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Background Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1–3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P= 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration NCT01207011 (ClinicalTrials.gov)

Background Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (Cb) therapy is one of the standard platinum-containing chemotherapy regimens for patients with advanced non-small cell lung cancer (NSCLC). Adding the anti-vascular endothelial growth factor antibody bevacizumab (BEV) to chemotherapy is an effective treatment option for non-squamous NSCLC. Because the efficacy and safety of the Cb + nab-PTX + BEV triplet regimen has not yet been assessed, we conducted a multicenter, open-label, phase I/II trial of Cb + nab-PTX + BEV therapy for patients with NSCLC. The phase II trial was based on the drug dose and schedule determined in the phase I trial. Methods In this phase II trial, the required number of patients was calculated to be 49 cases with α = 0.05 (one-sided) and β = 0.1 assuming a threshold response rate of 30% and an expected response rate of 50%. The patients were to receive 4–6 cycles of Cb (area under the curve = 6) + nab-PTX (100 mg/m2 on days 1, 8 and 15) + BEV (15 mg/kg on day 1) followed by a maintenance dose of nab-PTX + BEV every 3 weeks until disease progression. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included overall survival (OS), progression free survival (PFS) time and toxicity. Results The trial was terminated early because of slow patient accrual. Finally, 47 cases were registered, and the main analysis was performed in 46 cases, excluding one case who was unqualified. The median age of the patients was 66 years. The transition percentage to maintenance therapy was 58.7%. The ORR based on central judgment was 56.5% (26/46 cases) with a 95% confidence interval (CI) of 42.2–70.8%, and the primary endpoint was met. The median PFS and OS were 7.79 months and 18.9 months, respectively. The main toxicity was myelosuppression, with grade 3–4 neutropenia (72.0%), anemia (28.0%), thrombocytopenia (14.0%) and febrile neutropenia (2.0%). The grade 3–4 sensory and motor neuropathy commonly seen with paclitaxel was 0%. All adverse events were manageable, and there was no treatment-related death. Conclusions Cb + nab-PTX + BEV therapy is a favorable and well-tolerated treatment for patients with advanced non-squamous NSCLC. Clinical trial identification UMIN000014560. Legal entity responsible for the study TORG/OLCSG. Funding Taiho Pharmaceutical CO., LTD. Disclosure T. Kubo: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical; Honoraria (self): BMS. A. Bessho: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical. A. Morita: Honoraria (self): Chugai pharmaceutical. T. Yokoyama: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical. K. Kaira: Honoraria (self): Taiho pharmaceutical; Honoraria (self): BMS. T. Harada: Honoraria (self): Taiho pharmaceutical. T. Shimokawa: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical; Research grant / Funding (institution): BMS. K. Kiura: Research grant / Funding (institution): Chugai pharmaceutical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Taiho pharmaceutical. H. Okamoto: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Chugai pharmaceutical. All other authors have declared no conflicts of interest.

