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The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m 2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m 2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC., (© 2023 Merck Sharp & Dohme LLC and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted., (© 2023. The Author(s).)

Background: The usefulness of comprehensive genomic profiling (CGP) panels for thoracic malignancies after completion of the standard treatment is unclear., Methods: The results of CGP panels for malignant thoracic diseases performed at our hospital between December 2019 and June 2022 were collected. We examined whether CGP panel results led to new treatment, correlated with the effectiveness of immune checkpoint inhibitors (ICIs), or revealed secondary findings related to hereditary tumors., Results: A total of 60 patients were enrolled, of which 52 (86.6%) had lung cancer. In six (10%) patients, the panel results led to treatment with insurance-listed molecular-targeted agents; four patients had EGFR mutations not detected by the real-time polymerase chain reaction assay and two had MET ex.14 skipping mutations. In small-cell lung cancer, the tumor mutation burden was high in 4/6 (66.7%) patients and pembrolizumab was available. Another MET ex.14 skipping mutation was detected in two cases with EGFR-tyrosine kinase inhibitor resistance. ICI efficacy was ≤1 year in patients with STK-11, KEAP1, and NEF2L2 mutations. A BRCA2 mutation with a high probability of germline mutation was detected in one patient. A thymic carcinoma with no detectable oncogenic mutation responded to second-line treatment with Tegafur-Gimeracil-Oteracil Potassium (TS-1) for ≥9 years., Conclusions: CGP panels are useful in thoracic malignancies, especially lung cancer, because they can detect overlooked driver mutations and genetic alterations. We believe that the significance of conducting a CGP panel prior to treatment may also exist, as it may lead to the prediction of ICI treatment efficacy., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) is a complementary and alternative test to tissue-based NGS. We performed NGS analysis of ctDNA samples collected from patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received osimertinib; the samples were collected after second-line treatment, before osimertinib treatment, one week and one month after osimertinib treatment, and at the time of resistance formation. We examinedthe correlation with osimertinib efficacy. From January to December 2018, 34 patients with EGFR-mutated NSCLC harboring EGFR T790M mutations were enrolled, and a total of 132 peripheral blood samples were collected. The fragment sizes of EGFR-mutated ctDNAs were significantly shorter than that of their corresponding normal fragments. Osimertinib treatment of patients with shorter EGFR-mutated ctDNA fragments resulted in shorter progression-free survival (PFS). The disappearance time of EGFR-mutated fragment fractions and clonal evolution patterns (new driver mutation group, additional mutation group vs. attenuation group) were each associated with the PFS achieved with osimertinib treatment; however,multivariate analysis revealed that only shorter EGFR-mutated ctDNA fragments were associated with the PFS resulting from osimertinib treatment. EGFR-mutated ctDNA fragment size, time of disappearance of these fragments, and clonal evolution pattern were related to the effects of osimertinib. In particular, short EGFR-mutated ctDNA fragmentation may be closely related to osimertinib efficacy prediction., (© 2022. The Author(s).)

Abstract: Virtual automatic bronchoscopic navigation (VBN) systems to determine the route to peripheral pulmonary lesions (PPLs) in lung cancer can improve diagnostic biopsy yields. However, compared with VBN, drawing manual routes using computed tomography images, especially with oblique methods, can identify more routes. The Ziostation2 VBN system combines the benefits of these 2 methods; we evaluated this performance by comparing 3 different route-determining methods.We retrospectively collected data from 50 patients with PPLs measuring <30 mm who underwent transbronchial biopsy with an ultrathin bronchoscope at the Osaka International Cancer Institute during January to December 2018. We compared automatic VBN (Ziostation2), manual route modification using an oblique method after automatic VBN, and manual navigation using a general application computed tomography viewer. Concordance between predicted and actual branching were determined. We also compared the predicted relationship between the terminal bronchi and the lesion by 2 of the methods with ultrasonographic images (radial-probe endobronchial ultrasonography [radial-EBUS]).Manual modification after automatic VBN significantly increased the rate of determining routes to the target (66%) versus with the automatic VBN alone (32%) (P < .001). Expected route bifurcations were exact matches with actual branching in 45/48 of the patients using manual modification after automatic VBN. The predicted relationship between the terminal bronchi and the lesion using manual modification after VBN matched the radial-EBUS images in 35/50 of the patients.Manual modification of routes to PPLs using an oblique method after automatic VBN predicted actual radial-EBUS route imaging and could help determine appropriate patients for bronchoscopy., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The EGFR-A763&#95;Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763&#95;Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763&#95;Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763&#95;Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763&#95;Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation., (Copyright © 2021. Published by Elsevier Inc.)

