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Importance Few clinical trials have been specifically designed for elderly patients with advanced non–small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit. Objective To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC. Design, Setting, and Participants This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy–naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019. Interventions Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks. Main Outcomes and Measures The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model. Results Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056;Pfor noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed. Conclusion and Relevance Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC. Trial Registration University Hospital Medical Information Network Clinical Trials Registry Identifier:UMIN000011460

Background and objective: Patients with non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are usually excluded from most clinical trials because of acute exacerbation (AE) of ILD. Data on the efficacy and feasibility of chemotherapy are limited. Recently, the ILD-GAP index (total point score obtained from ILD subtype, sex, age, FVC, DLCO; range 0–8) was reported as a prognostic factor in patients with ILD. Therefore, we evaluated the incidence of ILD-AE during the clinical course of the disease and the overall survival (OS) in patients with NSCLC and ILD using a modified ILD-GAP index (total point score obtained from ILD subtype, sex, age, FVC; range 0–5). Materials and methods: Between September 2002 and December 2014, we performed a retrospective analysis of 78 patients with NSCLC and ILD treated platinum-based chemotherapy as first-line treatment. Among these patients, we compared the incidence of ILD-AE and OS between the modified ILD-GAP index. Results: Among these patients, 21 (27%; 95%CI 18–38) had ILD-AE during the clinical course of the disease. The median OS was 11.3 months. The incidence of ILD-AE increased gradually and the median OS decreased gradually with increasing the modified ILD-GAP index as shown figure A and B, respectively. Conclusion: The modified ILD-GAP index may be a useful tool to predict of the incidence of ILD-AE and its prognosis for patients with NSCLC and ILD.

PurposeManagement of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging regarding the control of severe headache, nausea, and vomiting due to intracranial hypertension. To investigate the improvements of performance status and outcome with cerebrospinal fluid (CSF) shunt surgery for LM-H in patients with lung adenocarcinoma.MethodsData on patients with leptomeningeal metastasis-related hydrocephalus from lung adenocarcinoma diagnosed by MR imaging and/or cytological examination were retrospectively analyzed. Between August 2008 and July 2017, the authors reviewed 31 patients requiring CSF shunt, who underwent ventriculo-peritoneal or lumbo-peritoneal shunt.ResultsThe patients consisted of 11 men and 20 women with a median age of 59 years. Twenty-six patients received EGFR-tyrosine kinase inhibitors (TKIs). CSF shunt surgery yielded rapid improvement in the performance status of 90.3% of patients. Median overall survival from the diagnosis of LM in patients with ECOG performance status less than 2 was 7.7 months, and this was significantly longer than those in patients with PS 3 or 4 (4.4 or 1.5 months; pConclusionCSF shunting may be a safe and effective strategy in patients with LM-H from lung adenocarcinoma. A prospective study is needed to establish the effectiveness and safety of palliative CSF shunt for LM-H.

TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common

The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.

Locally advanced non-small-cell lung cancer (NSCLC) is curable. Standard treatment is concurrent chemoradiotherapy, but its efficacy with cytotoxic agents seems to reach a plateau. Among patients with advanced NSCLC who have epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitor is the key drug. Thus, a similar strategy should be tested in patients with locally advanced NSCLC who have EGFR mutation. This single arm, phase II study aims to explore the efficacy and tolerability of gefitinib with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. The primary endpoint is progression-free survival rate at 2 years. The secondary endpoints are overall response rate, progression-free survival, overall survival, and safety. A total of 27 patients will be enrolled in this trial.

Background and objective Patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are commonly excluded from most clinical trials because of acute exacerbation (AE) of ILD triggered by chemotherapy. Data on the efficacy and feasibility of chemotherapy are limited in this patient population. Recently, the ILD-GAP index and staging system was reported as a clinical prognostic factor associated with mortality in patients with ILD. Therefore, we evaluated the incidence of ILD-AE during the surveillance term in this study and the prognosis in patients with NSCLC and ILD using a modified ILD-GAP (ILD-NSCLC-GAP) index scoring system. Materials and methods The medical records of patients with NSCLC and ILD who underwent a pulmonary function test before initiation of platinum-based chemotherapy as first-line treatment at the Shizuoka Cancer Center between September 2002 and December 2014 were reviewed retrospectively. Among these patients, we compared the incidence of ILD-AE, one-year survival rate, and overall survival (OS) between the ILD-NSCLC-GAP index scores and stages. Results Of the 78 patients included, 21 (27%; 95% confidence interval [CI], 18%–38%) had ILD-AE during the surveillance term in this study. The one-year survival and median OS rates were 49% and 11.3 months, respectively. The incidence of ILD-AE increased gradually and the one-year survival and median OS rates decreased gradually with increasing ILD-NSCLC-GAP index scores and stages. Conclusion The ILD-NSCLC-GAP index scoring and staging system may be a useful tool to calculate a prediction of the incidence of ILD-AE and its prognosis for patients with NSCLC and ILD.