Background Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with non-small cell lung cancer (NSCLC) and is also a known risk factor for pneumonitis. Approximately 10% of patients have concomitant IP diagnosed at the time of cancer diagnosis. IP is associated with smoking, microsatellite instability (MSI) and higher tumour mutation burden (TMB). Atezolizumab monotherapy is an established treatment for recurrent NSCLC. PD-L1 inhibitors are reported to have a lower risk of pneumonitis than PD-1 inhibitors. This study aims to assess the safety and efficacy of atezolizumab monotherapy for pretreated advanced or recurrent NSCLC patients with idiopathic IP. Trial design The Thoracic Oncology Research Group (TORG) 1936/AMBITIOUS study is a multicentre, single-arm, phase II trial. The key inclusion criteria are (1) histologically or cytologically proven NSCLC, (2) unresectable stage III/IV or recurrent disease, (3) prior chemotherapy, including platinum doublet chemotherapy, (4) chronic, fibrotic and idiopathic IP with a predicted vital capacity ≥ 70%, (5) age ≥ 20 years and (6) ECOG performance status 0, 1. The enrolled patients will receive atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria are satisfied. The primary end point is the 1-year survival rate. We set an expected value of 40% and a threshold value of 15%. Taking statistical points (two-sided α = 0.05; 1 − β = 0.9) and ineligible patients into account, the sample size was set at 38 based on the exact binomial test. The key secondary end points are the incidence of acute exacerbation of IP within 1 year after treatment initiation, overall survival, progression-free survival, objective response rate and safety. As a translational research, we will perform analysis of TMB, somatic mutations and MSI from tumour samples. Legal entity responsible for the study Thoracic Oncology Research Group (TORG). Funding Chugai Pharmaceutical Co., Ltd. Disclosure S. Ikeda: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. T. Kato: Honoraria (self), Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (self): Eli Lilly; Research grant / Funding (institution): Kyorin Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Kyowa Hakko Kirin; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution): Merck Sharp and Dohme; Honoraria (self): Nitto Denko; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Quintiles; Research grant / Funding (institution): Regeneron; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Takeda Pharmaceutical; Honoraria (self): F. Hoffmann-La Roche. H. Kenmotsu: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly ; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Novartis Pharma; Honoraria (self): Daiichi-Sankyo; Honoraria (self), Research grant / Funding (institution): AstraZeneca. T. Ogura: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Meiji Seika Pharma; Honoraria (self): Shionogi Pharmaceutical; Honoraria (self): Toray; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Astellas Pharma; Honoraria (self): Kyorin Pharmaceutical; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Actelion Pharmaceuticals; Honoraria (self): Novartis. S. Iwasawa: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): AstraZeneca. T. Iwasawa: Honoraria (self): Ono pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. T. Yamanaka: Honoraria (self), Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Sysmex; Honoraria (self): Huya Biosciences; Honoraria (self): Gilead Sciences. H. Okamoto: Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp and Dohme; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Daiichi Sankyo. 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.

Oral S-1 plus cisplatin is noninferior to docetaxel plus cisplatin in terms of overall survival with favorable QoL data. S-1 plus cisplatin is an option for the first-line treatment of patients with advanced NSCLC., Background Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). Patients and methods Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function were randomized to receive either oral S-1 80 mg/m2/day on days 1–21 plus cisplatin 60 mg/m2 on day 8 every 4–5 weeks, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3–4 weeks, both up to six cycles. Results A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837–1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. Conclusion Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. Clinical trial number UMIN000000608.

Background The VNR/Cis chemotherapy doublet has been evaluated in prior positive adjuvant trials in patients with completely resected Ns-NSCLC, whereas no phase III study has so far evaluated PEM/Cis in this population. And there are few data regarding outcomes based on EGFR mutation (EGFRm) status in adjuvant chemotherapies. Methods Patients with completely resected Ns-NSCLC were randomized in a 1:1 ratio to receive either PEM (500 mg/m2, day 1)/Cis (75 mg/m2, day 1) or VNR (25 mg/m2, days 1 and 8)/Cis (80 mg/m2, day 1), and stratified according to sex, age, pathologic stage, EGFRm status and institution. The primary endpoint was recurrence-free survival (RFS), and, the planned sample size was 800 patients in total (Trial Identifier, UMIN000006737). Results Between March 2012 and August 2016, 804 patients were randomized. Of 784 for the efficacy analysis (389 in PEM/Cis and 395 in VNR/Cis), median age was 65/65 years; stage IIIA 52.2%/52.4%; adenocarcinoma, 95.9%/95.9%; and EGFR mutation, 24.1%/24.9%. With a median follow-up of 45.2 months (mo), median RFS was 38.9mo in PEM/Cis and 37.3mo in VNR/Cis with a hazard ratio (HR) of 0.98 (95% CI, 0.81--1.20; log-rank test, P = 0.948), whereas HRs in patients with or without EGFRm were 1.38 (95% CI, 0.95--1.99) and 0.87 (95% CI, 0.69--1.09), respectively (Interaction, P = 0.046). As for patients without EGFRm, median RFS was 65.2mo in PEM/Cis and 39.9mo in VNR/Cis. The overall survival rate at 3 years was 83.5% versus 87.2% with a HR of 0.98 (95% CI, 0.71 --1.35). Rates of treatment completion were 87.9% (PEM/Cis) and 72.7% (VNR/Cis), respectively (P Conclusions Although this phase III study did not meet the primary endpoint, PEM/CDDP had a similar efficacy to VNR/CDDP with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. A significant interaction for RFS was found between treatment and EGFR mutation status. In patients without EGFR mutation, PEM/Cis seems to be a preferable regimen as the adjuvant chemotherapy. Clinical trial identification UMIN000006737. Legal entity responsible for the study The authors. Funding Health and Labor Sciences Research Grants, The Japan Agency of Medical Research and Development (AMED). Disclosure M. Tsuboi: Honoraria (self): AstraZeneca KK; Honoraria (self): Johnson & Johnson Japan; Honoraria (self): MSD; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Taiho Pharma; Honoraria (self): Eli Lilly Japan; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Ono Pharmaceutical Co., Ltd; Honoraria (self): Bristol-Myers Squibb KK; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Covidien Japan; Honoraria (self): Teijin Pharma; Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

