapy and performance status ≤1, were recruited across 25 centers in Japan. Patients were randomized 2:1 to tecemotide (930 μg as lipopeptide) or placebo subcutaneously once weekly for 8 weeks, then every 6 weeks until disease progression or treatment withdrawal. Cyclophosphamide 300 mg/m2 (maximum dose 600 mg) was given intravenously 3 days before the first dose of tecemotide. The primary endpoint was overall survival (OS). Secondary endpoints were progression–free survival, time to progression, time to treatment failure and safety. Results The intent–to–treat population comprised 172 patients; 114 received tecemotide and 58 placebo. Baseline characteristics were comparable between treatment arms. Most patients (94%) received primary concurrent chemoradiotherapy. There was no apparent trend toward increased OS time with tecemotide over placebo (median 32.4 versus 32.2 months, hazard ratio 0.95, 95% confidence interval 0.61–1.48; P = 0.83). No improvements in secondary efficacy endpoints were observed. The frequency of treatment–related adverse events was similar, and serious adverse event rates were the same in both arms. There were no new safety signals. Conclusions These results do not support those from a randomized phase III study (START) of improved OS with tecemotide in the subgroup of patients treated with primary concurrent chemoradiotherapy.

Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P < 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with the EGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). Although EGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related to MET copy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs. Mol Cancer Ther; 16(3); 506–15. ©2017 AACR.