Search

Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects., Mechanisms of acquired resistance to RET tyrosine kinase inhibitors in lung cancers are largely unknown. Here, the authors report in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.

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 We previously reported that toxicities were tolerable and manageable in both arms; however, febrile neutropenia was more frequently observed in the CDDP+S-1 arm. Response rate was 60%/64%. Here, we present primary analysis of 2-year survival data. Methods Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. The sample size was set at 100 patients. Results Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n = 17 (33%)/n=17 (34%); stage IIIB, n = 21 (40%)/n=20 (40%); ECOG PS of 1, n = 14 (27%)/n=14 (28%); never smoker, n = 12 (23%)/n=12 (24%); and adenocarcinoma, n = 47(90%)/n=45(90%); activating EGFR mutation, n = 9 (17%)/n=4 (8%); ALK fusion, n = 2 (4%)/n=3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR = 1.16, 95% CI, 0.73-1.84, p = 0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). After a median follow-up of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR = 1.05, 95%CI, 0.58-1.90, p = 0.883), and 2-year OS rate was 69.2% (95%CI, 56.7-81.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n = 7/n=5), ALK-TKIs (n = 0/n=3), and immunocheckpoint inhibitors (n = 6/n=10). Conclusions 2-year PFS rate in the CDDP+S-1 arm was better than that in the CDDP+PEM arm. We will select the CDDP+S-1 arm as the investigational arm in a future phase III study.

Background Progression patterns at the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for advanced non-small cell lung cancer (NSCLC) in patients harboring an EGFR mutation are clinically heterogeneous. We evaluated the association between progression patterns during EGFR-TKI treatment and prognosis after treatment in such patients. Methods From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring an EGFR mutation were treated with EGFR-TKIs (erlotinib or gefitinib). Among these, 104 who experienced RECIST-PD were retrospectively evaluated for initial response to EGFR-TKIs, progression sites, focus of progression (solitary lesion or multiple lesions), symptom status at RECIST-PD evaluation, and post-progression survival (PPS). Results Of 104 patients, 96 (92%) had an EGFR major mutation, and 50 (48%) received EGFR-TKIs as first-line treatment. Overall response rate and median time to RECIST-PD on EGFR-TKIs were 68% and 8.2 months, respectively. At the time of attaining RECIST-PD status, 44 (42%) patients were symptomatic, and 60 (58%) were asymptomatic. Progression sites at RECIST-PD were isolated brain in 17 (16%) patients and systemic in 87 (84%): 24 (23%) had a solitary lesion, and 80 (77%) had multiple lesions. After RECIST-PD assessment, 40 (38%) patients continued EGFR-TKIs, and 25 (24%) switched to cytotoxic agents; 10 (10%) received local radiotherapy for an isolated progression site (brain 6; bone 3; lung 1). Median PPS was 10.8 months. Multivariate analysis revealed that asymptomatic or solitary lesion status was associated with significantly longer PPS (asymptomatic: HR 0.36, 95% CI 0.21–0.62, P P = 0.04). Conclusions Progression patterns at the RECIST-PD during EGFR-TKI treatment of advanced NSCLC in patients harboring an EGFR mutation are widely diverse, and might be associated with clinical outcome after treatment failure.

Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung.We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas.Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (425 µm) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and α-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones.Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis.

The role of second-line chemotherapy in patients with non-small cell lung cancer (NSCLC) and preexisting interstitial pneumonia (IP) previously treated with platinum-based chemotherapy remains uncertain. This study was conducted to elucidate the efficacy and tolerability of second-line docetaxel monotherapy for patients with platinum-refractory advanced (stage IIIB, IV, or relapse) NSCLC and preexisting IP.A total of 35 patients (median age, 67 years) treated with docetaxel monotherapy in a second-line setting following first-line platinum-based chemotherapy between January 2002 and December 2013 were retrospectively reviewed.The overall response rate and disease control rate were 8.6 % [95 % confidence interval (CI) 0-17.9 %] and 37.1 % (95 % CI 21.1-53.1 %), respectively. The median progression-free survival and median overall survival periods were 1.6 months (95 % CI 1.2-2.0 months) and 5.1 months (95 % CI 3.2-6.7 months), respectively. The incidence of acute exacerbation (AE) of IP following docetaxel monotherapy was 14.3 % (5/35 patients). Of the five patients who developed AE of IP, three patients died. The toxicity of this regimen was substantial, with treatment-related deaths occurring in 5 (14.3 %) patients (AE of IP: 3, sepsis: 2).Docetaxel monotherapy has a poor activity and substantial risks when used for the treatment of platinum-resistant NSCLC with IP. Novel therapeutic approaches should be explored in this setting.

