Pemetrexed-based Chemotherapy Research Articles

Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non–Small-cell Lung Cancer

IntroductionPemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non–small-cell lung cancer (NSCLC). Materials and MethodsWe conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab. ResultsThe ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate < 364.5 nM had an ORR of 27% compared with 71% for patients with RBC total folate > 364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01). ConclusionA low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response.

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non–Small-Cell Lung Cancer

BackgroundOnartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. MethodsPatients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. ResultsEfficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). ConclusionOnartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

Efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement.

BackgroundROS1 rearrangement is a novel molecular subgroup of non-small-cell lung cancer (NSCLC). This study aimed to investigate the efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement.ResultsA total of 2309 patients received ROS1 fusion detection and 51(2.2%) patients had ROS1 rearrangement. There was no significant difference between ROS1 fusion-positive and fusion-negative cohorts in demographic data. For the ROS1 fusion-positive patients, crizotinb-treated group had a higher overall response rate (ORR, 80.0%), disease control rate (DCR, 90.0%) and longer progression-free survival (PFS, 294 days) compared with the rates in pemetrexed-treated group (ORR, 40.8%; DCR, 71.4%; PFS, 179 days) and non-pemetrexed-treated group (ORR, 25.0%; DCR, 47.7%; PFS, 110 days). Besides, ORR, DCR and PFS were similar in three major ROS1 fusion partners. For the first-line treatment, patients received pemetrexed had a significant longer PFS than those received non-pemetrexed chemotherapy (209 vs. 146 days, P = 0.0107). In pemetrexed-treated cohorts, ROS1-positive patients with low TS expression had a statistically significant longer PFS than those with high TS expression (184 vs. 110 days, P = 0.0105).Materials and methodsWe retrospectively identified patients with NSCLC who were screened for ROS1 fusion using multiplex reverse transcription-polymerase chain reaction (RT-PCR) from October 2013 to February 2016. The thymidylate synthase (TS) mRNA levels were tested using quantitative real-time RT-PCR.ConclusionsCrizotinib was also highly active at treating Chinese NSCLC patients with ROS1 rearrangement. TS expression could predict the efficacy of pemetrexed-based therapy in ROS1 fusion-positive patients.

High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer

Chromosomal rearrangements involving ROS1 define a rare entity of lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. We report clinical outcomes and genomic findings of patients with ROS1-positive lung cancer who were prospectively identified within a multiplex biomarker profiling program at the West German Cancer Center. Standardized immunohistochemical (IHC) analysis, fluorescence in situ hybridization (FISH), and hotspot mutation analyses were performed in 1345 patients with advanced cancer, including 805 patients with metastatic lung adenocarcinoma. Clinical and epidemiological data were retrieved from the institutional database. ROS1 positivity by IHC analysis was detected in 25 patients with lung cancer (4.8% of lung adenocarcinomas), including 13 patients (2.5%) with ROS1 FISH positivity with a cutoff of at least 15% of events. Of the ROS1 IHC analysis-positive cases, 36% presented with concomitant oncogenic driver mutations involving EGFR (six cases, five of which were clinically validated by response to EGFR-targeting agents), KRAS (two cases), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), and BRAF. Three cases initially classified as ROS1 FISH-negative passed the threshold of 15% positive events when repeat biopsies were analyzed at progression. The median overall survival of the ROS1-positive patients (104 months) was significantly superior to that of the 261 patients with EGFR/anaplastic lymphoma kinase/ROS1-negative lung adenocarcinoma (24.4 months, p= 0.044). Interestingly, the overall survival of the 13 ROS1-positive patients with lung cancer from initiation of pemetrexed-based chemotherapy was significantly prolonged when compared with that of 169 pemetrexed-treated patients with EGFR/anaplastic lymphoma kinase/ROS1-negative adenocarcinoma (p= 0.01). ROS1-positive metastatic lung adenocarcinomas frequently harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH-positive events are variable over time. This heterogeneity provides additional therapeutic options if discovered by multiplex biomarker testing and repeat biopsies.

Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site

ABSTRACTDuring the last decade the therapeutic landscape of Non Small Cell Lung Cancer (NSCLC) has profoundly changed with the identification of actionable genetic alterations that defined molecularly selected subgroups of patients with specific clinic-pathological characteristics and increased sensitivity to specific targeted agents. The presence of ROS1 rearrangements defines a small subgroup of lung adenocarcinomas (∼1–2%) with peculiar clinic-pathological characteristics and increased sensitivity to Crizotinib. It has been reported that ROS1-tranlslocated NSCLCs may also respond well to Pemetrexed-based chemotherapy. Moreover, patients with oncogene-addicted NSCLC may present peculiar pattern of metastatization and, in some instances, are associated with unusual site of metastases. Herein, we present a case of a young woman with bilateral ovarian metastases from a ROS1-positive adenocarcinoma of the lung with a lengthy progression-free survival on Pemetrexed-containing chemotherapy.

Abstract 2267: Efficacy of pemetrexed-based chemotherapy in patients with NSCLC harboring KRAS mutations

Abstract [Background] Biomarkers like epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) rearrangement have been discovered in lung cancer, leading to targeted therapies developed in non-small cell lung cancer (NSCLC). Several oncogenes have been reported to be negative biomarkers for response to tyrosine kinase inhibitors (TKIs), for example, NSCLC with KRAS mutations are resistant to EGFR-TKIs. A preclinical study showed that KRAS mutant lung cancer cells were sensitive to pemetrexed, while a retrospective study reported that pemetrexed-based chemotherapy didn't show a favorable outcomes in patients with KRAS mutant NSCLC. We, therefore, studied efficacy of pemetrexed-based chemotherapy in patients with NSCLC, and compared the efficacy between KRAS and wild-type NSCLC. [Methods] We retrospectively studied the medical records of patients diagnosed with NSCLC between 2013 to 2015. Genomic DNA (gDNA) was extracted from FFPE tissue samples (QIAamp DNA FFPE Tissue Kit, QIAGEN). KRAS mutations were evaluated using Ion Torrent NGS systems (Ion PGM, Thermo Fischer Scientific) or PCR-rSSO. AmpliSeq Colon and Lung Cancer Research Panel v2 was used in the present study. We used Ion Reporter software for next-generation sequencing data analysis. [Results] We analyzed the data of 226 patients with NSCLC and successfully extracted gDNA from 94 tissue samples. Among them, mutation analysis by Ion PGM system was performed in 48 samples and PCR-rSSO in 46 samples. We will report response rate and progression free survival in the patients treated with pemetrexed-based chemotherapy. Citation Format: Shunsuke Okumura, Takaaki Sasaki, Shin-ichi Chiba, Masatoshi Sado, Naoyuki Miyokawa, Hiroshi Funakoshi, Yoshinobu Ohsaki. Efficacy of pemetrexed-based chemotherapy in patients with NSCLC harboring KRAS mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2267.

Malignant pleural mesothelioma in the elderly patient. Retrospective study in the centers of Alessandria and Casale Monferrato

Introduction: This study aims to retrospectively evaluate the management of the diagnostic and therapeutic procedure and the clinical outcome of a case series of elderly patients followed at the Hospitals of Alessandria and Casale Monferrato. Methodology: From a total of 343 patients with MPM, treated between January 2005 and November 2011 at the Hospital SS. Antonio e Biagio and Cesare Arrigo Hospital in Alessandria and SS. Spirito Hospital in Casale Monferrato, 124 patients aged ≥70 years were selected. The following were analyzed for each patient: age, asbestos exposure, sex, histology, stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI), and treatment performed. Results: Median overall survival (OS) was 9 months. The most frequent histotype was epithelioid (59%). Asbestos exposure was documented in 96% of cases. The diagnosis of MPM was documented by histological examination in 91% of patients (the rate of histological diagnosis from the data of the Italian Mesothelioma Registry was much lower). The stage at diagnosis in most cases (60%) was reported as I-II. The ECOG-PS of this case series was between 0 and 1 in almost all cases, confirming that old age is not synonymous with poor performance status. No major comorbidities were observed in 64% of cases, whereas a mean score of 4 and 5 was found in 18% and 10% of cases, respectively. Survival analysis showed a negative impact on median OS in the presence of a CCI ≥4. Pemetrexed-based chemotherapy in this elderly population was found to be feasible with a more than acceptable toxicity profile. Conclusion: This study demonstrated the influence also in the elderly population of some prognostic factors such as histological subtype, IMIG stage, presence of comorbidities according to CCI, and therapy with pemetrexed-based or non-pemetrexed-based regimens. On the basis of these analyses, greater attention to this category of patients is needed, hoping for the possibility of conducting prospective studies aimed also at the elderly population.