Introduction: Data on the efficacy and risk of curative-intent chemoradiotherapy in patients with inoperable stage III non-small-cell lung cancer (NSCLC) and interstitial lung disease (ILD) are limited. The aim of this study was to explore the impact of ILD classification on acute exacerbation (AE) of ILD and prognosis in patients with stage III NSCLC and ILD treated with chemoradiotherapy. Materials and methods: We retrospectively reviewed the medical records of patients with stage III NSCLC and ILD treated with curative-intent chemoradiotherapy as the first-line treatment at the Shizuoka Cancer Center between June 2009 and May 2014. Results: Of 37 patients, 17 (46%) developed AE of ILD worse than grade 3 within 1 year after the last irradiation. In univariate analysis, the incidence rate of AE of ILD was lower in patients with a non-usual interstitial pneumonia (UIP) pattern than in those with a UIP pattern. Multivariate analysis showed that ILD classification was significantly associated with the incidence of AE of ILD. The median overall survival (OS) durations in patients with a non-UIP pattern and a UIP pattern were 16.5 and 9.3 months, respectively. In univariate analysis, patients with a non-UIP pattern showed better survival. Multivariate analysis showed that ILD classification was a significant independent prognostic factor. Conclusion: The incidence of AE of ILD was high in patients with stage III NSCLC and ILD treated with chemoradiotherapy as the first-line treatment. However, diagnosis of a non-UIP pattern could predict lower risk of AE of ILD and longer OS durations.

Background Thymic carcinoma is a rare malignant disease. Standard treatments have not been established for patients with advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy. Several trials reported the efficacy of multi-targeted inhibitors mainly targeting vascular endothelial growth factor receptor (VEGFR) for thymic carcinoma. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, fibroblast growth factor receptor (FGFR), RET, c-Kit etc.; it has shown anti-tumor activity with manageable toxicity profiles in several cancer types. We investigated the efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma (JMA-IIA00285). Methods An open-label, single-arm, multi-center phase II trial was conducted in patients with histologically confirmed thymic carcinoma. The eligibility criteria were disease progression after at least one prior platinum-based chemotherapy, ECOG-PS of 0 or 1, measurable lesions, and adequate organ functions. Patients received 24 mg of lenvatinib orally once daily until progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR) by independent radiological review. As per the SWOG two-stage design, the sample size of 40 had 80% power with one-sided alpha error of 5%; threshold ORR, 10%; and expected ORR, 25%. Results Between May 2017, and Feb 2018, 42 patients were enrolled from 8 institutions in Japan. The median follow-up period was 15.5 months (IQR 13.1-17.5). The 42 assessable patients had ORR of 38.1% (90%CI, 25.6-52.0), indicating statistically significant improvement in ORR. Of them, 16 had partial response, and 24 achieved stable disease. The most treatment-related adverse events of any grade were hypertension, diarrhea, and hand-foot syndrome, proteinuria, hypothyroidism, and decreased platelet count. Conclusions The efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These encouraging results suggest that lenvatinib could become one of the standard treatment options in patients with advanced or metastatic thymic carcinoma. Clinical trial identification JMA-IIA00285. Legal entity responsible for the study The authors. Funding Center for Clinical trials, Japan Medical Association and Eisai. Disclosure M. Satouchi: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Ignyta. J. Sato: Speaker Bureau / Expert testimony: AstraZeneca K.K.. Y. Okuma: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Pharmaceutical Company Ltd; Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Nippon Boehringer Ingelheim Co.; Speaker Bureau / Expert testimony: Bristol‐Myers Squibb Japan; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical.. S. Niho: Research grant / Funding (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. H. Mizugaki: Speaker Bureau / Expert testimony, Research grant / Funding (self): Boehringer Ingelheim; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Chugai Pharmaceutical. H. Murakami: Honoraria (self): AstraZeneca; Honoraria (self): Chugai pharma; Honoraria (self): Lilly Japan; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim. T. Kozuki: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical ; Honoraria (self), Research grant / Funding (self): Eli-Lilly; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical ; Honoraria (self): Ono Pharmaceutica; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): Beohringer-Ingelheim; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self): Pfizer; Research grant / Funding (self): Merck Biopharma. K. Nakamura: Speaker Bureau / Expert testimony: Eisai. A. Kuchiba: Speaker Bureau / Expert testimony: Chugai. N. Yamamoto: Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai; Advisory / Consultancy, Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa-Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Advisory / Consultancy: Otsuka; Advisory / Consultancy: Cimic. All other authors have declared no conflicts of interest.

Background Recent studies showed that EGFR-mutant Non-small cell lung cancer (NSCLC) was less likely to express PD-L1 than EGFR wild type NSCLC, and pembrolizumab demonstrated poor response in TKI naive patients (pts) with EGFR-Mutant NSCLC, even among those with 22C3-PD-L1 tumor proportion score (TPS) of 50% or higher. Methods We retrospectively evaluated 155 consecutive Japanese pts with EGFR-Mutant NSCLC whose tumors were tested for 22C3-PD-L1 TPS and EGFR mutations at the Shizuoka Cancer Center between February 2016 and November 2018. Results Of the 155 NSCLC, all had EGFR mutations: common mutations including exon 19 deletion (52%) and exon 21 L858R point mutation (35%), and uncommon mutations (13%). 22C3-PD-L1 TPS of 50% or higher was seen in 15% of all EGFR-Mutant NSCLC, 13% of common EGFR-Mutant NSCLC (CM), and 33% of uncommon EGFR-Mutant NSCLC (UC). UC was significantly associated with 22C3-PD-L1 expression, with an adjusted odds ratio of 3.2 (95% confidence Interval [CI], 1.1 to 9.0). Among 70 pts with 22C3-PD-L1 TPS of 1% or higher tumors, 14 pts were evaluable for the efficacy of pembrolizumab treatment. Of these 14 pts, only two pts with UC were TKI naive. Objective response was observed in 36% (95% CI, 16 to 61) of all 14 pts, 22% (95% CI, 6 to 55) of nine pts with CM, and 60% (95% CI, 23 to 88) of five pts with UC. Of nine pts with 22C3-PD-L1 TPS of 50% or higher tumors, five pts including two TKI naive pts had an objective response (56%; 95% CI, 27 to 81), while none of five pts with 22C3-PD-L1 TPS 1 to 49% tumors had an objective response. Conclusions PD-L1 Expression was significantly associated with subtype of EGFR mutation in Japanese pts with EGFR-Mutant NSCLC. 22C3-PD-L1 TPS of 50% or higher may be a predictive marker of pembrolizumab treatment for EGFR-Mutant NSCLC.