Objective Thymic carcinoma is a rare mediastinal neoplasm. While platinum-based chemotherapy has been reported to be effective for advanced thymic carcinoma in a first-line setting, little information is available regarding the benefits of salvage chemotherapy for platinum-refractory thymic carcinoma. This study assessed the efficacy and safety profiles of docetaxel monotherapy for platinum-refractory thymic carcinoma. Methods A total of 13 thymic carcinoma patients treated with docetaxel monotherapy in a second- or later-line setting between January 2003 and April 2014 were retrospectively reviewed. The median age was 61 years (range, 41-75 years). Results The overall response rate and disease control rate were 31% [95% confidence interval (CI), 6-56%] and 77% (95% CI, 54-100%), respectively. The median progression-free survival and overall survival after docetaxel monotherapy were 5.5 months (95% CI, 2.3-6.5 months) and 24.0 months (95% CI, 9.4-31.2 months), respectively. The most common Grade ≥3 toxicity was neutropenia (62%). No incidents of febrile neutropenia and no treatment-related deaths were recorded. Conclusions This retrospective analysis demonstrated that docetaxel was active against platinum-refractory thymic carcinoma with acceptable toxicities. Docetaxel monotherapy might be a promising therapeutic option for patients with platinum-refractory thymic carcinoma.

Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) are a favorable prognosticator in surgically resected small cell lung cancer (SCLC). Here we explore whether CAFs expressing PDPN influence proliferation of SCLC cells. Compared with control group (SCLC cells co-cultured with CAFs-Ctrl), numbers of SCLC cells co-cultured with CAFs overexpressing PDPN were decreased. Suppression of PDPN expression by shRNA in CAFs resulted in increased numbers of SCLC cells. In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs. Thus CAFs expressing PDPN inhibit growth of SCLC cells, suggesting that CAFs expressing PDPN represent a tumor inhibitory stromal cell component in SCLC.

Purpose: The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs. Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106). Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P < 0.01). Conclusions: Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs. Clin Cancer Res; 21(3); 642–51. ©2014 AACR.

Immunohistochemical analysis for the identification of clinically relevant biomarkers is important. However, there have been no detailed reports about the heterogeneous expressions of the various markers in squamous cell carcinoma of the lung. A total of 113 patients with squamous cell carcinoma of the lung with lymph node metastasis were included. The expression levels of 9 molecules (E-cadherin, S100A4, CD44, ALDH1, SOX2, EGFR, HER2, FGFR1 and VEGFR2) in the peripheral area and central area of primary tumor and metastatic lymph nodes were evaluated by immunohistochemistry. The differences in the staining scores of these molecules among the three areas were assessed. We also analyzed the relationships between the expression levels of these molecules and the recurrence-free survival. The E-cadherin expression was higher in the central area than in the peripheral area and metastatic lymph nodes (median staining score: 60 vs. 50, 30); the CD44 expression was higher in the central area than in the metastatic lymph nodes (117 vs. 90); and the EGFR expression was higher in the central area than in the peripheral area and metastatic lymph nodes (163 vs. 130, 110). Low CD44 expression in the central area, low EGFR expression in the peripheral area and high SOX2 expression in the metastatic lymph nodes were associated with a shorter recurrence-free survival (p

Hepatotoxicity is a major cause of the withdrawal of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) when treating EGFR mutation-positive non-small cell lung cancer (NSCLC). We report a case in which gefitinib- and elrotinib-induced severe hepatotoxicity arose in a patient with the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) and cytochrome p450 3A5 (CYP3A5) poor metabolizer phenotypes. Afatinib is not significantly metabolized by cytochrome p450-mediated pathways. We describe successful management of the patient's tumor by switching to afatinib. Evaluation of single nucleotide polymorphisms (SNPs) in metabolic enzymes might be useful to predict severe hepatotoxicity induced by EGFR-TKIs.

