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Although recent reports have revealed the importance of the inactivation of both RB1 and TP53 in the transformation from lung adenocarcinoma into neuroendocrine carcinoma (NEC), the requirements for complete transformation into NEC have not been elucidated. To investigate alterations in the characteristics associated with the inactivation of RB1/TP53 and define the requirements for transformation into NEC cells, RB1/TP53 double-knockout A549 lung adenocarcinoma cells were established, and additional knockout of REST and transfection of ASCL1 and POU class 3 homeobox transcription factors (TFs) was conducted. More than 60 genes that are abundantly expressed in neural cells and several genes associated with epithelial-to-mesenchymal transition were up-regulated in RB1/TP53 double-knockout A549 cells. Although the expression of chromogranin A and synaptophysin was induced by additional knockout of REST (which mimics the status of most NECs), the expression of another neuroendocrine marker, CD56, and proneural TFs was not induced. However, coexpression of ASCL1 and POU3F4 in RB1/TP53/REST triple-knockout A549 cells induced the expression of not only CD56 but also other proneural TFs (NEUROD1 and insulinoma-associated 1) and induced NEC-like morphology. These findings suggest that the inactivation of RB1 and TP53 induces a state necessary for the transformation of lung adenocarcinoma into NEC and that further inactivation of REST and coexpression of ASCL1 and POU3F4 are the triggers for complete transformation into NEC.

Objectives SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study. Materials and methods Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m2 on day 1 and S-1 80 mg/m2 on days 1–14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients. Results A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73–1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5–49.6)/32.1 % (95 %CI, 18.9–45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58–1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7–81.8)/66.4 % (95 %CI, 53.0–79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients). Conclusion The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.

Loss of the chromatin remodeling SWItch/Sucrose Non-fermentable (SWI/SNF) complex is implicated in the pathogenesis of several types of neoplasms. The aim of this study was to examine the clinicopathological features of non-small cell lung cancer (NSCLC) with loss of expression of the SWI/SNF complex.Specimens from a total 1013 NSCLC cases used for tissue microarrays (TMAs) were immunohistochemically examined for expression of SWI/SNF complex (BAF) subunits, namely SMARCA4, SMARCA2, ARID1A, and ARID1B. We examined the clinicopathological features and PD-L1 expression status in NSCLC cases with loss of expression of one or more subunits of the SWI/SNF complex (BAF-Loss). Moreover, we compared the tumor mutation burden (TMB) between NSCLC cases with BAF-Loss and those with intact expression of the four subunits (BAF-Intact).Using TMA, BAF-Loss was observed in 5.4% of cases (SMARCA4: 2.4%, SMARCA2: 2.4%, ARID1A: 1.3%, and ARID1B: 0.3%). Concurrent loss of expression of two or more subunits of the SWI/SNF complex was detected in 0.7% of cases. BAF-Loss was significantly associated with smoking history, young age, male sex, pulmonary emphysema/bullae, large invasive tumor size, pleural invasion, vascular invasion, solid-predominant morphology, and absence of a lepidic growth component. A higher proportion of PD-L1-positive cases was observed among NSCLC patients with BAF-Loss than BAF-Intact (42% vs 26%, P 0.01). In stage I NSCLC, SWI/SNF-Loss (n = 23) was associated with shorter overall survival (HR: 2.43; 95% CI: 1.18-5.01; P = 0.01) and recurrence-free survival (HR: 2.22; 95% CI: 1.17-4.24; P 0.01) compared to BAF-Intact (n = 563). The degree of TMB was significantly higher among NSCLC patients with BAF-Loss (n = 3) than BAF-Intact (n = 7) (median 437 vs 113 mutations/whole-exome, P = 0.02).The current results suggest that loss of SWI/SNF expression in NSCLC is associated with aggressive clinicopathological features, PD-L1-positive status and high TMB.

Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused.The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021.A total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database.The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMIN000026777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

Objectives Comprehensive genomic analysis of small-cell lung cancer (SCLC) revealed various genetic alterations. However, obtaining suitable samples for genetic analysis is difficult in advanced SCLC. Thus, the prognostic effect of genetic alterations on the outcome of SCLC patients has not been well investigated. Therefore, this study evaluated the effect of genetic alterations on the survival of SCLC patients. Materials and methods We collected samples obtained from 220 patients with advanced SCLC before cancer treatment. Genomic DNA extracted from the samples was subjected to a 1.499 Mb-sized custom panel that captured all exons of 244 cancer-related genes, and the captured DNA was analyzed through next-generation sequencing. The associations between genetic alterations and overall survival were evaluated. Results Genetic analysis was successful in 204 samples (93%). Genetic alterations in the PI3K/AKT/mTOR pathway and inactivating mutations inTP53 and RB1 were detected in 14 (7%), 150 (74%), and 85 (42%) of the tumors. In extensive disease (ED, N = 126) patients, multivariate analysis revealed that the presence of genetic alterations in the PI3K/AKT/mTOR pathway was significantly associated with unfavorable survival [hazard ratio (HR), 2.14; 95% CI 1.02–4.06; P = 0.04]. In limited disease (LD, N = 78) patients, the presence of TP53 mutation and the absence of RB1 mutation were significantly associated with unfavorable survival (HR, 2.41; 95% CI 1.21–5.34; P = 0.01, and HR, 0.45; 95% CI 0.25–0.79; P Conclusions Sequencing-based genetic profiling is feasible and useful to predict the prognosis in advanced SCLC. Genetic alterations in the PI3K/AKT/mTOR pathway, TP53 mutations and RB1 mutations were associated with prognosis in SCLC patients. The genetic alterations associated with the prognosis were different between ED-SCLC and LD-SCLC.

Summary Background Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR -mutation-positive non-small-cell lung cancer (NSCLC). Methods In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. Findings Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3–23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1–16·6) in the dacomitinib group and 9·2 months (9·1–11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47–0·74; p vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Interpretation Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR -mutation-positive NSCLC and should be considered as a new treatment option for this population. Funding SFJ Pharmaceuticals Group and Pfizer.

There is little information on the clinical outcome of patients with small-cell lung cancer (SCLC) treated with third-line chemotherapy. The purpose of this study was to clarify the prognostic factors of SCLC patients receiving third-line chemotherapy.Between November 2001 and October 2011, 202 of 648 consecutive SCLC patients at the National Cancer Center Hospital East received third-line chemotherapy. Multivariate Cox regression analysis was performed to identify the prognostic factors for overall survival after third-line chemotherapy.The demographics of the 202 patients were as follows: median age 66 years, 83% male, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, and 3 values of 22, 122, 49, and 9, respectively. Median time to treatment failure after second-line chemotherapy (TTF2) was 4.5 months (TTF2 ≥ 5/5 months, 82/120). The median overall survival after third-line chemotherapy was 5.1 months. Multivariate Cox regression analysis showed that PS 0-1 (hazard ratio, 0.38; 95% confidence interval, 0.27-0.54; P .001) and TTF2 ≥ 5 months (hazard ratio, 0.57; 95% confidence interval, 0.41-0.79; P .001) were independent prognostic factors. TTF2 threshold of 5 months was determined on the basis of concordance probability adjusted by PS.PS 0-1 and TTF2 ≥ 5 months were associated with a favorable prognosis among SCLC patients receiving third-line chemotherapy. These 2 factors might be helpful for the selection of candidates for third-line chemotherapy and for patient stratification when conducting future clinical trials in the third-line setting.

Background Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors—erlotinib and gefitinib. Patients and Methods From 2008 to 2011, 130 consecutive patients with advanced non–small-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. Results Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and non-users groups, the ORR was 64% and 63% ( P = .92), while the median PFS was 8.7 and 10.7 months ( P = .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P = .60) and diarrhea (34% vs. 29%; P = .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. Conclusion Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations.