Background. The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients. Patients and methods. We retrospectively analyzed 71 LD-SCLC patients with performance status (PS) 0-2 who received first-line chemoradiotherapy and had disease recurrence between September 2002 and March 2013 at Shizuoka Cancer Center (Shizuoka, Japan). We determined the correlation between PFS and OS and between PPS and OS at the individual level. In addition, we performed univariate and multivariate analyses to identify significant prognostic factors of PPS. Results. OS is more strongly correlated with PPS (Spearman’s r = 0.86, R 2 = 0.72, p < 0.05) than PFS (Spearman’s r = 0.46, R 2 = 0.38, p < 0.05). In addition, the response to second-line treatments, the presence of distant metastases at recurrence and the number of additional regimens after first-line chemoradiotherapy were significant independent prognostic factors for PPS. Conclusions. PPS has more impact on OS than PFS in recurrent LD-SCLC patients with good PS at beginning of the treatment. Moreover, treatments administered after first-line chemoradiotherapy may affect their OS. However, larger multicenter studies are needed to validate these findings.

MEDI-575 is a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor alpha (PDGFRα). This open-label Phase I study assessed the safety and tolerability of MEDI-575 in Japanese patients with advanced solid tumors. The study comprised two parts: Part A, dose escalation; Part B, dose expansion in patients with hepatocellular cancer. In Part A, patients were enrolled into three cohorts: MEDI-575 was administered intravenously over a 21-day treatment cycle at doses of 9 and 15 mg/kg/week (cohorts 1, 2) and 35 mg/kg/3-weekly (cohort 3). In Part B, MEDI-575 25 mg/kg/3-weekly was administered. Secondary measures included assessment of the maximum tolerated dose, pharmacokinetics, immunogenicity and anti-tumor activity. Ten and 12 patients were treated in Parts A and B, respectively. There were no dose-limiting toxicities; the maximum tolerated dose was not determined. Common treatment-related adverse events were fatigue (30 %) and decreased appetite (20 %) in Part A and decreased appetite (33.3 %) in Part B. All treatment-related adverse events were grade 1 or 2 in severity. No patients discontinued MEDI-575 because of an adverse event and there were no patient deaths due to adverse events. MEDI-575 binding with PDGFRα resulted in a dose-dependent increase in PDGF-AA ligand, with plateau levels observed within 2 days and sustained during the dosing interval. None of the patients in Part A or B experienced complete or partial responses to treatment. MEDI-575 once weekly and 3-weekly was well tolerated with a favorable pharmacokinetic profile in Japanese patients with advanced solid tumors. ClinicalTrials.gov, NCT01102400.

Introduction: Anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies. Methods: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single-dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model. Results: Twenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response. Conclusions: Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing.

Objectives Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients and methods This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0–1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. Results Twenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0 (22.0–133.0) days for the EGFR wild-type group (n = 9) and 107.0 (74.0–224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. Conclusion Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed.

The prognosis of non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is unclear. To assess the prognosis of NSCLC patients with ILD treated with platinum-based chemotherapy, we retrospectively analyzed the clinical course of those with ILD.One hundred and four NSCLC patients with ILD treated with platinum-based chemotherapy at Shizuoka Cancer Center between August 2002 and June 2013 were retrospectively reviewed.The combination of carboplatin with paclitaxel was most frequently used as the first-line treatment for NSCLC patients with ILD (61 %). The overall response rate was 38 % in 104 NSCLC patients with ILD treated with platinum-based chemotherapy. In all patients, median progression-free survival and overall survival were 4.8 and 9.9 months, respectively. During first-line platinum-based chemotherapy, 9 % of the 104 patients with ILD developed chemotherapy-related exacerbation of ILD. Multivariate analysis demonstrated that clinical stage was a significantly independent prognostic factor (hazard ratio 0.517; 95 % confidence interval 0.314-0.842, p = 0.0079). Patients with clinical stage IV or recurrence after surgical resection showed poor prognosis (median survival time 8.5 months).Our study suggests that the prognosis of NSCLC patients with ILD is poor. The risk of exacerbation of ILD in patients treated with platinum-based chemotherapy as the first-line treatment was slightly lower than in previous reports.