Acute and Progressive Tracheal Stenosis after Proton Beam Therapy with Concurrent Chemotherapy for Non–Small Cell Lung Cancer Yoshitaka Zenke, MD, Shigeki Umemura, MD, PhD,* Atsushi Motegi, MD, Kinya Furukawa, MD, Keisuke Kirita, MD, Shingo Matsumoto, MD, Kiyotaka Yoh, MD, Seiji Niho, MD, Hironobu Ohmatsu, MD, Masahiro Tsuboi, MD, Tetsuo Akimoto, MD, Koichi Goto, MD Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan Tokyo Medical University, Ibaraki Medical Center, Inashiki-gun, Ibaraki, Japan

Cell-free and concentrated ascites reinfusion therapy (CART) is recognized as a useful treatment to improve the symptoms caused by refractory ascites. Recently, a few clinical studies have reported the effects of CART for malignant ascites, especially in gynecological and gastrointestinal cancers. We report the case of malignant ascites in a patient with malignant pleural mesothelioma (MPM) whose symptoms were relieved by CART. A 59-year-old Japanese male with MPM who had undergone pleural decortication had pleural and peritoneal recurrence. His general status deteriorated as he developed massive ascites due to peritoneal metastases. With the initiation of CART, he recovered well enough to receive cisplatin-based systemic chemotherapy. Repeated use of CART contributed to the maintenance of his good general condition and enabled him to undergo successive systemic chemotherapy, which might have lengthened his life. This is the first report that demonstrates the efficacy of CART for palliative care in a patient with MPM. Our experience indicates that CART should be considered as a treatment option to control refractory malignant ascites regardless of the type of cancer.

Although a few investigators have demonstrated the effect of concurrent chemoradiotherapy (CRT) for postoperative recurrent non-small cell lung cancer (NSCLC), the outcome of this treatment remains unclear. The aim of this study was to elucidate the efficacy and tolerability of concurrent CRT with cisplatin (CDDP) and vinorelbine (VNR) in patients with postoperative locoregional recurrent NSCLC. A total of 40 patients who had received concurrent CRT with CDDP and VNR between January 1999 and December 2014 were retrospectively analyzed. Patients were treated with CDDP (80 mg/m2 on day 1) and VNR (20 mg/m2 on days 1 and 8) every 4 weeks. Radiotherapy was administered concurrently during cycle 1. The delivered x-ray radiation dose was 60 Gy in all 37 patients who received x-ray radiotherapy; 3 patients received proton beam radiation (66 Gy [RBE] in 1 patient and 60 Gy [RBE] in 2 patients). The objective response rate was 85% (95% confidence interval [CI], 70.9%–92.9%). The median progression-free survival was 20.3 months (95% CI, 12.9 months–not reached). The 2-year survival rate was 78.9% (95% CI, 63.0%–89.1%). The most common grade ≥3 toxicity was neutropenia (18%). No grade ≥3 radiation pneumonitis and no treatment-related deaths were observed. Our study revealed that concurrent CRT with CDDP and VNR was active and safe for patients with postoperative locoregional recurrent NSCLC. Salvage CRT for postoperative locoregional recurrent NSCLC might be a promising treatment for selected patients.

The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m2 on day 8 plus oral S-1 at a dosage of 40 mg/m2 twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years. Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4–74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5–27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively. Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC.

The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy. We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, ezrin, and ALDH1 in cancer cells, the number of CD204-positive tumor-associated macrophages (TAMs), and the presence of podoplanin-positive cancer-associated fibroblasts (CAFs) in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed. Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, ezrin, or ALDH1. Although the number of CD204-positive TAMs was not associated with the PFS, the presence of podoplanin-positive CAFs was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P = 0.028). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P = 0.087). The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell-derived factors should be incorporated into predictions of the effectiveness of chemotherapy.