Smoking History as a Predictor of Pemetrexed Monotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer

Background: Pemetrexed monotherapy has come to be recognized as the standard of care for second-line therapy of non-squamous non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) expression is recognized as a potential predictor of the response to pemetrexed-based chemotherapy in patients with advanced NSCLC. The purpose of this study was to identify useful predictors of the response to pemetrexed other than TS expression. Methods: The records of non-squamous NSCLC patients without driver mutations who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2009 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated. Results: In the 116 patients with non-squamous NSCLC, the overall response rate and progression-free survival (PFS) were 10.3% and 2.1 months, respectively. The disease control rate and PFS differed significantly among current smokers and never-smokers/former light smokers (44.9 vs. 65.8%, and 1.8 vs. 4.0 months, respectively). Furthermore, multivariate analysis identified Eastern Cooperative Oncology Group Performance Status and smoking status as independent predictors of the PFS. Conclusion: The clinical data obtained in this study may provide a valuable basis for the use of smoking status as a predictor of pemetrexed monotherapy in wild-type NSCLC patients.

Association of glucocorticoid receptor expression with the treatment outcome of pemetrexed-based chemotherapy in NSCLC patients.

e20525 Background: Pemetrexed is the preferred chemotherapy in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), yet in lack of biomarkers for predicting efficacy. Dexamethasone which is one of premedication of pemetrexated, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cell (PBMC) on pemetrexed efficacy. Methods: One hundred and twenty-two patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC were measured before treatment with pemetrexed using flow cytometry, and Real-Time PCR was used to detect the level of GRα and GRβ. Results: The response rate for all patients was 38.5%, with a median PFS of 5.9 months and OS of 14.3 months. In univariate analyses, patients with low level of GRα/GRβ ratio in PBMC had higher RR, better PFS, and better OS than those with high level of GRα/GRβ ratio(RR: 48.2% vs. 30.3%, p = 0.043; mPFS: 6.9 months vs. 4.0 months, p = 0.000; mOS: 18.7 months vs. 12.2 months, p = 0.005). The baseline GRα/GRβ ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95%CI: 0.208-0.978, p = 0.044), PFS (HR = 1.584, 95%CI: 1.094-2.295, p = 0.015), and OS (HR = 1.761 , 95%CI: 1.195-2.595, p = 0.004). Conclusions: Baseline GRα/GRβ ratio detcteted by FCM is the same as RT-PCR in PBMC may predict the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sqNSCLC patients.

Efficacy of Pemetrexed-Based Chemotherapy in Patients with ROS1 Fusion–Positive Lung Adenocarcinoma Compared with in Patients Harboring Other Driver Mutations in East Asian Populations

IntroductionThe efficacy of pemetrexed-based chemotherapy in patients with advanced lung adenocarcinoma with novel ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) oncogenic rearrangement is unclear. This study aimed to compare the efficacy of pemetrexed-based chemotherapy in patients with advanced ROS1-fusion lung adenocarcinoma with its efficacy in those having different driver mutations. MethodsWe retrospectively identified patients with advanced lung adenocarcinoma who were screened for epidermal growth factor receptor gene (EGFR) mutations, echinoderm microtubule associated protein like 4 gene (EML4)–anaplastic lymphoma receptor tyrosine kinase gene (ALK) translocation, Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutations, and ROS1 fusion by using multiplex reverse-transcriptase polymerase chain reaction. Patients who received pemetrexed-based therapy were enrolled for further analysis. The demographic data, clinical outcomes, and thymidylate synthase immunostaining (H-score) of patients with ROS1 fusion–positive lung adenocarcinomas were compared with those of patients harboring EGFR mutations, EML4-ALK fusion, KRAS mutations, and quadruple negativity. ResultsA total of 253 patients with advanced lung adenocarcinoma received a pemetrexed-based regimen and were classified on the basis of molecular findings as follows: 102 patients (40.3%) with EGFR mutations, 32 patients (12.6%) with EML4-ALK translocation, three patients (1.2%) with KRAS mutations, 19 patients (7.5%) with ROS1 fusion, and 97 patients (38.3%) with quadruple-negative status. Patients with ROS1 fusion had a better overall response rate (57.9%, p = 0.026), disease control rate (89.5%, p = 0.033), and longer progression-free survival (7.5 months, p = 0.003) compared with patients harboring other driver mutations. However, the H-score of thymidylate synthase was not associated with the response to pemetrexed therapy in patients with different molecular subtypes of lung adenocarcinoma. ConclusionsROS1 fusion positivity is probably a favorable factor of pemetrexed-based therapy for patients with lung adenocarcinoma.