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m 2 , day1, 8) every 3 weeks followed by Bev (15 mg/kg, day1) plus nab-PTX (100 mg/m 2 , day1, 8) every 3 weeks without disease progression or unacceptable severe toxicities. The primary endpoint was objective response rate (ORR). Results The study enrollment was ceased because of suspension of the registration period (as scheduled) after 12 of 20 planned patients were treated successfully between March 2014 and February 2018. The ORR was 58.3 % (95 % CI, 27.7-84.8 %), and the disease control rate was 100 % (95 % CI, 73.5-100 %). Eight patients received maintenance therapy. Median progression-free and overall survival times were 14.4 and 26.9 months, respectively. Most patients experienced hematological toxicities, including ≥ grade 3 neutropenia and anemia; none experienced severe bleeding events and grade 5 toxicities. Conclusion The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-naïve non-SQ NSCLC patients with MPE.Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.

Introduction: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib., Methods: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration., Results: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022)., Conclusions: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard treatment for advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations, such as exon 19 deletion or L858 point mutation. However, the effectiveness of EGFR-TKIs for patients with uncommon EGFR mutations remains unclear., Methods: We retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at five participating institutions. Data from NSCLC patients with uncommon mutations (including single or compound mutations), who were treated with systemic therapy between May 2016 and October 2018, were collected and analyzed., Results: A total of 23 of the 524 patients whose data were collected had uncommon EGFR mutations. Of these, 22 received EGFR-TKIs (gefitinib = 6, erlotinib = 4, and afatinib = 12). Patients who received first EGFR-TKIs had overall response and disease control rates of 59.1% and 81.8%, respectively. The median progression-free survival (PFS) of patients with G719X mutation (n = 13, median PFS = 32.9 months) was favorable, compared with those of patients with L861Q mutation (n = 4, median PFS = 6.4 months) and compound mutations (n = 4, median PFS = 7.3 months). The PFS of patients who received first- and second-generation EGFR-TKIs was 14.0 months (n = 10) and 7.3 months (n = 12), respectively. The median cumulative duration of treatment (DOT) with EGFR-TKIs was 30.4 months, which was longer than those of cytotoxic chemotherapy (median DOT = 10.7 months) or immune checkpoint inhibitors (median DOT = 6.6 months)., Conclusions: EGFR-TKIs elicit favorable responses and contribute to long-term disease control in NSCLC patients with uncommon EGFR mutations., Key Points: Significant findings of the study: Our results demonstrate that both first- and second-generation EGFR-TKIs elicit favorable responses in NSCLC patients with uncommon EGFR mutations. What this study adds This study revealed all clinical courses for NSCLC patients with uncommon EGFR mutations. In addition to EGFR-TKIs, CCT and ICIs were found to contribute to long-term disease control in this cohort., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background/aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients., Patients and Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC., Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group., Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR-mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment., Materials and Methods: We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site., Results: MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation., Conclusion: MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms., Patients and Methods: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS., Results: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab., Conclusion: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introductions: When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin-fixed paraffin-embedded (FFPE) tumor samples., Patients and Methods: Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole-exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR-TKI., Results: A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy-seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR-TKI-resistant mutation (EGFR p.T790M) during the course of treatment., Conclusion: Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR -mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry).