Background Dacomitinib (d) is effective first-line (1L) therapy in patients (pts) with EGFR-mutation-positive (EGFR+) advanced NSCLC. In the ARCHER 1050 study (NCT01774721), 1L treatment with d was manageable and resulted in clinically meaningful, statistically significant improvement in PFS vs gefitinib (g). Here we present results for Japanese pts from ARCHER 1050. Methods Pts with newly diagnosed stage IIIB/IV or recurrent EGFR+ advanced NSCLC were randomized to once-daily (qd) oral d 45 mg or g 250 mg. Randomization was stratified by race and EGFR mutation subtype. The primary endpoint was PFS. All pts enrolled were part of the efficacy analysis. Pts who received ≥1 dose of study drug were part of the safety analysis. Results Of 452 total pts, 81 were Japanese; d (n = 40), g (n = 41). Median PFS was 18.2 mo for d (95% confidence interval [CI], 11.0-31.3) vs 9.3 mo for g (95% CI, 7.4-14.7). All 81 pts received study treatment. No grade (G) 4 or 5 adverse events (AEs) occurred in d-treated pts. Three G4 AEs (hepatic enzyme increases [n = 2], suicide attempt) and a G5 AE (disease progression) occurred in g-treated pts. The most common G3 AEs were dermatitis acneiform (27.5%) and paronychia (22.5%) with d and ALT increased (12.2%) and abnormal hepatic function (7.3%) with g. Dose reduction occurred in 85% of d-treated pts; 24.4% of g-treated pts changed from qd to every other day dosing. Frequency and severity of special interest AEs (diarrhea, stomatitis, dermatitis and paronychia) were generally decreased after d dose reduction. Although the frequency of d dose modifications in Japanese pts was higher than in the ARCHER 1050 overall population, median treatment duration for pts who had d dose reductions was longer vs those who did not. Conclusion D significantly improved PFS over g in 1L treatment of Japanese pts with EGFR+ advanced NSCLC and had a manageable safety profile. Tolerability was improved and treatment duration was prolonged in pts who had their d dose reduced.

Background While atezolizumab, an anti-PD-L1 monoclonal antibody, is clinically effective against non-small cell lung cancer (NSCLC), its immunological effects on the tumor microenvironment (TME) have not been fully clarified. Methods For the biomarker analyses, tumor samples were obtained at baseline, 6 weeks after the initiation of therapy, and/or at the end of therapy. Tumor-infiltrating lymphocytes (TILs) were extracted from those tumor specimens and were subjected to flow cytometry and/or CyTOF for detailed immune profiling. Results Twenty-seven eligible patients were analyzed in this trial. The preliminary efficacy results showed an overall RR of 19%, a DCR of 63%, and a median PFS of 4.1 months. To elucidate biomarkers, we compared the immune profiling results between 8 responders (CR, PR, or SD ≥ 6 weeks) and 18 non-responders (SD Conclusions PD-1 expression by CD8+TILs could be a predictive biomarker for the efficacy of PD-1/PD-L1 blockade therapies. Atezolizumab increased PD-1 expression by CD8+T cells but not by Treg cells in TILs, suggesting that atezolizumab can activate CD8+T cells but not Treg cells in the TME. Legal entity responsible for the study National Cancer Center Hospital. Funding Chugai Pharma. Disclosure K. Kirita: Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): MSD Oncology. Y. Togashi: Honoraria (self): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono Pharmaceutical; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Brystol-Myers Squibb. H. Udagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Amgen. S. Nomura: Honoraria (self): Taiho Pharmaceutical. Y. Zenke: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): MSD Oncology; Research grant / Funding (institution): Ono Pharmaceutical. S. Matsumoto: Honoraria (self), Research grant / Funding (institution): Ono pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca KK; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Riken Genesis; Research grant / Funding (institution): MSD. K. Yoh: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Kirin Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ono Pharmaceutical. S. Niho: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Ono Pharmaceutival; Research grant / Funding (institution): Merck Serono. A. Sato: Honoraria (self), Research grant / Funding (institution): Sumitomo Dainippon Pharma; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): Aspyerian Therapeutics. H. Nishikawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb Japan; Honoraria (self), Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): BD Biosciences; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyowa Hakko Kirin; Research grant / Funding (self): Zenyaku Kogyo; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Asahi Kasei; Research grant / Funding (self): Sysmex. K. Goto: Honoraria (self), Advisory / Consultancy: Otsuka; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Chugai Pharma; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Lilly; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self): Quintiles; Honoraria (self), Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (self): Life Technologies; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (self): Riken Genesis; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): SRL Diagnostics; Research grant / Funding (self): Sumitomo Dainippon Pharma. All other authors have declared no conflicts of interest.