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

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.

To elucidate the factors which influence the value of hemoglobin, the nadir value of hemoglobin, frequency of blood transfusion and prognostic value of blood transfusion in patients with primary lung cancer during intensive chemotherapy, the hematological features of 124 patients entered into a randomized phase III study containing cisplatin were retrospectively analyzed. There was no difference in the percent nadir hemoglobin value of the first course of chemotherapy (% of pretreatment value) in any of the subgroups with respect to sex, body weight loss, performance status, age, stage, number of metastatic sites or treatment arms. The only predictive indicator for the nadir hemoglobin value in the first course of chemotherapy was the pretreatment value of hemoglobin. The equation for the regression line was y = 1.07 + 0.73x (R2 = 0.663, p < 0.001). The lowest nadir hemoglobin value (% of pretreatment value) during all chemotherapy courses was significantly lower in the subgroups older than 60 years and those with body weight loss. There was an inverse correlation between the accumulated dose of cisplatin and the lowest nadir hemoglobin value (p < 0.05). The frequency of blood transfusion in patients with more than two metastatic sites was significantly higher than in those with one or no metastatic sites (p < 0.05). Survival of patients who had required blood transfusion after chemotherapy was significantly shorter than that of patients who had not (p < 0.05).

Background: A synergistic interaction between nedaplatin (NP) and irinotecan (CPT) has been demonstrated in three-dimensional analytical models (Clin Cancer Res 2001). Phase I/II studies for lung cancer showed high efficacy of the combination of NP and CPT (Cancer Chemother Pharmacol 2003). In addition, a meta-analysis suggested that the combination of NP and CPT was more feasible in squamous cell carcinoma (SCC) than non-squamous cell carcinoma (J Thorac Oncol. 2011). This study explored the efficacy and safety of an NP and CPT regimen in SCC of the lung. Methods: We conducted a multicenter phase II study of NP and CPT for stage III and IV SCC of the lung. Treatment consisted of 4 to 6 cycles of NP at 100mg/m2 (day 1) and CPT at 60mg/m2 (days 1 and 8) every 4 to 5 weeks. The primary endpoint was the response rate and secondary endpoints were overall and progression-free survival rates, and safety. Results: Fifty patients were registered and evaluated. Twenty-seven patients received 4 to 6 cycles of chemotherapy. A median of 4 cycles were given. One patient achieved a complete response and sixteen showed partial responses, with an overall response rate of 34.0% (95% confidence interval 21.2% to 48.8%). The disease control rate was 74.0%. The median progression free survival time was 4.3 months. The major toxicities included grade 4 anemia (10.0%), neutropenia (46.0%) and thrombocytopenia (10.0%), and grade 3 or 4 anorexia, diarrhea, hyponatremia, febrile neutropenia and infection occurred in 22.0%, 12.0%, 12.0%, 16.0% and 10.0% of patients, respectively. All of the toxicities were manageable and no treatment-related deaths were observed. Conclusions: The NP and CPT combination therapy is feasible for patients with advanced SCC of the lung.