Objective The American Society of Clinical Oncology published the goals of individualized care including advance care planning for advanced cancer patients in 2011. However, no data are available on the implementation status of advance care planning. Methods We retrospectively reviewed the electronic medical records and informed consent forms of consecutive Stage IV non-small cell lung cancer patients treated with chemotherapy between January 2010 and December 2012 at our institution. Two outcomes were defined to investigate the advance care planning implementation status: C-D, the duration from the last day of chemotherapy to death and D-D, that from the day of confirmed do-not-attempt-resuscitation order to death. Results The study included 136 eligible patients. The advance care planning implementation status in participating patients was as follows: 96 (70%) patients received information on 'incurable disease before first-line chemotherapy', 69 (50%) were informed about 'supportive care before first-line chemotherapy', whereas 43 (32%) learned about their prognosis. The do-not-attempt-resuscitation decision was reflected in 29 patients' will (21%). The median C-D was 64 days. Receipt of ≤2 chemotherapy regimens and provision of prognosis information to patients were significantly associated with long C-D in multivariate analysis. The median D-D was 25 days. Provision of information on supportive care before first-line chemotherapy and provision of prognosis information to patients were significantly associated with long D-D in multivariate analysis. Conclusions Our results suggest that there is possible benefit from providing information on supportive care before first-line chemotherapy and informing patients about their prognosis in prolonging the duration of supportive care.

Background S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC. Patients and methods Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40–60 mg) and leucovorin (25 mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety. Results Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths. Conclusions S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC.

Background Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of hospital stay, and inpatient medical costs among elderly patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy. Methods Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to receive first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. ADL was assessed using the Barthel index. The disability-free survival time (DFS) was calculated as the time between the date of study entry and the date of onset of a disabling event, which was defined as a 10-point decrease in the Barthel index from that at baseline. The mean cumulative function of the length of hospital stay and inpatient medical costs (¥, Japanese yen) was calculated. Results The study patients comprised 11 women and 19 men, with a median age of 74 (range, 70–82) years. Cachexia was diagnosed in 19 (63%) patients. Cachectic patients had a shorter DFS (7.5 vs. 17.1 months, p

// Nobuaki Mamesaya 1 , Kazushige Wakuda 1 , Katsuhiro Omae 2 , Eriko Miyawaki 1 , Mie Kotake 1 , Takumi Fujiwara 1 , Takahisa Kawamura 1 , Haruki Kobayashi 1 , Kazuhisa Nakashima 1 , Shota Omori 1 , Akira Ono 1 , Hirotsugu Kenmotsu 1 , Tateaki Naito 1 , Haruyasu Murakami 1 , Keita Mori 2 , Hideyuki Harada 3 , Masahiro Endo 4 , Takashi Nakajima 5 and Toshiaki Takahashi 1 1 Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan 2 Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan 3 Division of Radiation Therapy, Shizuoka Cancer Center, Shizuoka, Japan 4 Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan 5 Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan Correspondence to: Kazushige Wakuda, email: k.wakuda@scchr.jp Keywords: small-cell lung cancer; limited disease; prophylactic cranial irradiation; brain metastases Received: November 21, 2017 Accepted: March 02, 2018 Published: April 03, 2018 ABSTRACT Background: Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI. Results: Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years–8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years–NR) in the non-PCI group ( p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404). Conclusions: Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy. Patients and Methods: We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan–Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics.

Elderly patient with advanced cancer is one of the most vulnerable populations. Skeletal muscle depletion during chemotherapy may have substantial impact on their physical function. However, there is little information about a direct relationship between quantity of muscle and physical function. We sought to explore the quantitative association between skeletal muscle depletion, and muscle strength and walking capacity in elderly patients with advanced non–small cell lung cancer (NSCLC). Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to initiate first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. Lumbar skeletal muscle index (LSMI, cm2/m2), incremental shuttle walking distance (ISWD, m), and hand-grip strength (HGS, kg) were assessed at baseline, and 6 ± 2 weeks (T2) and 12 ± 4 weeks (T3) after study enrollment. Associations were analyzed using linear regression. Altogether, 11 women and 19 men with a median age of 74 (range, 70–82) years were included in the study; 24 received cytotoxic chemotherapy and 6, gefitinib. Mean ± standard deviation of LSMI, ISWD and HGS were 41.2 ± 7.8 cm2/m2, 326.0 ± 127.9 m, and 29.3 ± 8.5 kg, respectively. LSMI and ISWD significantly declined from baseline to T2 and T3. HGS significantly declined from baseline to T2 and T3 only in men. Change in LSMI was significantly associated with change in HGS (β = 0.3 ± 0.1, p = 0.0127) and ISWD (β = 8.8 ± 2.4, p = 0.0005). Skeletal muscle depletion accompanied with physical functional decline started in the early phase of the chemotherapy in elderly patients with advanced NSCLC. Our results suggest that there may be a need for early supportive care in these patients to prevent functional decline during chemotherapy. Trial registration number: UMIN000009768 Name of registry: UMIN (University hospital Medical Information Network). URL of registry: Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.