Background Treatment-related pneumonitis typically occurs 4 weeks later following durvalumab consolidation therapy in patients with non-small cell lung cancer (NSCLC). However, the clinical outcome of early development of pneumonitis within 4 weeks following durvalumab consolidation therapy remain unclear. We retrospectively evaluate clinical outcome of early development of pneumonitis in NSCLC patients who had received durvalumab. Methods We retrospectively reviewed all consecutive cases of NSCLC patients who had received durvalumab after chemoradiotherapy in our hospital from June 2018 to January 2019. The clinical characteristics of the patients who had developed pneumonitis were reviewed and compared between occurred pneumonitis within 4 weeks and 4weeks later. Results We identified 28 patients who had received durvalumab. The development of pneumonitis of any grade was 79% (n = 22). The median times to the occurrence of pneumonitis were 4 weeks (range: 2-8). Among the 22 patients who had developed pneumonitis, 14 patients (64%) occurred pneumonitis within 4 weeks (early group), while the remaining 8 patients (36%) occurred pneumonitis 4 weeks later (non-early group). Clinical characteristics in predictive for pneumonitis risk were not significantly different in both groups. The development of grade 2 or higher pneumonitis was 32% (n = 7) and 6 out of 7 patients (86%) were in early group. The patients who discontinued durvalumab due to pneumonitis were observed higher in early group than non-early group (42% vs. 13%). In early group, all patients resumed durvalumab by the management with systemic corticosteroids. Only 1 patients (5%) definite terminated durvalumab due to grade 3 pneumonitis in non-early group. Conclusion Grade 2 or higher pneumonitis often developed within 4weeks following durvalumab consolidation therapy. Almost patients could continue durvalumab without definite termination with appropriate supportive care in early development of pneumonitis.

Background: PD-L1 expression is a predictive biomarker of response to nivolumab in non-squamous non-small cell lung carcinoma (Non-Sq NSCLC). PD-L1 expression in NSCLC exhibits significant intratumoral heterogeneity. Although multiple biopsy samples are usually obtained during a biopsy procedure, the evaluation of PD-L1 expression is typically performed using only one small sample. The aim of this study was to investigate the required numbers of samples and tumor cells (TCs) to assess PD-L1 expression using biopsy samples to predict the response to nivolumab. Methods: A total of 225 biopsy samples obtained from 80 Non-Sq NSCLC patients treated with nivolumab between January 2016 and August 2017 were collected. In each patient, the samples were obtained from the same lesion at the same time before nivolumab treatment. The number of TCs and the PD-L1 score after staining with anti-PD-L1 antibody (Dako 28-8) were evaluated. We defined the sample containing the largest number of TCs as Max-TCs, the sample containing the smallest number of TCs as Min-TCs and the sum of all the samples from each patient as Multiple-TCs. The concordances of the PD-L1 scores among the Max-TCs, Min-TCs and Multiple-TCs were assessed. And then, the impacts of the numbers of samples and TCs on the prediction of the efficacy of nivolumab using the evaluation of PD-L1 expression were evaluated. Results: The median number of samples was 2 (range: 2-6). The median number of TCs was 148 (13-2976) for the Mini-TCs, 570 (29-4826) for the Max-TCs, and 1022 (55-7062) for the Multiple-TCs.The correlation of the PD-L1 scores between the Max-TCs and Multiple-TCs was significantly high (R2 = 0.98). A mismatch of PD-L1 Conclusion: Evaluating the PD-L1 score using multiple biopsy samples did not provide any added benefit. One biopsy sample containing ≥80 TCs is required to evaluate PD-L1 expression to predict the response to nivolumab. Citation Format: Jun Sato, Tomoyuki Naito, Hibiki Udagawa, Hidehito Horinouchi, Shuji Murakami, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, Noboru Yamamoto, Yuichiro Ohe, Yoshitaka Zenke, Keisuke Kirita, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Noriko Motoi, Genichiro Ishii, Koichi Goto. Required numbers of biopsy samples and tumor cells for the assessment of PD-L1 expression to predict a response to nivolumab treatment in patients with NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4919.