Background: The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Chemotherapy-naïve patients with advanced NSCLC were eligible. In the phase I dose-escalation cohort (3 + 3 design), patients received nab-paclitaxel (80 or 100 mg/m 2 given intravenously on days 1, 8 and 15) plus cisplatin (60 or 75 mg/m 2 given intravenously on day 1) every 4 weeks. The maximum tolerated dose was not reached. Nab-paclitaxel (100 mg/m 2 given intravenously on days 1, 8 and 15) plus cisplatin (75 mg/m 2 given intravenously on day 1) every 4 weeks was selected for the phase II cohort. The primary endpoint was the objective response rate (ORR)., Results: Twenty-three patients (phase I, n = 6; phase II, n = 17) were enrolled, and 22 patients were eligible. The median age was 67.5 years (range 37-75), 90.9% were males, 45.5% had adenocarcinoma and 81.8% had stage IV disease. The ORR was 59.1% (90% confidence interval (CI); 41.8-74.4), and the disease control rate was 86.4% (95% CI; 66.7-95.3). The median progression-free survival was 5.1 months (95% CI; 4.0-6.7), and the median overall survival was 24.2 months (95% CI; 8.4 months to not estimable). The common grade ≥ 3 adverse events were neutropenia (31.8%), leukopenia (27.3%), lung infection (18.2%) and hyponatremia (18.2%). There was one instance of grade 2 interstitial pneumonia and no treatment-related death., Conclusions: Nab-paclitaxel plus cisplatin was well tolerated and associated with encouraging response outcomes in chemotherapy-naïve patients with advanced NSCLC. Further investigation is warranted., Trial Registration: UMIN Clinical Trials Registry: UMIN000011776; Date of registration: 17 September 2013; Date of enrolment of the first participant to the trial: 23 January 2014.

Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient., Materials and Methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples., Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model., Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose concerning the study., (Copyright © 2019. Published by Elsevier Inc.)

Background: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported., Methods: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point., Results: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group., Conclusions: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: 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., Methods: 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., Findings: 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; p<0·0001). 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., Interpretation: 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., Funding: Eli Lilly., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

Purpose: To assess the utility of the cobas EGFR Mutation Test, with tissue and plasma, for first-line osimertinib therapy for patients with EGFR -mutated ( EGFR m; Ex19del and/or L858R) advanced or metastatic non-small cell lung cancer (NSCLC) from the FLAURA study (NCT02296125)., Experimental Design: Tumor tissue EGFR m status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFR m status was retrospectively determined with the central cobas plasma test., Results: Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFR m positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74-84] and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFR m-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFR m-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months)., Conclusions: Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFR m advanced NSCLC for first-line osimertinib treatment. Lack of EGFR m detection in plasma was associated with prolonged PFS versus patients plasma EGFR m positive, potentially due to patients having lower tumor burden., (©2019 American Association for Cancer Research.)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group)., Materials and Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions., Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195)., Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m 2 , the standard dosage in Japan., Patients and Methods: Patients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety., Results: Patient characteristics in the Japanese subgroup (n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group., Conclusions: This Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.

Introduction: The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638., Materials and Methods: Chemotherapy-naïve patients aged ≥ 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted., Results: 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8-12.4); median OS was 15.6 months (95% CI 15.6-not evaluable); ORR was 68.9% (95% CI 55.7-80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8-95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes., Conclusion: The results presented are inconclusive due to the early termination of the study., (Copyright © 2018. Published by Elsevier Ltd.)

Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care., Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study., Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient)., Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised., Clinical Trial Registration: NCT02296125 (ClinicalTrials.gov).