Aim: A previous study has shown that PCI reduced the risk of brain metastases (BM) and prolonged the overall survival (OS) of patients with ED-SCLC (Slotman B et al, NEJM 2007). There were, however, several concerns that arose in association with that study, including the lack of magnetic resonance imaging (MRI) assessment to confirm the absence of BM before enrollment, the use of induction chemotherapy other than platinum, and variations in the radiation doses. The aim of this study is to assess the efficacy and safety of the PCI in the patients with ED-SCLC. Methods: From March 2009, patients with ED-SCLC who had any response to first-line chemotherapy (platinum agent plus irinotecan or etoposide) were randomized to either PCI (25Gy/10 fractions) or observation (Obs) alone. The patients were required to prove the absence of BM by MRI prior to enrollment. The primary endpoint was OS and a planned sample size of 330 was determined to detect the hazard ratio (HR) of 0.75 at a significance level of 0.05 and a power of 80%. Secondary endpoints included time to BM, progression-free survival (PFS), and adverse effects (AEs). Results: In July 2013, a preplanned interim analysis was conducted for the survival data of 163 pts from 41 centers. The study was terminated because of futility; with a median follow-up of 9.4 months and 111 observed deaths, the median OS was 10.1 and 15.1 months for PCI (n=84) and Obs (n=79), respectively (HR=1.38, 95%CI= 0.95-2.01; stratified log-rank test, P=0.091). Bayesian predictive probability of showing superiority of PCI over Obs was 0.01%. PCI significantly reduced the risk of BM as compared to Obs (32.4% vs 58.0% at 12 months; Gray's test, P Conclusions: PCI after response to chemotherapy might have a negative impact on OS in pts with ED-SCLC. Updated safety data will be presented at the conference. Disclosure: All authors have declared no conflicts of interest.

Aim: The effect of irinotecan in treatments for LD-SCLC in the elderly is unclear, and the optimal timing of TRT when combined with chemotherapy has not been fully evaluated. We report a phase I/II trial of induction chemotherapy with carboplatin and irinotecan followed by sequential TRT in this population? Methods: Patients with untreated, measurable LD-SCLC >70 years with performance status (PS) 0 to 2 and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8 every 21 days for four cycles. TRT of 54Gy in 27 fractions was then administered sequentially. Carboplatin dose was escalated from AUC of 4 to 5 (Levels 1 and 2, respectively)?with a fixed dose of irinotecan at 50 mg/m2. The primary objective of the phase II portion was evaluation of efficacy. Results: A total of 41 patients were enrolled [median age 75 years, range 70-86 years; 31 male, 10 female; PS 0/1/2: 22/18/1]. At Level 1 (n=6), one patient experienced dose-limiting toxicity (DLT) as Grade 3 hypertension. At Level 2 (n=6), two patients experienced DLT as Grade 4 thrombocytopenia. Therefore, level 1 was chosen as the recommended dose. The phase II trial was then expanded by 35 patients in the level 1 based on the Simon minimax design. In all cohorts, the median chemotherapy cycle was 4 (1/2/3/4 courses administered as 4/2/2/33); median radiation dose was 54Gy (range 36-60). Toxicities were generally mild, as expected.?Gr 3/4 leukopenia and thrombocytopenia were both observed in six (15%) patients. No Gr 3/4 diarrhea or esophagitis was noted. Although Gr 3 febrile neutropenia and Gr 3 pneumonitis were seen in two patients each, no treatment-related deaths occurred. There were five complete responses and 32 partial responses, for a response rate of 90%. With median follow-up of 80.4 months (n=41), median progression-free and overall survival times were 12.4 and 27.1 months, respectively. Conclusions: Induction chemotherapy with carboplatin plus irinotecan followed by sequential TRT was well tolerated and highly active in elderly patients with LD-SCLC. Further confirmatory studies are warranted. Disclosure: All authors have declared no conflicts of interest.