Background: Among patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, T790M mutation is the most common mechanism of drug resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). However, the proportion of patients with T790M mutation at re-biopsy is varied by studies or biopsy methods. Methods: A total of 126 patients who were treated with first- or second-generation EGFR TKIs and had disease progression in our institution from January 2017 to September 2018 were eligible for this study. We retrospectively evaluated re-biopsy methods and the proportion of patients who harbor T790M mutation. Result: A total of 126 patients (male, 36.5% ; median age, 69 year ) were included. Among 126 patients, 118 patients (93.7%) underwent re-biopsy by any methods: tissue biopsy or cytology sampling in 68 patients and plasma sampling in 50 patients during a first re-biopsy, and 44 patients (37.3%) had T790M mutation. During the first biopsy, in the 68 patients who underwent tissue biopsy or cytology sampling, 32 patients (47%) were positive for T790M mutation, nevertheless there were no tumor samples in 4 patients and only atypical cells in 3 patients and 1 patient was identified transformation to SCLC. In the 50 patients who performed plasma sampling during a first re-biopsy, T790M mutation was detected in only 12 patients (24%). Second re-biopsy was conducted in 19 patients among 74 patients resulted in T790M-negative or unknown after the first re-biopsy, and 10 patients were positive for T790M mutation. Eventually, a total of 80 patients were performed tissue biopsy or cytology sampling, 74 patients (96.1%) were found to have any EGFR mutations and T790M mutation was detected in 39 patients (48.1%). On the other hand, 59 patients underwent plasma sampling and 31 patients (52.5%) were found to have any EGFR mutations and T790M mutation was detected in only 17 patients (28.8%). Totally 54 patients (42.9%) were detected T790M mutation, and 52 patients (41.3%) received Osimertinib subsequently. Conclusion: After progression of first- or second-generation EGFR-TKIs, about 95% of patients underwent re-biopsy, and T790M mutation was present in approximately half of patients who underwent re-biopsy and almost all patients who were positive for T790M mutation could receive Osimertinib. In patients who underwent tissue biopsy or cytology sampling, high frequency of detecting any EGFR mutations contributed to higher detection rate of T790M mutation compared to plasma sampling. To improve the sensitivity for T790M mutation detection, tissue biopsy or cytology sampling should be performed if possible. Citation Format: Tetsuya Sakai, Hibiki Udagawa, Yoshitaka Zenke, Keisuke Kirita, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Genichiro Ishii, Koichi Goto. A status of re-biopsy for non-small-cell lung cancer patients after first EGFR-TKI failure and incidence of T790M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4920.

Prognostic factors for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5-year disease-free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.

Background: We conducted a multicentre feasibility study for single agent long-term S-1 chemotherapy following docetaxel plus cisplatin in patients with curatively resected stage II–IIIA non-small cell lung cancer. Methods: Patients received three cycles of docetaxel (60 mg m−2) plus cisplatin (80 mg m−2) and then received S-1 (40 mg m−2 twice daily) for 14 consecutive days with a 1-week rest for >6 months (maximum, 1 year). The primary end point was feasibility, which was defined as the proportion of patients who completed eight or more cycles of S-1 chemotherapy. If the lower 95% confidence interval (CI) of this proportion was 50% or more, then the treatment was considered as feasible. The sample size was set at 125 patients. Results: One hundred and thirty-one patients were enrolled, of whom 129 patients were eligible and assessable. In all, 109 patients (84.5%) completed 3 cycles of docetaxel plus cisplatin and 66 patients (51.2%, 95% CI: 42.5–59.8) completed 8 or more cycles of S-1 treatment. Grade 3/4 toxicities during the S-1 chemotherapy included anaemia (7.3%), neutropaenia (3.7%), and anorexia (3.7%). Conclusion: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule for S-1 chemotherapy might improve the treatment compliance.

Adenosquamous carcinoma of the lung (Ad-Sq) is an uncommon subtype with poor prognosis. We analyzed the clinicopathological characteristics of Ad-Sq, focusing the correlation between Epidermal Growth Factor Receptor (EGFR) mutation and clinicopathological factors. A total of 67 cases were selected from September 1992 to May 2011. EGFR mutational analysis (n = 59) was performed by direct sequence. We also performed immunohistochemical staining for EGFR mutated cases using the two mutation-specific antibodies for deletion and L858R. Postoperative 3-year survival rate of Ad-Sq was 58.7%, statistically worse in comparison with adenocarcinoma (58.7% vs. 78.1%, P = 0.038). Twenty-four percent (14/59) were positive for EGFR mutations. Patients who had never been smokers and who were lymphatic permeation positive were seen more frequently in the mutation positive group (P = 0.035, 0.027, respectively). Moreover, the EGFR mutated group tended to have a more positive prognosis than negative. Focusing on the pathological features, the lepidic growth pattern was more frequently seen in the positive group (P = 0.018). Immunoreactivity for the DEL-specific and L858-specific antibody were observed in both adenocarcinoma and squamous cell carcinoma components. Our study demonstrated that EGFR mutated Ad-Sq had similar clinicopathological features as EGFR mutated adenocarcinoma.

