Thoracic Oncology Research Group Research Articles

P1-018 - A Phase I/II Trial of Erlotinib S-1 Therapy in Patients with Previously Treated Non-Small-Cell Lung Cancer: Thoracic Oncology Research Group (TORG) 0808/0913

ABSTRACT 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.

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902

Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population. This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500mg/m(2)) combined with carboplatin (area under the curve: AUC 6) every 3weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival. Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90%) patients completed four cycles, and 33 (67%) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51%) and stable disease in 18 patients (37%). Median progression-free survival (PFS) and overall survival (OS) were 6.3months and 24.3months, respectively. The median PFS and OS were 7.9months and 24.3months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3months and 21.0months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p=0.09) and OS (p=0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33%) and 9 (18%) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths. The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).

Feasibility trial of adjuvant chemotherapy with docetaxel (DOC) plus cisplatin (CDDP) followed by maintenance chemotherapy of S-1 in completely resected non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0809.

7012 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 (pts) with curatively resected stage II and IIIA NSCLC. Methods: Pts received 3 cycles of DOC (60mg/m2 d1) plus CDDP (80mg/m2 d1), q3-4w, and subsequently S-1 at 40mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary endpoint was determination of feasibility, which was defined as the proportion of pts 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 Jun 2009 and Nov 2010, 131 pts were enrolled, of whom 129 pts 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 pts, 109 pts (84.5%) completed 3 cycles of DOC+CDDP. 106 pts initiated the maintenance S-1 and 66 pts (51.2%, 95% CI: 42.5-59.8) completed 8 cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 pts terminated maintenance S-1 at 3 cycles or less. Grade 3/4 toxicities 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. One pt developed interstitial pneumonia and sepsis, resulting in treatment-related death. Recurrence-free survival data will be presented. Conclusions: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule of maintenance S-1, such as a 2-week rest period rather than 1-week, might improve treatment compliance.

9108 POSTER Randomized Phase II Trial of Gemcitabine and Carboplatin (G/C) With or Without Dexamethasone (Dex) Pretreatment in Chemotherapy-naive Patients (pts) With Advanced Non-small Cell Lung Cancer (NSCLC) – Results of Kyoto Thoracic Oncology Research Group (KTORG) Trial 0501

9108 POSTER Randomized Phase II Trial of Gemcitabine and Carboplatin (G/C) With or Without Dexamethasone (Dex) Pretreatment in Chemotherapy-naive Patients (pts) With Advanced Non-small Cell Lung Cancer (NSCLC) – Results of Kyoto Thoracic Oncology Research Group (KTORG) Trial 0501

Phase I/II trial of gemcitabine plus oral TS-1 in elderly patients with advanced non-small cell lung cancer: Thoracic oncology research group study 0502

A phase I/II trial of TS-1 combined with gemcitabine was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients older than 70 years of age received TS-1 orally b.i.d. on days 1–14 and gemcitabine intravenously on days 8 and 15 every 4 weeks. In phase I ( n = 22), each cohort received escalating doses of TS-1 (30–40 mg/m 2 b.i.d.) and gemcitabine (800–1000 mg/m 2); MTD was 40 mg/m 2 b.i.d. TS-1 and 1000 mg/m 2 gemcitabine; RD was 30 mg/m 2 b.i.d. TS-1 and 1000 mg/m 2 gemcitabine. Dose-limiting toxicities included a grade 3 infection, skin toxicity, and stomatitis. In phase II ( n = 37), the overall response rate was 27% (90% confidence interval (CI): 15–42%) and the median time to progression and overall survival were 4.2 months (90% CI: 3.2–5.7) and 12.9 months (90% CI: 10.4–14.7), respectively. The most common grade 3 or higher toxicity was neutropenia (45.9%), and thrombocytopenia was observed in 13.5% of patients. Two cases each of grade 3 pneumonitis and skin toxicity were observed, but nonhematological toxicities occurred at generally low frequencies. TS-1 with gemcitabine is a promising doublet regimen in elderly patients with advanced NSCLC with acceptable toxicities.

Topoisomerase II, carbonyl reductase I, and chemosensitivity for amrubicin in the treatment of patients with small-cell lung cancer

