The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.

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

Elements of End-of-Life Discussions Associated With Patients' Reported Outcomes and Actual End-of-Life Care in Patients With Pretreated Lung Cancer.

BACKGROUND: End-of-life discussions for patients with advanced cancer are internationally recommended to ensure consistency of end-of-life care with patients' values. This study examined the elements of end-of-life discussions associated with end-of-life care. MATERIALS AND METHODS: We performed a prospective observational study among consecutive patients with pretreated non-small cell lung cancer after the failure of first-line chemotherapy. We asked oncologists whether they had ever discussed "prognosis," "do not attempt resuscitation," "hospice," and "preferred place of death" with a patient at baseline. The quality of life (QOL) and depressive symptoms of patients were assessed using validated questionnaires at baseline and 3 months later. The end-of-life care that patients received was investigated using medical records. Oncologists' compassion and caregivers' preferences for hospice care were also assessed using questionnaires. Multiple regression analyses were conducted to examine the association between elements of end-of-life discussions and patient-reported outcomes as well as actual end-of-life care. RESULTS: We obtained 200 valid responses at baseline, 147 valid responses 3 months later, and 145 data points for medical care at the end-of-life stage. No element of the end-of-life discussion between the patient and their oncologist was significantly associated with patients' reported outcomes or actual end-of-life care. In addition, oncologists' compassion was significantly associated with improvement in both comprehensive QOL and depressive symptoms, and caregivers' preferences for hospice care and high educational level were significantly associated with hospice death. CONCLUSION: Oncologist-patient alliances and caregivers' involvement in end-of-life discussions may be influential in achieving optimal end-of-life care.

Unrealistic expectations and disclosure of incurability in patients with non-small cell lung cancer.

PURPOSE: Determining whether patients' unrealistic expectations of chemotherapy as a cure were associated with their perception of the disclosure of incurability. METHODS: This prospective study included consecutive patients with pretreated non-small cell lung cancer from four study sites. Patients and their oncologists were asked whether they perceived the disclosure of cancer incurability. Patients were also asked if they thought that chemotherapy was curative. We followed up on whether the deceased patients received specialized palliative care 14 months after their last enrollment. Multiple regression analyses were conducted to examine the association between the expectation of chemotherapy as a cure and patient/oncologist-reported perceptions of the disclosure of incurability. RESULTS: We analyzed 200 patients, 77 (38.5%) of whom had unrealistic expectations of a cure. Based on patients' perceptions, incurability was disclosed to 138 (69.0%) patients, and based on their oncologists' perceptions, incurability was disclosed to 185 (92.5%) patients (patient/oncologist agreements, κ = 0.19). Patients without a perception of the oncologist's disclosure of incurability-regardless of their oncologist's perception-were more likely to have unrealistic expectations of a cure than patients for whom both patient and oncologist perceptions were present. Patients who had unrealistic expectations of chemotherapy as a cure were shown to be significantly less likely to have received specialized palliative care, after adjusting for covariates (adjusted OR, 0.45; 95% CI, 0.23-0.91; p = .027). CONCLUSION: Oncologists' disclosure of incurability was not fully recognized by patients, and expectations of chemotherapy as a cure were associated with patients' perception of the disclosure of incurability.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.

Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma.

The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10-2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment.

Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma.

INTRODUCTION: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC). METHODS: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs) and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFß, and TNFα (n = 3). RESULTS: Patients with high P-AMs had significantly shorter overall survival (OS) (p < 0.01); however, patients with high D-AMs did not have significantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a significantly shorter OS (p < 0.01). In multivariate analysis, a higher number of P-AMs were an independent poor prognostic factor (p = 0.02). Ex vivo BALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2-, 3.0-, and 10.0-fold; CCL-2: 3.0-, 3.1-, and 3.2-fold). Moreover, the addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. CONCLUSION: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of the peritumoral tumor microenvironment in lung SqCC progression.

Prognostic Awareness and Discussions of Incurability in Patients with Pretreated Non-Small Cell Lung Cancer and Caregivers: A Prospective Cohort Study.

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

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

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 greater 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). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 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 patients (52%) and four 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 greater. The trial is registered with ClinicalTrials.gov: NCT02142738.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

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.

Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101).

LESSONS LEARNED: This phase II trial evaluated the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. The 17 cerebrospinal fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation. The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%-54.3%). The median time to progression was 2.2 months. The rate of cerebrospinal fluid penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis. BACKGROUND: Leptomeningeal metastases (LM) occur in approximately 5% of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting. METHODS: Patients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%). RESULTS: Between December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 cerebrospinal fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%-54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean cerebrospinal fluid penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and cerebrospinal fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome. CONCLUSION: Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM.

Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA.

Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.

The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Pneumonectomy after induction chemoradiotherapy for locally advanced non-small cell lung cancer: should curative intent pulmonary resection be avoided?