Denosumab reduces the incidence of skeletal-related events (SREs) in solid tumor patients with bone metastases (BM). However, there have been no detailed reports of the efficacy of denosumab in untreated non-squamous non-small cell lung cancer (NSCLC) patients with BM. The medical records of patients with untreated non-squamous NSCLC and BM at diagnosis at our institution were reviewed retrospectively. The overall survival (OS) and the time to SREs were analyzed according to the treatment for the BM. Of the total of 149 patients who were eligible, 52 had received denosumab (Dmab group), 51 had received zoledronic acid (ZA group), and 46 had received no treatment (No-Tx group) for the BM. The frequencies of prior SREs were higher in the Dmab group and ZA group than in the No-Tx group (44, 41 and 22%, respectively); however, there were no significant differences in any of the other clinicopathological characteristics examined among the three groups. The median OS in the Dmab group, ZA group and No-Tx group were 21.4 months, 12.7 months and 10.5 months, respectively; the OS was significantly longer in the Dmab group than in the ZA group (P

Objectives We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m 2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Results Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1–17.1%) in the S-1 group and 64.1% (90% CI, 50.0–76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Conclusions Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities.

Objectives TAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer. Methods This was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35mg/m 2 /dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled. Results Eighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9–1.8) versus 2.7 months (range 1.0–6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68–8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients. Conclusion TAS-102 showed no evidence of activity in second-line small cell lung cancer.

Objective To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer. Methods The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated. Results Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44-87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60-66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9-32%), and the mean normal lung dose was 11.9 GyE (range: 6.0-19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01-63.6%), the mean heart V40 GyE was 13.4% (range: 1.4-29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9-48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities. Conclusions Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters.

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

The aim of this study was to assess the tolerability of cisplatin (CDDP) in patients with moderate renal dysfunction.To investigate the relationship between CDDP dose and nephrotoxicity, a retrospective chart review was conducted of patients with a creatinine clearance (Ccr) of 30-60 mL/min. Subjects were classified into three groups according to the CDDP dose, as determined by the physician, and the nephrotoxicity among these groups was compared. Additionally, we investigated the correlation coefficients between maximum serum creatinine (Scr) level or minimum estimated glomerular filtration rate (eGFR) and baseline Ccr.Fifty-six patients were included in this study. Among these patients, 13 patients received 30-40 mg/m(2) CDDP (group I), 18 patients received 40-70 mg/m(2) (group II), and 25 patients received 70-80 mg/m(2) (group III). No significant difference in nephrotoxicity was observed (median Scr 1.53, 1.61, and 1.53 mg/dL, respectively), and no correlation was observed between baseline Ccr and maximum Scr (r = 0.004, p = 0.979) or minimum eGFR (r = 0.21, p = 0.119). Only two patients (3.5 %) experienced grade 3 or 4 Scr elevation-one patient with a Ccr of 52.6 mL/min received 60 mg/m(2) CDDP, and the other patient with a Ccr of 52.1 mL/min received 70 mg/m(2) of CDDP. Hemodialysis was not observed.CDDP was tolerated at doses of 35-80 mg/m(2) among patients with moderate renal impairment. Empiric dose reduction might create a risk of under-treatment.

Background We conducted a feasibility study of induction chemotherapy followed by gefitinib and thoracic radiotherapy (TRT) for unresectable locally advanced adenocarcinoma of the lung. Patients and methods Patients received induction chemotherapy with cisplatin (80 mg/m2, days 1 and 22) and vinorelbine (25 mg/m2, days 1, 8, 22, and 29) followed by gefitinib (250 mg daily, beginning on day 43, for 1 year) and TRT (60 Gy/30 fractions, days 57–98). The primary end point was feasibility, which was defined as the proportion of patients who completed 60 Gy of TRT and received >75% of the planned dose of gefitinib without developing grade 2 or worse pneumonitis. Results Of the 38 enrolled patients, 23 patients [60.5% ; 80% confidence interval (CI) 48.8–71.3] completed treatment without experiencing grade 2 or worse pneumonitis. During the chemoradiation phase, grade 3–4 alanine aminotransferase elevations were observed in 37.1% of the patients. The overall response rate was 73.0% . The median survival time was 28.5 months (95% CI 22.5–38.2), and the 2-year survival rate was 65.4% . Conclusions Although the results did not meet our criterion for feasibility, the toxicity was acceptable. This treatment warrants further evaluation among patients with locally advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations.