This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naive Japanese patients treated systemically with etoposide plus platinum for lung cancer. The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated. Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia. These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

Background: The effect of second-line chemotherapy in patients with non-small cell lung cancer (NSCLC) who received first-line chemotherapy at the age of ≥ 75 years is unclear. Methods: Sixty-five elderly patients with NSCLC who received first-line chemotherapy at the age of ≥ 75 years and treated with second-line chemotherapy at Shizuoka Cancer Center between January 2005 and December 2014 were retrospectively reviewed. Results: The overall response rate of the second-line chemotherapy was 9.2% [95% confidence interval (CI) 4-19]. The median progression-free survival at the second-line chemotherapy was 2.2 months. The median overall survival at the second-line chemotherapy was 7.5 months. Multivariate analysis of prognostic factors showed that an Eastern Cooperative Oncology Group performance-status score (PS 0–1/PS 2; HR, 0.396; 95% CI, 0.192–0.899; p=0.03) and histology (squamous/non-squamous; HR, 0.465; 95% CI, 0.228–0.884; p=0.02) were significantly independent prognostic factors. On the other hand, the number of treatment-related deaths was 2 (3.1%) due to pneumonitis. Moreover, the proportion of patients who received third-line chemotherapy was only 35.9%. Conclusion: Our study suggests that elderly patients have difficulty moving on to the next line of chemotherapy; however, selected elderly patients well tolerated the adverse effects of second-line chemotherapy, and second-line chemotherapy might be effective for elderly patients with NSCLC who received first-line chemotherapy at the age of ≥ 75 years. Therefore, prospective study should be planned in order to demonstrate the efficacy of second-line chemotherapy for elderly patients with NSCLC.

Cancer cachexia (CC) is commonly seen in advanced lung cancer patients and associated with poor prognosis. However, little is known about CC that develops during chemotherapy. We evaluated the prognostic impact of CC and skeletal muscle wasting that develops during the course of chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. The clinical data of 134 newly diagnosed NSCLC patients were retrospectively reviewed. CC was defined as a body weight loss >5 or >2 % in patients with a body mass index of

It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR).We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation.A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival.PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

Background Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood. Patients and methods Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR , KRAS , BRAF , PIK3CA , NRAS , MEK1 , AKT1 , PTEN , and HER2 and amplifications in EGFR , MET , PIK3CA , FGFR1 , and FGFR2 . In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes. Results Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc. ) by deep sequencing. Conclusions Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.

The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m(2) ) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5-3.5 months) for the DZ group and 2.6 months (95% CI, 1.5-3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0-15.8 months) for the DZ group and 9.7 months (95% CI, 6.1-12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).

BACKGROUND Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype. METHODS Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes (EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions. RESULTS Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients. CONCLUSIONS This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer. Cancer 2014;120:1471–1481. © 2014 American Cancer Society.

ObjectivesWe conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC).Patients and methodsPatients with chemotherapy-refractory SCLC received 40mg/m2 AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.ResultsBetween November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1–22 cycles). ORR was 32.9% [P

Among patients with locally advanced lung adenocarcinoma, the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations was unknown. In addition, it has not been fully evaluated about the role of these mutations treated with concurrent chemoradiotherapy (CCR).The clinical records of locally advanced lung adenocarcinoma patients treated with CCR at Shizuoka Cancer Center between September 2002 and December 2009 were reviewed.Forty-four patients were eligible for this study. EGFR mutation was detected in 13 (29.5%) of 44 patients, and KRAS mutation was detected in 2 (6.5%) of 31 patients. Among EGFR mutation status known patients, overall response rate, median progression-free survival (PFS), and median survival time were 52.3%, 11.5 months, and 35.8 months, respectively. Overall response rate was significantly higher in EGFR mutant group than in EGFR wild-type group (76.9% vs. 41.9%, P=0.02), but this difference did not translate into a significant PFS benefit (9.6 vs. 13.2 mo, P=0.78). Locoregional relapse occured less frequently in patients with EGFR mutation than those with EGFR wild-type, but not significant (15.4% vs. 32.3%, P=0.46). Brain was the most frequent metastatic site of relapse in EGFR mutant group.Among locally advanced lung adenocarcinoma, EGFR mutation was detected in 29.5% and KRAS mutation was detected in 6.5%. We were not able to detect a difference in PFS or overall survival between EGFR mutant and wild-type patients treated with conventional CCR. Locoregional relapse was approximately half in the EGFR mutant group compared with the EGFR wild-type group; however, this finding did not reach statistical significance.

Background S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non-small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. Methods We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. Results A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0–17%) for Sq NSCLC and 11% (95% CI 3–19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. Conclusion S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC.

Purpose To determine ombrabulin’s maximum tolerated dose and dose recommended for Japanese patients with advanced solid tumors and to assess its antitumor activity and overall safety and pharmacokinetic profiles. Methods This was a multi-center, open-label, sequential-cohort, dose-escalation phase I study of ombrabulin, a vascular disrupting agent, administered once every 3 weeks. Patients were treated with 15.5, 25, 35, or 50 mg/m2 ombrabulin over a 30-min intravenous infusion. The recommended dose was the highest dose at which

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). Performance status at the beginning of second-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS (P < 0.05). Analysis of individual-level data suggested that PPS could be used as a surrogate for OS in patients with advanced non-squamous NSCLC with unknown oncogenic driver mutations and therefore limited options for subsequent chemotherapy. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. These results should be validated in other larger populations.

Introduction Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Methods Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. Results All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). Conclusions This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.