Introduction: Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI-sensitizing mutations., Methods: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety., Results: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively., Conclusion: In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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/m 2 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)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To identify clinical benefits of dose escalation in accelerated hyperfractionated radiotherapy (AH-RT) for stage III non-small-cell lung cancer (NSCLC) using propensity score-matched (PSM) analysis., Materials and Methods: Our study retrospectively examined 294 patients undergoing definitive radiotherapy [131 patients, conventional once-daily radiotherapy (OD-RT); and 163, AH-RT] who were followed-up for a median of 40.4 months. The impact of overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) was investigated., Results: Pre-PSM, the median OS, PFS, and LRC durations were 23.1 vs. 39.9 (p=0.03), 8.9 vs. 13.5 (p<0.01), and 12.9 vs. 50.3 (p<0.01) months in the OD-RT and AH-RT groups, respectively. After-PSM (two matched groups of 144 patients), AH-RT was associated with better LRC [adjusted hazard ratio (aHR)=0.59, 95% confidence interval (CI)=0.33-0.99, p=0.04] and marginally better PFS (aHR=0.65, 95% CI=0.41-1.03; p=0.06), but not OS (aHR=0.75, 95% CI=0.46-1.24; p=0.26)., Conclusion: After PSM analysis, dose escalation using AH-RT improved LRC and PFS in patients with locally advanced NSCLC. AH-RT can be a promising option for patients with advanced NSCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Recent studies have revealed that liver metastasis is associated with poor outcomes after treatment using immune checkpoint inhibitors, although the cause remains unclear., Patients and Methods: We retrospectively identified 201 patients at three Japanese Centers who received nivolumab for advanced non-small cell lung cancer between December 2015 and July 2016. The patients' baseline clinical characteristics and subsequent outcomes were compared according to liver metastasis status., Results: Liver metastasis was associated with inferior progression-free survival (PFS) and a lower response rate. Additionally, liver metastasis was significantly associated with younger age, poorer Eastern Cooperative Oncology Group performance status (ECOG PS), and more metastatic sites. Multivariate analyses revealed that poor PFS was independently associated with poor baseline ECOG PS (p=0.039) and high number of metastatic sites (p=0.007), although liver metastasis (p=0.2) was not., Conclusion: Baseline clinical characteristics were a strong predictor of outcome in nivolumab-treated patients with liver metastasis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Compared to conventional cytotoxic chemotherapy, immune checkpoint inhibitors have shown a significant efficacy in the treatment of lung cancer. Although interstitial lung disease (ILD) is an important adverse event in immunotherapy, risk factors for ILD remain unclear., Patients and Methods: In this multicenter cohort study (UMIN000025908), 201 patients who were treated with nivolumab were retrospectively reviewed. Associations between the incidence of ILD and patient characteristics were evaluated. ILD grade and progression-free survival were analyzed according to the presence or absence of imaging findings of airway obstruction adjacent to lung tumors (IAOT)., Results: In the multivariate analysis, the odds ratio (OR) of ILD for patients with a history of radiation pneumonitis or IAOT was 3.96 (p=0.012) and 6.59 (p=0.004), respectively. ILD occurred in six (37.5%) out of 16 patients with IAOT and 19 (10.3%) out of 185 patients without IAOT. Three out of the six patients with ILD and IAOT had ILD of grade 4 or more. The median progression-free survival of patients with and without IAOT was 0.9 and 3.2 months, respectively (p<0.001)., Conclusion: IAOT was strongly associated with the occurrence of ILD after therapy with nivolumab., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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/m 2 ) 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.)., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Rationale: Acute thrombosis has not been reported in the literature so far in lung cancer patients as an immune-related adverse event (irAE) associated with PD-1 pathway inhibitors., Patients Concerns: Here, we for the first time present two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin infusion improved their symptoms and enabled them to continue pembrolizumab administration., Methods: Ethical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patients., Diagnosis: Serum D-dimer level testing, venous ultrasonography, enhanced computed tomography (CT)., Interventions: Continuous heparin infusion, direct oral anticoagulants (DOAC)., Outcomes: Immediate continuous heparin infusion improved their symptoms and continuing pembrolizumab with direct oral anticoagulant successfully induced tumor shrinkage., Lessons: Reinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal.

Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study., Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days)., Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient., Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC., Clinicaltrials.gov Identifier: NCT01828112.

Objectives: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting., Materials and Methods: Clinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived >5 years from initiation of first-line treatment., Results: The full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months; 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs., Conclusions: This large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting., Patients and Methods: The medical records of patients with NSCLC who started receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese institutes were collected. Early death was defined as any death within 3 months from the start of nivolumab treatment, irrespective of its cause. Treatment response was evaluated using the Response Evaluation Criteria In Solid Tumors criteria, version 1.1., Results: A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab-induced immune-related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score ≥ 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95% CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03-4.14; P = .041) were independent predictors for early death., Conclusion: Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment C-reactive protein-to-albumin ratio > 0.3, and poor response to prior treatment were associated with early death., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To conduct a retrospective multicenter trial to determine the significance of metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer., Methods: This study was conducted across three medical centers in Japan. We retrospectively reviewed all patients who commenced nivolumab treatment at these centers between December 17, 2015 and July 31, 2016. Clinical data were collected, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status, and metastatic site (lymph nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant pleural effusion) at the time of commencing nivolumab treatment. Patients were followed-up until March 31, 2017., Results: Two hundred and one patients were enrolled. The median age at the time of commencing nivolumab treatment was 68 (range, 27-87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had a performance status of 0-1, and 42 patients had squamous cell carcinoma. The median progression-free survival of all patients was 2.5 months. In the univariate analysis, a performance status of ≥2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33-2.69; p < 0.001) and liver (HR: 2.09, 95.0% CI: 1.35-3.25; p < 0.001) and lung (HR: 1.57, 95.0% CI: 1.14-2.16; p < 0.01) metastases correlated with a significantly shorter progression-free survival in nivolumab-treated patients. In the multivariate analysis, a performance status of ≥2 (HR: 1.54, 95.0% CI: 1.05-2.25; p < 0.05) and liver (HR: 1.90, 95.0% CI: 1.21-2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI: 1.00-1.99; p < 0.05) metastases were independently correlated with a significantly shorter progression-free survival in nivolumab-treated patients., Conclusion: Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.