PURPOSE: We conducted a retrospective analysis to assess the practicality of pneumonectomy, especially after concurrent induction chemoradiotherapy (i-CRT), for locally advanced non-small cell lung cancer (LA-NSCLC). The operative risks vs. the survival benefit of this procedure for such patients is a subject of controversy. METHODS: The subjects of this retrospective study were 71 consecutive LA-NSCLC patients with cStage IIIA-C NSCLC, who underwent i-CRT followed by curative intent pulmonary resection between February, 2001 and March, 2013. RESULTS: Thirty-two patients underwent pneumonectomy (group P) and 39 patients underwent lobectomy (group L). In group P, 17 (54.8%) patients underwent right pneumonectomy. There was no 30-day postoperative mortality in either group and no significant difference in 90-day postoperative mortality between the groups (3.1% vs. 2.6% in groups P and L, respectively). The 5-year overall survival (OS) rate was 58.7% (95% CI: 41.5-75.9%) in group P and 57.3% (95% CI 41.2-73.4%) in group L, without a significant difference between the groups. CONCLUSION: Our findings suggest that i-CRT followed by pneumonectomy is feasible, with a similar survival benefit to lobectomy. Thus, pneumonectomy after i-CRT should not be avoided as it is a potentially curative intent strategy for carefully selected patients.

Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing.

Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance-conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non-small-cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M-including copy number gain of NRAS or MET-were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression-free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR-TKI treatment.

Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer.

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors.

Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

Post-recurrence survival of elderly patients 75 years of age or older with surgically resected non-small cell lung cancer.

PURPOSE: The purpose of this study was to evaluate the outcomes of elderly patients 75 years of age or older with recurrent non-small cell lung cancer (NSCLC). METHODS: A total of 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence. The rate of the post-recurrence survival and predictors were analyzed independently in a group of younger patients (<75 years) and a group of elderly patients (≥75 years). RESULTS: There were 215 younger patients (<75 years) and 65 elderly (≥75 years) patients at the time of diagnosis of recurrence. The median post-recurrence survival time and the five-year survival rate of all cases were 25 months and 20.8%, respectively. There were no significant survival differences between the younger and elderly groups (p = 0.20). A univariate analysis determined that gender, Eastern Cooperative Oncology Group performance status, smoking status, histological type and epithelial growth factor receptor (EGFR) mutation status were factors influencing the post-recurrence survival among the elderly patients. In addition, a multivariate analysis determined the EGFR mutation status to be an independent prognostic factor for the post-recurrence survival. CONCLUSIONS: Elderly patients 75 years of age or older in this study achieved satisfactory long-term outcomes.

The Role of Radiotherapy in the Treatment of Small-Cell Lung Cancer.

OPINION STATEMENT: The standard therapy for limited disease small cell lung cancer (LD-SCLC) is concurrent chemoradiotherapy and prophylactic cranial irradiation (PCI) for those who achieve complete remission (CR) or good partial response (PR) with initial therapy. On the other hand, the standard therapy for extensive disease (ED-SCLC) is chemotherapy only. After the two phase III study conducted by Slotman et al., PCI with/without thoracic radiotherapy (TRT) is also recommended in the treatment of ED-SCLC. However, a Japanese phase III study failed to confirm the benefit of PCI for patients with ED-SCLC. All studies have demonstrated the effectiveness of PCI for preventing brain metastasis, but PCI seems to have a limited influence on OS. In the 2014 edition of the Guidelines for the Treatment of Lung Cancer from the Japan Lung Cancer Society (JLCS), use of PCI for patients with ED-SCLC has been changed from "recommended" to "not recommended". Appropriate selection of patients for PCI with/without TRT is very important. It is hoped that the characteristics of patients for whom PCI with/without TRT should be considered or avoided will be better defined in the future.

Mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance.

PURPOSE: This study retrospectively assessed the mutations of the epidermal growth factor receptor (EGFR) and K-ras genes and their clinical significance in patients with resected stage I adenocarcinomas. METHODS: A total of 354 patients with resected lung adenocarcinomas were included, and 256 patients with stage I disease were analyzed for the prognostic and predictive value of these mutations. RESULTS: Mutations of EGFR and K-ras genes were detected in 149 (41.1 %) and 23 (6.4 %) of all tumors, and in 122 (47.6 %) and 14 (5.5 %) of stage I tumors, respectively. There were no significant differences in the disease-free survival (DFS) and overall survival (OS) between the EGFR-mutant and wild-type groups. However, the DFS and OS were significantly shorter in patients with K-ras mutations than in those without (5-year DFS: 50.8 vs. 76.9 %, 5-year OS: 70.0 vs. 86.6 %, p < 0.01). A multivariate analysis showed that K-ras mutations were an independent poor prognostic factor. Twenty-four of the 41 patients with recurrent disease after surgery were treated with an EGFR-TKI. Fifteen EGFR-mutant patients treated with an EGFR-TKI had a better prognosis than did the nine EGFR-wild-type patients. CONCLUSION: The presence of an EGFR gene mutation was a predictive factor for the response to EGFR-TKI treatment in patients with resected stage I adenocarcinoma, but was not a prognostic factor. The presence of a K-ras gene mutation was a poor prognostic factor.