8104 Background: Amrubicin (AMR) has been suggested to provide a new effective therapeutic option for small-cell lung cancer (SCLC). It is a totally synthetic 9-aminoanthracyclin and converted by carbonyl reductase I (CBR-I) to its active form, amrubicinol, that has higher potent activity than the parent drug and inhibits purified human topoisomerase II (topo-II). We previously reported the promising result of a prospective phase II trial for AMR monotherapy in patients with second-line SCLC (Thoracic Oncology Research Group Study 0301). Using blood samples at enrollment in this trial, the clinical significance of topo-II and CBR-I expression levels on antitumor effect as well as toxicity has been examined. Methods: Total RNA was extracted from the blood with an RNeasy Mini Kit (Qiagen Inc.) and DNase treatment was performed using the RNase-Free DNase Set (Qiagen Inc.). RT-PCR analysis was performed using TaqMan technology. Quantification of target cDNA (Top-II alpha, CBR-I and beta-actin gene) was conducted using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems Inc.). Quantification was performed using the relative standard curve method. Results: The trial registered a total of 60 patients, of which 40 blood samples were available. Nineteen patients achieved a CR or PR to AMR according to the RECIST assessment and 21 did not. Patients with tumor response had a significantly lower Topo-II level than those without (p=0.0465, Wilcoxon test), although there was no association between tumor response and the level of CBR-I (p=0.3229, Wilcoxon test). We did not find any significant association between the levels of the two enzymes and toxicity. Conclusions: Topo-II may be a potential predictor of response in the treatment of AMR for second-line SCLC. Further investigations in larger patient materials are warranted. No significant financial relationships to disclose.

Prostacyclin synthase (PTGIS) expression and epigenetic regulation in non-small cell lung cancer (NSCLC)

e22160 Background: Prostacyclin synthase (PTGIS) inhibits platelet aggregation and promotes vasodilation. Overexpression of this gene has been shown to inhibit lung cancer growth in a mouse model. Hypermethylation of the PTGIS promoter resulting in downregulation of PTGIS expression has been implicated in colorectal cancer. In this study we have examined both the expression patterns and epigenetic regulation of PTGIS in NSCLC. Methods: DNA/RNA and protein was extracted from matched tumour/normal samples (Thoracic Oncology Research Group BioBank, St James Hospital). PTGIS in these samples and a panel of retrospective resected lung samples was examined by immunohistochemistry and western blotting. A panel of NSCLC cell lines were treated with inhibitors to histone deacetylases (HDi) and DNA methyltransferases (DNMTi) and PTGIS expression examined by RT-PCR. Chromatin immunoprecipitation (ChIP) was used to examine changes to the PTGIS promoter in response to HDi. Results: PTGIS was found to have variable expression in both tumour samples and a panel of lung cancer cell lines. PTGIS expression was demonstrated in the vascular endothelial and bronchial epithelial cells of normal and cancerous sections. A striking variation in intratumoural PTGIS expression was observed. Methylation analysis of cell lines demonstrated hypermethylation of the PTGIS promoter. Treating cells with epigenetic inhibitors resulted in significant upregulation of PTGIS expression. Direct chromatin remodelling of the PTGIS promoter was confirmed. Conclusions: PTGIS is epigenetically regulated. The discrepancy between PTGIS mRNA and protein levels in tumor samples indicates that post-transcriptional and post-translational regulation of PTGIS is central to expression and requires further elucidation. Increased PTGIS expression is a potential therapeutic strategy for tumour prevention. [Table: see text]

Phase I/II study of S-1 combined with gemcitabine in elderly patients with advanced non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0502

19050 Background: Optimal treatment for elderly patients with NSCLC has been under active investigation. This study evaluated the safety and initial efficacy of a novel combination regimen of oral fluoropyrimidine S-1 plus gemcitabine (GEM) for elderly patients (pts) with advanced NSCLC. Methods: A phase I/II study in 11 participating centers examined S-1 plus GEM combination in pts with 70 years of age or older, stage IIIB or IV previously untreated NSCLC. The starting dose was 60 mg/m2/day (days 1 to 14) for S-1 and 800 mg/m2 for GEM (days 8 and 15), with the cycle repeated every 3 or 4 weeks. GEM was increased to 1000 mg/m2 at level 2 and S-1 was increased to 80 mg/m2/day at level 3. Phase II portion of the study assessed the efficacy and tolerability of the combination regimen at the dose determined in the phase I portion. The primary endpoint was objective response rate. Results: Patients were registered in the study between May 2005 and December 2006. A total of 19 evaluable pts were enrolled in the phase I portion: 6 pts on dose level 1, 7 on dose level 2, and 6 on dose level 3. Median age of the phase I cohort was 75 years (range 70–85). Maximum tolerated dose was the level 3 and dose-limiting toxicities at this level included grade 4 neutropenia (2 pts) and grade 3 rush (4 pts). The recommended dose (RD) was determined to be the level 2 of S-1 60 mg/m2/day and GEM 1000 mg/m2, with which 27 pts were subsequently treated in the phase II portion. The median age of 34 pts treated with the RD was 77 years (range, 70–85). Grade 3 or 4 toxicities were neutropenia (12 pts; 6 with grade 4), thrombocytopenia (4 pts; 0 with grade 4), and rush (3 pts; 0 with grade 4). Ten pts (29%; 95% confidence interval [CI], 15–47%) had a partial response and 19 (56%; 95% CI, 38–73%) had a stable disease. The median survival time and 1 year survival rate were 14.2 months and 52%, respectively. Conclusions: Encouraging antitumor activity and safety of S-1 plus gemcitabine support further development of this combination therapy for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