Background: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC)., Methods: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival., Results: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%)., Conclusions: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil-to-lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44-5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment., Patients and Methods: In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand., Results: Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated patients tended to show better objective response rates with nivolumab (27% vs. 13%, p=0.06); the objective response rate to nivolumab was significantly higher in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%, p=0.02)., Conclusion: Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab., Competing Interests: Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. S. Isa, Dr. K. Nakahama, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. T. Inoue, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report grants from Ono Pharmaceutical and Bristol-Myers Squibb. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Ono Pharmaceutical. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Bristol-Myers Squibb during the conduct of the study. Dr. Y. Taniguchi reports personal fees from Chugai Pharmaceutical outside the submitted work. Dr. A. Tamiya reports personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work. Dr. K. Okishio reports personal fees from Ono Pharmaceutical outside the submitted work. Dr. T. Shiroyama reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, and AstraZeneca outside the submitted work. Dr. H. Suzuki reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, and Eli-Lilly outside the submitted work. Dr. M. Tamiya reports personal fees from Chugai Pharmaceutical, Pfizer, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Asahi Kasei Pharmaceutical, Daichi Sankyo CO. LTD. Alere Medical and Boehringer Ingelheim outside the submitted work. Dr. K. Nishino reports personal fees from Chyugai, Boehringer Ingelheim, Eli Lilly, and AstraZeneca outside the submitted work. Dr. T. Kumagai reports personal fees from Ono Pharmaceutical, Astra Zeneca, and Boehringer Ingelheim outside the submitted work. Dr. T. Hirashima reports grants and personal fees from MSD Oncology, Lilly Japan, AstraZeneca, Chugai Pharma, and Boehringer Ingelheim, grants from Eisai, Daiichi Sankyo, Merck Serono, Taiho Pharmaceutical, Kyowa Hakko Kirin, and Takeda, and personal fees from Bayer outside the submitted work. Dr. F. Imamura reports personal fees from Pfizer Inc., AstraZeneca K.K., Novartis Pharma K.K., Kyowa Hakko Kirin Co. Ltd., Boehringer Ingelheim GmbH, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd. outside the submitted work. Dr. S. Atagi reports grants from Pfizer, Chugai Pharmaceutical, AstraZeneca, MSD, Taiho Pharmaceutical, Yakult Pharmaceutical Industry, Eli Lilly, and Boehringer Ingelheim, and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Nivolumab has shown promising effects in patients with non-small-cell lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to identify patients who would not experience any benefit from nivolumab treatment., Materials and Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement. We investigated the relationship between progression-free survival (PFS) and patient characteristics., Results: In both univariate and multivariate analysis, performance status (PS) score ≥2, steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were significantly associated with poor PFS (all p<0.05)., Conclusion: PS score ≥2, steroid use at baseline and a high LDH level were predictive of poor PFS in patients with NSCLC treated with nivolumab. Careful monitoring is recommended for treating such patients with nivolumab (UMIN-ID: UMIN000025908)., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Nivolumab has a promising efficacy for patients with non-small-cell lung cancer (NSCLC) as second-line or later treatment, and after radiotherapy as abscopal effect. However, the effects of radiation pneumonitis history before nivolumab have not been clarified. Therefore, we retrospectively analyzed the correlation of a history of radiation pneumonitis before nivolumab with onset of interstitial lung disease (ILD) and progression-free survival (PFS) after nivolumab treatment in patients with previously treated NSCLC., Patients and Methods: A total of 201 patients treated with nivolumab were retrospectively reviewed. We collected clinical data of patients at the time of starting nivolumab and we evaluated ILD incidence and PFS in relation to patient characteristics, including radiation pneumonitis history., Results: The median age was 68 years; 135 patients were men, 157 had a smoking history, and 153 had performance status of 0 or 1. Thirty-four patients experienced radiation pneumonitis before nivolumab, and 50 patients received radiotherapy to the chest (31 patients received curative radiotherapy). The overall median PFS was 2.8 months and the overall ILD rate was 12.4%. Higher ILD incidence was observed in the group with a history of radiation pneumonitis (26.5%) compared to the group without radiation pneumonitis (9.6%). The median PFS was 3.6 and 2.3 months, respectively. On multivariate analysis, a history of radiation pneumonitis was also significantly correlated with good PFS (p=0.023)., Conclusion: Although increasing the risk of ILD, a history of radiation pneumonitis before nivolumab also contributes to the prolongation of PFS after nivolumab., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib., Methods: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316)., Findings: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group., Interpretation: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study., Funding: Chugai Pharmaceutical Co, Ltd., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained. Dormant lung cancer cells were found to be resistant to EGFR tyrosine kinase inhibitor (TKI) treatment. In terms of mechanism, we found that a negative regulator of ERBB signaling, MIG6/ERRFI1/RALT/Gene33, was induced by hypoxia both in vitro and in vivo. MIG6 expression prevented heterodimer formation of ERBB family RTKs, and suppressed their downstream signaling. Knockdown of MIG6 enhanced tumor cell growth under hypoxic conditions, and promoted the phosphorylation of ERK and AKT via increased EGFR-HER3 binding. Critically, sensitivity to an EGFR-TKI, as well as to irradiation under hypoxic conditions, was increased in MIG6 knockdown cells. The expression of MIG6 was partly correlated with a pS6 negative zone in patient tumors. Analyses of tumor sections from 68 patients with activating EGFR mutations showed that patients with high MIG6 expression showed significantly shorter survival after EGFR-TKI treatment than other groups. Collectively, our data suggest that dormant cancer cells with a high MIG6 expression level might be one of the causes of EGFR-TKI resistance in EGFR mutant lung cancer cells.