Objectives Lung adenocarcinoma is heterogeneous, characterized by various histological subtypes. Determination of the predominant histological subtype (lepidic, papillary, acinar or solid-predominant) has been shown to correlate with genetic abnormalities and clinicopathological features. Although subtyping using small biopsy samples is important for tailored approaches to clinical management, limited data exist on the concordance of predominant subtype between resected specimens and biopsy specimens. Materials and methods We compared the diagnosed predominant subtypes in resected specimens and matched biopsy specimens in a series of 327 lung adenocarcinomas. The accuracy of preoperative diagnosis by biopsy and the factors that influence concordance with resected specimen analysis were examined. Results In 211 of the 326 patients (66.0%), the predominant adenocarcinoma subtype diagnosed from biopsy matched the findings of resection analysis. Overall, the concordance rate in biopsy samples with larger tumor areas (≥0.7mm 2 ) was significantly higher than in those with smaller tumor area ( 2 ; 71.2% vs 60.7%, respectively; p =0.015). In the biopsy samples with smaller tumor areas, the concordance rate was 77% in lepidic subtype, 71% in papillary subtype, 60% in solid subtype, and 40% in acinar subtype. Concordance rate in the biopsy samples with larger tumor area was higher in papillary and solid subtypes (88% and 76%, respectively), but remained low in acinar subtype (37%). Conclusion The current results indicate that accuracy of adenocarcinoma subtyping based on small biopsy samples is influenced by tumor area. Our study also suggests that subtyping of acinar histology using biopsy specimen is particularly error-prone.

Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes.The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n=20 each).SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P0.01 for both) and PPA (P0.01 for both) and tended to be higher than in APA (laminin-5: P=0.096, PD-L1: P=0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P0.01) and CD204 (+) tumor-associated macrophages (P0.05) than the other subtypes.Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

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.

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

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 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.

Background:Pericardial effusion is defined as M1a in the Union Internationale Contre le Cancer seventh tumor, node, metastasis edition for lung cancer. The clinical course of small cell lung cancer (SCLC) with pericardial effusion but without distant metastasis (M1a) has not been adequately investigated.Methods:The medical records of patients with SCLC treated at the National Cancer Center Hospital East between July 1992 and December 2007 were reviewed. During this period, 766 patients were newly diagnosed as having SCLC. Thirty-three of the 416 patients with limited disease (LD) SCLC (8%) had pericardial effusion. Seventy-nine patients with LD-SCLC (19%) had ipsilateral pleural effusion or dissemination. Of these, 16 patients had both pericardial and ipsilateral pleural effusion. We divided the 96 M1a patients into two subgroups: group A (n = 33) included patients with pericardial effusion, and group B (n = 63) included patients with ipsilateral pleural effusion or disseminated pleural nodules but without pericardial effusion.Results:The median survival time among the patients with LD-M1a was 13.4 months (95% confidence interval: 10.7–16.6 months), and the 1-, 2-, 3-, and 5-year survival rates were 56%, 18%, 9%, and 8%, respectively. The survival of the patients with LD-M1a was intermediate between those of the patients with LD-M0 and patients with extensive disease M1b (p < 0.0001). The overall survival period was not statistically different between groups A and B (p = 0.5182). Nineteen patients in group A received chemoradiotherapy, but only two patients survived for more than 2 years (2- and 5-year survival rate: 11% both). Twenty-six patients in group B received chemoradiotherapy, and four patients survived for more than 5 years (5-year survival rate: 18%).Conclusions:Long-term survival was achieved among patients with SCLC with pericardial effusion but without distant metastasis who successfully underwent chemoradiotherapy, although 5-year survival rate in these patients was relatively lower than in patients with SCLC with ipsilateral pleural effusion but without pericardial effusion or distant metastasis.

There has been no report about re-challenge chemotherapy (RC) consisting of the same regimen as first-line chemotherapy in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy of RC as second-line chemotherapy in patients with relapsed NSCLC. We conducted a retrospective review of 28 consecutive NSCLC patients who were treated with RC and compared their clinical outcomes with those of 38 consecutive NSCLC patients who were treated with docetaxel (DOC) at our hospital between July 1992 and December 2003. The RC group consisted of 21 men and 7 women, with a median age of 62 years (range, 42-76 years). Most first-line regimens were platinum-based and the median administered course was 3 (range, 2-7). All patients had responded to the first-line chemotherapy and had performance status (PS) 1 at relapse. The median interval from the end of first-line chemotherapy to relapse was 5.0 months (range, 1.6-36.1 months). The overall response rate of RC was 29%. The median survival time from the beginning of RC was 17.0 months and the 1-year survival rate was 60%. RC led to a significantly better overall survival rate than DOC (p=0.0342). RC could be an active second-line regimen in patients with relapsed NSCLC who responded to first-line chemotherapy.