Background c-Met is a receptor tyrosine kinase overexpressed in 30-50% of solid tumors. c-Met protein overexpression have been associated with poor clinical outcomes in many cancers. T (teliso-v, ABBV-399) is a first-in-class c-Met specific antibody drug conjugate that is cytotoxic to cancer cells with overexpressed c Met and demonstrates antitumor activity in human tumor xenografts. This Ph 1 study evaluates safety, PK and preliminary efficacy of T in Japanese patients (pts) with advanced solid tumors. Methods In this non-randomized, dose-escalation Ph 1 study (NCT03311477) in Japanese pts, 3 pts were treated with 2.4 mg/kg every 3 weeks (Q3W) and 6 pts with 2.7 mg/kg Q3W. Serial blood samples were collected in Cycle 1 and 3 for PK assessments. IHC of c-Met status was retrospectively evaluated. Results As of Nov 2018, 9 pts were enrolled. 8 pts experienced adverse events (AEs). The most frequent treatment-emergent AEs (any grade) were neuropathy (44%), decreased appetite (33%) and nausea (33%). 5 pts (56%) had dose interruption due to an AE. Grade 3/4 AEs including decreased neutrophil count in 2 pts (22%). There were no dose limiting toxicities and 2.7 mg/kg Q3W was tolerable. 2 pts (ovarian and urothelial carcinoma) had confirmed partial responses, both of which are ongoing. c-Met expression levels from archived specimens from these 2 pts were not high (H-Score:35 and 10, respectively). Median progression free survival was 7 (95% CI; 1, not calculated) months. The maximum observed serum concentration (Cmax) of T was 55.5-63.0 µg/mL (%CV: 22-26%) and the area under the serum concentration-time curve (AUCinf) of T was 4400-5200 µg*h/mL (%CV: 19-23%) across the 2 doses in Japanese pts. The half-life for T and the free MMAE payload was determined to be 3-4 days and 4-6 days respectively. Conclusions Preliminary safety, PK and efficacy in Japanese pts with solid tumors suggest T was tolerated and showed encouraging anti-cancer effects, warranting continued study.

Background The objective of this study was to select, for a phase III trial, the more promising of weekly-dose intensive chemotherapy or amrubicin plus cisplatin as subsequent therapy after induction chemoradiotherapy for previously untreated limited-disease small cell lung cancer (LD-SCLC). Methods Patients (pts) aged 20-70 years with untreated clinical stage II/III LD-SCLC were eligible. After one cycle of accelerated hyperfractionation thoracic radiotherapy with etoposide plus cisplatin, pts without progression were randomized to either 3 cycles of cisplatin 25 mg/m2 (days 1, 8), doxorubicin 40 mg/m2 (day 1), etoposide 80 mg/m2 (days 1-3), and vincristine 1 mg/m2 (day 8) every 2 weeks (CODE) or amrubicin 40 mg/m2 (days 1-3) and cisplatin 60 mg/m2 (day 1) every 3 weeks (AP). The primary endpoint was the 1-year progression-free survival (PFS) after randomization. The sample size was 72 to select the arm yielding a better 1-year PFS (55% vs. 65%) with a correct selection probability of 80%. Results From March 2011 to February 2014, 85 pts were registered. After the induction chemoradiotherapy, 75 pts were randomized to CODE (n = 39) or AP (n = 36). The one-year PFS (95% CI) was 41.0% (25.7-55.8) in the CODE arm and 54.3% (36.6-69.0) in the AP arm. Grade 4 neutropenia and grade 3 febrile neutropenia occurred in 47% and 16% in the CODE arm and 78% and 42% in the AP arm, respectively. In patients aged 61 years or older, they were noted in 48% and 19% in the CODE arm and 88% and 48% in the AP arm, respectively. In women, they were noted in 20% and none in the CODE arm and 86% and 71% in the AP arm, respectively. Grade 3 pneumonitis was noted in one patient each in both arms. Secondary malignancies developed in 4 pts in the CODE arm and 2 pts in the AP arm. The 5-year survival (95% CI) in all 85 pts was 43.2% (32.5-53.4). The 5-year survival in all pts after randomization for CODE and AP arms were 35.3% (20.6-50.2) and 45.2% (28.3-60.7), respectively. The HR (95% CI) of AP arms to CODE arm was 0.70 (0.39-1.25). Conclusions An overall survival profile of AP was relatively good when compared to that of the historical control, but hematological toxicity was severe in AP, especially in older and female patients. Legal entity responsible for the study JCOG. Funding JCOG. Disclosure All authors have declared no conflicts of interest.

e20551 Background: Pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy are the standard therapies for advanced non-small cell lung cancer (NSCLC) patients with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) ≥ 50%. Apart from PD-L1 status, predictive factors for the efficacy of pembrolizumab treatment remain unclear. High tumour burden has been shown to be a negative predictor for the efficacy of PD-1 inhibitors in melanoma. Hence, the purpose of this study was to evaluate the association between tumour burden and efficacy of pembrolizumab in NSCLC patients with PD-L1 TPS ≥ 50%. Methods: This single-center retrospective observational study evaluated patients with advanced NSCLC with PD-L1 TPS ≥ 50% who received pembrolizumab monotherapy as first line therapy between March 2016 and November 2018. The primary endpoint was progression-free survival (PFS). Tumour burden was estimated by the baseline number of metastases (BNM) and the baseline sum of the target lesions’ longest diameters (BSLD; measured according to RECIST criteria). Results: Of 52 patients with target lesions, the median age was 69 years; ECOG-PS 0-1 94%; non-squamous histology 79%; and PD-L1 TPS ≥ 75% was 65%. The optimal cut-off values for predicting PFS were 4 for BNM and 115 mm for BSLD, based on the minimum P-value method for PFS. The low BNM group included 20 (38%) patients, and the low BSLD group 33 (63%). Low BNM was significantly associated with longer PFS (median PFS not reached vs 4.0 months, HR = 0.35, P = 0.021) and with higher response rate (60% vs 31%, P = 0.041) compared to high BNM. There was no significant difference in PFS between low BSLD and high BSLD groups (12.4 vs 4.0 months, HR = 0.52, P = 0.098). Multivariate analysis showed that both low BNM (≤ 4 vs. > 4, HR = 0.32, P = 0.02) and PD-L1 TPS (75-100% vs. 50-74%, HR = 0.41, P = 0.032) were significantly associated with longer PFS. There was no association between PD-L1 TPS and BNM (Spearman’s rho = -0.0985, P = 0.487) Conclusions: BNM may be an independent predictive factor of efficacy of pembrolizumab monotherapy. Patients with low BNM can be candidates for pembrolizumab monotherapy.