A 62-year-old Japanese female with primary lung adenocarcinoma received seven cycles of nivolumab as an eighth line of chemotherapy until she presented with hemoptysis. After transcatheter arterial embolization therapy, she received subsequent chemotherapy with paclitaxel and S-1. Four weeks later, a chest computed tomography examination revealed infiltrative shadows mainly in the right lung field, in addition to enlargement of the lung metastasis in the right middle lung lobe. Bronchofiberscopic examination revealed infiltration of lymphocytes without any malignant cells in the right segment 1 of the lung, which suggested interstitial lung disease. Corticosteroid therapy not only improved the infiltrative shadows but also reduced the lung metastasis. Even after the infiltrative shadows improved, the lung metastasis reduced further. This phenomenon resembles manifestation of pseudoprogression during treatments with immune checkpoint inhibitors, such as nivolumab., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC)., Methods: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group)., Results: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients., Conclusions: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

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 (930μg as lipopeptide) or placebo subcutaneously once weekly for 8 weeks, then every 6 weeks until disease progression or treatment withdrawal. Cyclophosphamide 300mg/m 2 (maximum dose 600mg) was given intravenously 3days 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., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Early evaluation of the effect of treatment is helpful in the management of cancer patients. Circulating biomarkers are an ideal tool for this if they are highly specific to tumors and respond rapidly to tumor volume changes. Circulating tumor DNA (ctDNA) is one such candidate. We conducted a prospective study to test the utility of EGFR ctDNA in early evaluation of EGFR-TKI effects., Results: Twenty-one patients with EGFR-mutant lung cancer who were naïve to EGFR-TKI were enrolled. PM scores of EGFR ctDNA with activating mutations decreased rapidly in response to EGFR-TKI. Of the 14 patients with positive pretreatment PM scores, complete disappearance of major EGFR ctDNA was observed in 14.3%, 42.9%, and 57.1% on days 2 - 4, 8, and 15, respectively. These responses of EGFR ctDNA were most prominent among the measures used to evaluate responses, and correlated with early radiologic responses evaluated by chest X-rays., Materials and Methods: EGFR ctDNA in serial plasma samples was amplified and 105 copies were sequenced with a next-generation sequencer. Plasma mutation (PM) score was defined as the number of reads containing deletions/substitutions in 105EGFR cell free DNA (cfDNA). When EGFR mutation in ctDNA was the same as that detected in cancer tissue, the ctDNA was defined as major EGFR ctDNA., Conclusions: The results indicate the usefulness of ctDNA as a highly specific biomarker for prediction of early response to treatment and that it can be applied to various types of cancer.