Aim: DTX is one of the standard drugs for patients (pts) with previously treated NSCLC. However, its efficacy seems insufficient. The efficacy of AMR for NSCLC has been previously reported. Thus, we conducted a randomized phase III trial comparing AMR to DTX, sponsored by Dainippon Sumitomo Pharma Co., Ltd. Methods: We enrolled pts with NSCLC, Eastern Cooperative Oncology Group Performance Status 0-1, undergoing second- or third-line treatment, and aged 20–74 years. Pts were classified by histology, prior treatment, and institution into 2 groups and then randomly assigned (1:1 ratio) to treatment with AMR (35 mg/m2/day i.v., on days 1–3, q3w) or DTX (60 mg/m2/day i.v., on day 1, q3w). We planned a sample size of 100 patients per group, with a 2-sided alpha of 5% and power of 90%. We hypothesized a median progression-free survival (PFS) time of 3.3 and 2.0 months for AMR and DTX, respectively. The primary endpoint was PFS; secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events according to Common Terminology Criteria for Adverse Events v 4.03. Results: From October 2010 to June 2012, 202 pts were enrolled from 32 institutions. Patient characteristics were well balanced between both groups. OS was measured after a median follow-up of 13.5 months. Median PFS was 3.6 and 3.0 months with AMR and DTX, respectively (adjusted Hazard Rate (HR) 0.96, 95% Confidence Interval (CI) 0.69–1.34, p = 0.831). Median OS was 14.6 and 13.5 months with AMR and DTX, respectively (adjusted HR 1.02, 95% CI 0.72–1.43, p = 0.933). ORR was 14.8% and 18.8% with AMR and DTX, respectively (p = 0.544). DCR was 55.7% for both AMR and DTX (p = 1.000). The most frequent adverse events (≥grade 3) for AMR and DTX were neutropenia (82.7% and 78.8%, respectively) and leukopenia (63.3% and 70.7%, respectively). Two treatment-related deaths occurred in the DTX arm: a case of interstitial pneumonia and another of drowning in a bath. Conclusions: We were not able to demonstrate superiority of AMR over DTX for PFS, despite the 20-day PFS prolongation. Our results suggest that AMR may become a treatment option for patients with previously treated NSCLC. Disclosure: All authors have declared no conflicts of interest.

Background Synergistic effects of gefitinib used in combination with S-1 have been reported because of a reduction in the expression of thymidilate synthase in use of gefitinib. Erlotinib also reduced TS expression and activity. The present studies were designed to evaluate the efficacy and safety of erlotinib/S-1 combination therapy as a second/third-line therapy for recurrent/advanced NSCLC. Methods Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily from days 1 to 14 of each 21-day cycle. In phase I trial (TORG0808), the primary end points were to evaluate the DLT and MTD for the following phase II study, and the secondary end points were the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary end points were PFS, disease control rate, OS and safety. Results Seven patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and II trials, respectively. In phase I trial, the recommended doses for the phase II study were determined to be 150 mg/body for erlotinib and 80 mg/m2 for S-1. The ORR was 67%, and three of four responders were EGFR-positive patients. In phase II trial, the ORR was very low (only one patient). Myelosuppression was relatively mild, but grade 3 or worse non-hematological toxicities including diarrhea, mucositis and dermatitis were observed in six patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination. Conclusions Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR-positive patients, but phase II trial demonstrated less effective and too toxic results in EGFR negative patients.