e20583 Background: Systemic steroids use before starting immune checkpoint inhibitors (ICI) has negative impacts on survival. The aim of this study was to evaluate whether steroid against immune-related adverse events (irAE) reduces efficacy in patients with non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed patients who had advanced NSCLC and undergone ICI therapy between December 2015 and June 2018. Patients whose irAE was treated with ≥ 10mg/day of predonisone were classified into steroid group (S), otherwise into non-steroid group (N). Results: A total of 257 patients (pts) were treated with ICI and irAEs was observed in 103 pts (40%). Twenty-eight pts were S-group and 75 patients were N-group. There was no significant difference in age, sex, stage, performance status, histology, smoking status, gene alteration, expression of PD-L1, or treatment line between the groups. Main irAEs included pneumonitis (43% in S-group / 12% in N-group), diarrhea or colitis (25% / 9%), rash (21% / 20%), and hypothyroidism (14% / 37%). Grade 2 or higher irAEs were pneumonitis in 39% / 0%, diarrhea or colitis in 21% / 5%, hypothyroidism in 7% / 19%. Among S-group, steroids were used for pneumonitis in 11 pts, diarrhea or colitis in 7 pts, stomatitis in 2 pts, and rash in 2 pts. There was no significant difference in overall survival (median; 14.5 vs 30.0 months, P = 0.30, Hazard ratio, 0.69), progression-free survival (median; 7.8 vs 9.6 months, p = 0.11, Hazard ration, 0.65), and objective response rate (46% vs 41%, p = 0.64), respectively. Conclusions: Systemic steroid was mainly used in pts with ≥Gr2 pneumonitis or colitis. This study indicated that steroids use did not reduce efficacy of ICI. Thus, steroid should not be avoided in patients with moderate to severe irAEs with concern over reducing efficacy.

9031 Background: The aim of this phase III randomized trial is to determine the efficacy of pemetrexed and carboplatin followed by pemetrexed for elderly patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Cytotoxic chemotherapy-naïve, ECOG-PS 0-1, aged 75 years or older, and advanced stage non-squamous NSCLC pts were randomized to receive either docetaxel 60 mg/m2 on day 1 every 3 weeks [DOC] or carboplatin AUC 5 mg/ml/min and pemetrexed 500 mg/m2 on day 1 every 3 weeks followed by maintenance therapy with pemetrexed 500 mg/m2 every 3 weeks after 4 cycles of carboplatin and pemetrexed [CBDCA/PEM] given until disease progression or unacceptable toxicities. The primary endpoint was OS. Non-inferiority of CBDCA/PEM arm was planned to be demonstrated if upper limit of 95% confidence interval (CI) for hazard ratio (HR) did not exceed 1.154. Results: Between August 2013 to February 2017, 433 pts with a median age of 78 years (range, 75 to 88) were randomly assigned to the DOC arm (n = 217) or the CBDCA/PEM arm (n = 216). Non-inferiority of CBDCA/PEM arm was confirmed in all enrolled patients (HR for OS, 0.850; 95% CI, 0.684 to 1.056, P < 0.01). The median OS for DOC and CBDCA/PEM arms were 15.5 months and 18.7 months, respectively. In the CBDCA/PEM arm, PFS was significantly better (HR, 0.739; 95% CI, 0.609 to 0.89) and response rate was better (28.2% vs. 36.8%; P = 0.07), and incidence of neutropenia or febrile neutropenia of grade 3 or 4 was significantly lower. Grade 3 or 4 thrombocytopenia or anemia was more common in the CBDCA/PEM arm. Four treatment-related deaths (two in each treatment arm) occurred. QOL (FACT-LCS) was favorable for CBDCA/PEM arm throughout 18 weeks after enrollment. Conclusions: Pemetrexed/carboplatin followed by pemetrexed maintenance is a valid therapeutic option for the first-line treatment of elderly pts with advanced non-squamous NSCLC. Clinical trial information: 000011460.