Purpose This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods Chemonaive patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone ( p =0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p =0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p =0.9526). No new safety signals were detected. Conclusion Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Tumor budding is morphologically defined as infiltration by small clusters of cancer cells. While the biological properties of budding cells in adenocarcinoma (decreased expression of adhesion molecules and of differentiation markers) have been elucidated, those of the cells in squamous cell carcinoma (SqCC) of the lung still remain to be clarified. We examined the clinicopathological data of 217 patients with SqCC of the lung. Furthermore we evaluated the immunohistochemical properties of the budding cells. Tumor budding was observed in 83 (38.2%) patients. A statistically significant difference was observed in overall 5-year survival rates between the cases showing tumor budding and the cases not showing budding (45.6% vs. 64.0%, p

Background The overall clinicopathological features or the optimal therapy for large cell neuroendocrine carcinoma (LCNEC) have yet to be defined, because LCNEC has not been studied in the same depth as had small cell lung carcinoma (SCLC) in both clinical and biological standpoints. The aim of this study was to elucidate the clinical features of high-grade neuroendocrine carcinoma (HGNEC)-probable LCNEC diagnosed by biopsy, and compare therapeutic efficacy with patients with SCLC. Methods We retrospectively examined the chart of total of 25 patients who underwent chemotherapy or chemoradiotherapy as initial therapy for a histologic diagnosis of HGNEC-probable LCNEC, using biopsy samples and compared their data with those of 180 patients with SCLC. We analyzed their responses to chemotherapy and/or radiation therapy and survival outcomes. Results In 25 patients with HGNEC-probable LCNEC, 18 patients initially received chemotherapy (17 (94%) of whom received platinum-based chemotherapy) with an overall response rate (ORR) of 61%. The remaining 7 patients received chemoradiotherapy with an ORR of 86%, and 12 of the 25 patients who received second-line chemotherapy had an ORR of 17%. A total of 101 patients with SCLC who initially received chemotherapy had an ORR of 63%, and 79 patients who initially received chemoradiotherapy had an ORR of 98%, and 102 of the 180 patients who received second-line chemotherapy had an ORR of 45%. The 1-year overall survival rate for patients with stage IV HGNEC-probable LCNEC ( n =13) and those with ED-SCLC ( n =80) was 34% and 49%, respectively ( p =0.84). Conclusion The overall response rate to initial treatment and the survival outcomes of HGNEC-probable LCNEC were comparable to those of SCLC, but the effectiveness of second-line chemotherapy appeared to differ between the 2 groups.

Background The treatment of squamous cell carcinoma of the lung has not advanced sufficiently. Nedaplatin is a second-generation platinum compound that is active against squamous cell carcinoma of the lung, with a response rate of ∼40%. Patients and methods Eligible patients with advanced squamous cell carcinoma of the lung were treated with docetaxel (60 mg/m2) and nedaplatin (100 mg/m2) administered i.v. on day 1; these doses were determined in an earlier phase I study. The treatment cycles were repeated every 3 weeks. The primary end point was the response rate, and the secondary end points were overall survival, progression-free survival, and toxicity. Results Twenty-one patients were enrolled. Eighteen of the patients were male, and the median age was 67 years. The objective response rate was 62%. The median progression-free survival time was 7.4 months. The median survival time was 16.1 months, and the 1-year survival rate was 66.7% (95% confidence interval 46.5% to 86.8%). The most common adverse event was neutropenia (grade 3/4, 86%). Non-hematological toxic effects were relatively mild. One patient died of sepsis. Conclusions Combination chemotherapy with nedaplatin and docetaxel is highly active and has an acceptable toxicity. Further investigation of nedaplatin and docetaxel is warranted.