Background The standard treatment of locally advanced non-small cell lung cancer (NSCLC) has been considered to be chemo-radiotherapy (CRT). However, the benefit of this combined therapy for elderly patients (patients) is still unclear. This trial was set up to evaluate whether thoracic radiotherapy (RT) with daily low-dose carboplatin (CBDCA) would result in longer survival in elderly patients with unresectable stage III NSCLC than RT alone (JCOG0301). Methods Patients older than 70 years with unresectable stage III NSCLC were randomized to either RT alone (RT arm), a total dose of 60 Gy, or CRT arm including the same RT plus concurrent chemotherapy with carboplatin 30 mg/m2/day, 5 days/week for 20 days. The primary end point was overall survival (OS). The planned sample size was 100 patients in each arm with one-sided alpha of 5% and 80% power to detect a difference in median survival time (MST) from 10 months in the RT arm to 15 months in the CRT arm. Results Between September 2003 and May 2010, 200 patients were randomized. Baseline characteristics were similar in the RT (n = 100) versus CRT (n = 100) arms: median age, 77 versus 77 years; stage IIIB (n), 46 versus 49; PS 0/1/2 (n), 41/55/4 versus 41/56/3. The second planned interim analysis was carried out 10 months after the completion of accrual. In accordance with the pre-specified stopping rule, the JCOG Data and Safety Monitoring Committee recommended early publication of this trial because of the difference in OS favoring the CRT arm. In the updated analysis, OS was better in the CRT arm than the RT arm (HR = 0.64, 95% CI = 0.46–0.89, one-sided P = 0.0033 by stratified log-rank test). In each arm (RT/CRT), MST was 16.5 months/22.4 months with 3-year OS of 14.3%/34.6%, response rate of 44.9%/54.6% (P = 0.201) and median progression-free survival of 6.9 months/8.9 months (P = 0.003). Grade 3/4 toxic effects were (RT/CRT): neutropenia 0%/57.3%, infection 4.1%/12.5%, dysphagia 0%/1.0%, late RT toxic effects 7.4%/7.5%. The pattern of relapse site and post-protocol treatment were almost similar between the arms. Even after an adjustment by the Cox regression analysis with six variables (stage, PS, sex, age, histology, smoking status), the CRT arm showed better survival (HR = 0.71, P = 0.038).

Background Maintenance chemotherapy could prolong overall and/or progression-free survival in advanced NSCLC. S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The TORG 0809 study was conducted to evaluate the feasibility and efficacy of maintenance chemotherapy of S-1 following DOC + CDDP in patients with curatively resected stage II and IIIA NSCLC. Methods Patients received three cycles of DOC (60 mg/m2 d1) plus CDDP (80 mg/m2 d1), q3-4w, and subsequently S-1 at 40 mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary end point was determination of feasibility, which was defined as the proportion of patients who had completed maintenance for 8 cycles of S-1 or more. If the lower confidence interval (CI) of this proportion was 50% or more, the feasibility of the treatment was considered confirmed. The sample size was set to be 125. Results Between June 2009 and November 2010, 131 patients were enrolled, of whom 129 patients were eligible and assessable. The median age was 63 (23–74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 patients, 109 patients (84.5%) completed three cycles of DOC + CDDP. One hundred and six patients initiated the maintenance S-1 and 66 patients (51.2%, 95% CI: 42.5–59.8) completed eight cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 patients terminated maintenance S-1 at three cycles or less. Grade 3/4 toxic effects during the maintenance S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. Conclusions The toxicity level was acceptable, although the results did not meet our criterion for feasibility.