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

e14732 Background: Human trophoblast cell surface glycoprotein (TROP2) is expressed on the cell surface of trophoblasts and various solid cancer cells. Recently, an antibody-drug conjugate (ADC) targeting TROP2 has been developed. The objective of this retrospective study is to evaluate the prevalence of TROP2 expression in the specimen of lung cancer and its changes during anticancer treatments. Methods: TROP2 expression was evaluated prior to and following anticancer treatment by immunohistochemical (IHC) analysis using an anti-TROP2 antibody (SP295). IHC scores were graded from 0 to 3 and grade ≥2 was considered to be positive. Pre- and post-treatment IHC scores of TROP2 expression were compared by Wilcoxon signed rank test. Results: Among 160 patients with evaluable tissue samples, median age was 65 (range, 39-89) years with 69% in stage III-IV. Histological diagnosis included 81% adenocarcinoma (Ad), 12% squamous cell carcinoma (Sq), 5% neuroendocrine carcinoma (NEC), and others. Among 130 Ad patients, 59% had EGFR mutations. Anticancer treatments included cytotoxic chemotherapy (77%), targeted therapy (42%), and radiotherapy (19%). TROP2 was expressed in 143 (89%) and 139 (87%) in pre- and post-treatment samples, respectively. Pre-treatment TROP2 positive expression were more frequently observed in Ad (92%) or Sq (100%) than NEC histology (25%, p < 0.001). There was no significant change in TROP2 expression after treatment (p = 0.509). Conclusions: TROP2 was commonly observed in the specimen of lung cancer especially in non-NEC histology regardless of anticancer treatments. TROP2-targeted ADC might have a therapeutic potential to be tested in TROP2-expressing lung cancer. [Table: see text]

The aim of this study was to investigate the relationship between the expression levels of thymidylate synthase (TS) and 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake on positron emission tomography (PET) in various thoracic neoplasms. In total, 392 patients [non-small cell lung cancer (NSCLC) (n=140), malignant pleural mesothelioma (MPM) (n=21), pulmonary metastatic tumors (PMT) (n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine (NE) tumor (n=34)] who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained using immunohistochemistry for determination of TS, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), vascular endothelial growth factor (VEGF), microvessel density (MVD), CD34 and p53. The expression of TS in thoracic neoplasms had a positivity of 58% (230/392), and the positive rates of TS expression in NSCLC, PMT, thymic epithelial tumor, NE tumor and MPM samples were 56, 57, 57, 85 and 47%, respectively. The positivity of TS expression was significantly higher in NE tumors compared to that in other thoracic tumors. A statistically significant correlation between TS expression and ¹⁸F-FDG uptake was observed in thoracic neoplasms, in particular primary lung adenocarcinomas, high-grade NE tumors, thymomas and MPMs. Moreover, TS expression was closely associated with angiogenesis, DPD, OPRT and p53. Our results indicated that SUV(max) by ¹⁸F-FDG uptake may be an alternative biomarker for predicting TS expression in patients with primary lung adenocarcinoma, high-grade NE tumor, thymoma and MPM.

Background: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. Methods: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. Results: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ⩾3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (⩾24 weeks) were reported. Conclusion: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.

Pleural dissemination detected by computed tomography (CT) is considered to be unfavorable for patients with non-small-cell lung cancer (NSCLC). However, the prognosis of NSCLC patients who are diagnosed with pleural dissemination at the time of surgery has yet to be adequately elucidated. To assess the outcomes of platinum-based chemotherapy in NSCLC patients in whom pleural dissemination was detected during exploratory thoracotomy with or without a videoscope, the clinical records of NSCLC patients who were admitted to Shizuoka Cancer Center between September, 2002 and April, 2009 were reviewed. A total of 19 patients were included in this study, 12 males and 7 females, with a median age of 65 years. All patients were diagnosed with adenocarcinoma and 6 were epidermal growth factor receptor (EGFR) gene mutation-positive. The median number of treatment cycles of first-line platinum-based chemotherapy was 4 (range, 1–6 cycles) and the objective response rate was 21% [95% confidence interval (CI): 8.5–43]. The median progression-free and overall survival were 10.4 (95% CI: 6.3–18.4) and 50.5 months (95% CI: 32.5–98.0), respectively. Of the 18 patients with reported disease progression, 9 (50%) developed locoregional tumor progression. In conclusion, NSCLC patients in whom pleural dissemination is detected during surgery tend to have a favorable prognosis for survival. Systemic chemotherapy and additional local treatment may improve their clinical outcomes.

Background Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ∼20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methods Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. Results Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0–12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. Conclusion Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.

Background: There is no standard therapy for relapsed patients who have received postoperative platinum-based adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of platinum combination chemotherapy re-challenge for such patients. Methods: Medical records from 3 institutes from April 2005 to July 2012 were retrospectively reviewed. Patients who underwent complete surgical resection were eligible if they received postoperative adjuvant chemotherapy consisting of cisplatin plus vinorelbine once and then re-challenge with platinum combination chemotherapy. Results: Sixteen patients were enrolled in this study. After re-challenge with platinum combination chemotherapy, we observed an overall response rate of 31.2% (5/16) and a disease control rate of 81.2% (13/16). Median progression-free survival and overall survival from the start of the re-administration of platinum combination chemotherapy were 6.5 and 28.0 months, respectively. Frequently observed severe adverse events (≥grade 3) included neutropenia (31.2%), thrombocytopenia (31.2%), leukopenia (12.5%) and hyponatremia (12.5%). Frequently observed non-hematological toxicities (≥grade 2) were anorexia (37.5%) and nausea (37.5%). Conclusion: Re-challenge with platinum combination chemotherapy was effective and safe; therefore, this therapy should be considered as a treatment option for relapsed patients after postoperative cisplatin-based adjuvant chemotherapy for resected NSCLC.