PD4-3-5: Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small-cell-lung cancer (NSCLS): Thoracic Oncology Research Group Study 0502

PD4-3-5: Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small-cell-lung cancer (NSCLS): Thoracic Oncology Research Group Study 0502

Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group 0502

18137 Background: Optimal treatment for elderly patients with NSCLC has been under active investigation. This study evaluated the safety and initial efficacy of a novel combination regimen of oral fluoropyrimidine TS-1 plus gemcitabine (GEM) for elderly patients (pts) with advanced NSCLC. Methods: A phase I/II trial in 11 centers examined TS-1 and GEM in pts with age = 70, stage IIIB/IV previously untreated NSCLC. The starting dose was 60 mg/m2day (day 1–14) for TS-1 and 800 mg/m2 for GEM (day 8, 15). GEM was increased to 1,000 mg/m2 at dose level 2 and TS-1 was increased to 80 mg/mg2/day at dose level 3. Phase II portion of the study assessed the efficacy and tolerability of the combination regimen at the dose determined in the phase I portion. The primary endpoint was objective response rate. Results: Twenty two pts were enrolled in the phase I portion: 6 pts on dose level 1, 10 on dose level 2 and 6 on dose level 3. Median age of this group was 75 yrs (range 70–85). Dose limiting toxicities included Gr. 4 neutropenia (2 pts) and Gr.3 skin toxicity (4 pts). The recommended dose (RD) was TS-1 60 mg/day and GEM 1,000 mg/m2, with which 20 pts were subsequently treated in the phase II portion. The median age of 30 pts treated with the RD was 76 yrs (range 70–85). Grade (Gr) 3/4 toxicities include neutropenia (12 pts; 7 with Gr 4), thrombocytopenia (4 pts; 0 with Gr 4), skin toxicity (8 pts), thrombus (1 pt) and peumonitis (2 pts). Nine patients (30%, 95% confidence interval [CI] = 14 to 46%) had partial responses and 16 (53%, 95% CI = 35 to 71%) had stable disease. Conclusions: Encouraging antitumor activity and safety of TS-1 plus gemcitabine support further development of this combination therapy for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

Phase II study of amrubicin, a new active drug in refractory or relapsed small-cell lung cancer (SCLC): Thoracic Oncology Research Group Trial 0301

7060 Background: Amrubicin, a totally synthetic 9-aminoanthracycline, is a topoisomerase II inhibitor. The response rate to amrubicin at 45 mg/m2 on days 1–3 in chemotherapy-naive patients with extensive stage SCLC was 75.8% on an intent-to-treat analysis, with major dose-limiting toxicities of neutropenia, anemia, thrombocytopenia, and anorexia. The very high activity of amrubicin as a single agent in this disease led us to carry out the phase II trial reported here, which was designed to determine the antitumor activity and toxicity of amrubicin in previously treated pts with SCLC. Methods: Pts with cytologically or histologically proven SCLC who were previously treated with at least one platinum-based chemotherapy and ECOG PS 0–2 were eligible. They received amrubicin 40mg/m2 intravenously on days 1–3 every 3 weeks. The primary end-point was the response rate, which determined the sample size of 44 pts in the sensitive cases and 15 pts in the refractory cases, respectively. Secondary objectives were to determine the progression-free survival, overall survival, and 1-year survival rate. Results: In total, 60 pts consisting of 44 sensitive cases and 16 refractory cases with median age 67 years (range 52–79) and 46 out of 60 male were enrolled. The median treatment cycles were 4 (1–8). Grade 3/4 hematological toxicity per patient (pt) was neutropenia (83%), thrombocytopenia (20%) and anemia (33%). Febrile neutropenia was observed in 3 pts. Grade 3/4 non-hematological toxicity per pt was pneumonia (3%), anorexia (15%), low Na levels (8.3%), pneumonitis (1.7%) and cerebral hemorrhage (1.7%). No treatment-related death was observed. The overall response rates were 52% (95% CI: 37–68) in the sensitive cases, and 50% (95% CI: 25–75) in the refractory cases. The progression-free survival, overall survival and 1-year survival in the sensitive cases and the refractory cases were 4.0 and 3.2 months, 11.7 and 10.9 months and 48.2 and 37.8%, respectively. Conclusions: Amrubicin has a significant activity in SCLC, particularly in pts refractory to prior chemotherapy, with predictable and manageable toxicities. Further studies to evaluate the survival benefit of amrubicin in this setting are warranted. No significant financial relationships to disclose.