Background Four cycles of EP plus AHTRT is the standard treatment for LD-SCLC. IP demonstrated statistically significant overall survival (OS) improvement compared with EP for extensive-stage SCLC (JCOG9511; Noda et al., N Eng J Med, 2002). EP plus AHTRT followed by three cycles of IP is feasible with acceptable toxic effects for LD-SCLC (Kubota et al., CCR, 2005). Method Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, age: ≤20, ≤70 years old. Eligible patients received one cycle of EP (etoposide 100 mg/m2 on days 1–3 and cisplatin 80 mg/m2 on day 1) plus AHTRT (1.5 Gy b.i.d. total 45 Gy/3 weeks). Patients who achieved CR, good PR, PR or SD with induction EP/AHTRT were randomized to receive either three cycles of consolidation EP or IP (irinotecan 60 mg/m2 and cisplatin 60 mg/m2 on days 1, 8, 15). Patients with CR or good PR after consolidation chemotherapy received prophylactic cranial irradiation. The primary end point is OS after the randomization. The planned sample size for randomization is 250 with a one-sided alpha of 2.5% and at least 70% power to detect a difference between groups, 30% in EP versus 42.5% in IP group in 3-year survival. Results From September 2002 to September 2006, 281 patients from 36 institutions were registered. After the induction EP/AHTRT, 258 patients were randomized to consolidation EP (n = 129) or IP (n = 129). Patient demographics were well balanced between the two groups. At the final analysis, the superiority of IP in OS was not demonstrated (hazard ratio of IP to EP, 1.085 [95% CI 0.80–1.46]; one-sided P = 0.70, stratified log-rank test). Median OS, 3-year survival and 5-year survival on EP were 3.2 years, 53% and 36%, versus 2.8 years, 47% and 34%, respectively (one-sided P = 0.7030). Median PFS on EP was 1.14 years and 1.03 years on IP (P = 0.7259). Grade 3/4 neutropenia (95%/78%), anemia (35%/39%), thrombocytopenia (21%/5%), neutropenic fever (17%/14%), diarrhea (2%/10%) were observed in EP and IP groups, respectively. Conclusion EP plus AHTRT followed by three cycles of IP failed to demonstrate survival advantage over four cycles of EP plus AHTRT which still is the standard treatment of LD-SCLC.

Background Platinum-based chemotherapy has been a standard of care in patients with advanced non-small-cell lung cancer (NSCLC). S-1 plus cisplatin (SP) was shown good activity and tolerability in previous phase II trials. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival (OS) and quality of life (QOL), compared with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Method This randomized phase III study compared the OS between SP and DP in patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions. Patients received oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks in SP arm, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks in DP arm, both up to six cycles. The non-inferiority study design was employed as upper confidence interval (CI) limit for HR Results From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n = 303) or DP (n = 305). Patient demographics were well balanced between the two arms. Two interim analyses were preplanned. At the final analysis, a total of 480 death events were observed. OS for SP was non-inferior to DP (median survival, 16.1 versus 17.1 months, respectively; HR = 1.013; 96.4% CI, 0.837–1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), grade 1/2 alopecia (59.3% versus 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusion S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.

Background Quality of life (QOL) should be an explicit priority throughout the course of care for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel plus cisplatin (DP) is the only third-generation regimen that has demonstrated statistically significant improvements in overall survival and QOL by a head-to-head comparison with a second-generation regimen (vindesine plus cisplatin) in patients with advanced NSCLC. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Method Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). A non-inferiority study design was employed; the upper confidence interval (CI) limit of the hazard ratio (HR) was Results From April 2007 through December 2008, 608 patients were randomly assigned to SP (n = 303) or DP (n = 305) at 66 sites in Japan. Patient demographics were well balanced between the two groups. Two interim analyses were preplanned. At the final analysis, a total of 480 deaths had occurred. The primary endpoint was met. OS in the SP arm was non-inferior to that in the DP arm (median survival, 16.1 vs. 17.1 months, respectively; HR = 1.013; 96.4% confidence interval, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. The rates of febrile neutropenia (7.4% vs. 1.0%), grade 3/4 neutropenia (73.4% vs. 22.9%), grade 3/4 infection (14.5% vs. 5.3%), and grade 1/2 alopecia (59.3% vs. 12.3%) were significantly lower in the SP arm than in the DP arm. In terms of physical functioning and global functioning on the EORTC QLQ-C30 and lung cancer module (LC-13), QOL was worse in the DP arm (repeated measures ANOVA: p Conclusion S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC. Disclosure M. Nishio: HONORARIA: Chugai Pharma. K. Kobayashi: HONORARIA: a reasonal payment for lectuture speech from Taiho Pharmaceutical Company. M. Takeuchi: CONSULTANT OR ADVISORY ROLE; Taiho. All other authors have declared no conflicts of interest.