Phase II Study of High-Dose Pemetrexed Plus Cisplatin as First-Line Chemotherapy In the Treatment of Patients with Brain Metastases from Lung Adenocarcinoma

Brain metastases (BMs) occur in up to 40% of patients with nonsmall-cell lung cancer (NSCLC). When surgery or radiosurgery is not possible, whole-brain radiotherapy (WBRT) is the standard treatment, with a cerebral response rate of approximately 30%. Pemetrexed-based chemotherapy presents an approximately 40% response rate on brain lesions of NSCLC with brain metastases. This trial assessed the efficacy and safety of high-dose pemetrexed plus cisplatin in NSCLC with BMs after WBRT. Thirty-two patients with Karnofsky Performance Status ≥70 were enrolled. Patients of NSCLC with brain metastases were eligible for WBRT, which was administered at 30 Gy/10f. Thereafter, high-dose pemetrexed plus cisplatin was given up to 6 cycles. Primary end point was objective response rate (RR) and progression-free survival on BM. Secondary end points included extracerebral and overall RR, safety profile, and survival. The objective cerebral RR (complete and partial response) was 68.8 % (22 of 32 patients). Extracerebral and globe RR was 37.5% and 31.3%, respectively. The median progression-free survival of BM was 13.6 months, and median overall survival was 19.1 months. This modality of treatment appears to a better efficacy and a good safety of BM, as well as extracerebral. Further clinical studies are warranted.

Prolonged response to pemetrexed-based chemotherapy in a patient with peritoneal mesothelioma: a case report and review of the literature

Abstract Peritoneal mesothelioma is a rare tumor typically presenting with ascites and associated with occupational asbestos exposure with a latency period of 20–40 years. Intensive multi-modality approach combining cytoreductive surgery, intraperitoneal chemotherapy and possibly radiotherapy can be considered, but otherwise the prognosis is rather poor. Palliative chemotherapy may be an option in these rare cases. However, no approved systemic treatment exists for peritoneal mesothelioma. We present here a patient with peritoneal mesothelioma who was treated with the combination of pemetrexed with cisplatin shortly after the failure of hyperthermic intraperitoneal chemotherapy. The patient experienced durable partial response to the treatment, resolution of ascites, and returned to his normal daily life activities. With the exception of palliative chemotherapy in case of patients in good condition, therapeutic options in patients with peritoneal mesothelioma are currently very limited. The combination of pemetrexed and cisplatin can lead to long-term control in selected patients.

Research progress of the effect of folic acid in pemetrexed-based chemotherapy

This review analyzed the effect of folic acid on pemetrexed efficacy and toxicity, especially high-does folic acid supplementation. The optimal duration for supplementation prior to the first dose of pemetrexed has not been defined. The review also explored whether total plasma homocysteine levels can be as a marker to predict and avoid toxicity from pemetrexed therapy. Key words: Demetrexed; Folic acid; Homocysteine; Dose

Efficacy of chemotherapy in epidermal growth factor receptor (EGFR) mutated metastatic pulmonary adenocarcinoma patients who had acquired resistance to first-line EGFR tyrosine kinase inhibitor (TKI)

Introduction: Salvage chemotherapy is frequently used when tumour epidermal growth factor receptor (EGFR) mutated patients experience disease progression with first-line EGFR-tyrosine kinase inhibitor (TKI) treatment. However, the efficacy of salvage chemotherapy is still unknown.Methods: We retrospectively reviewed the chart records of our pulmonary adenocarcinoma patients between 2010 and 2013.Results: Five hundred and six of the 1240 stage IV adenocarcinoma patients had an EGFR mutation and 338 received first-line EGFR-TKI treatment. In all, 169 patients in this group received salvage chemotherapy after failure of EGFR-TKI, and 102 patients were eligible for this study. The chemotherapy response rate of these 102 patients was 24.5%, with a median progression-free survival (PFS) of 4.5?months, and median survival time was 14.6?months. Patients who received pemetrexed-based chemotherapy had longer PFS and overall survival (OS), although the extent was statistically insignificant. Progression-free survival and OS were longer for patients who received combination chemotherapy than single-agent chemotherapy.Conclusions: Pemetrexed-based combination chemotherapy is preferred before a more efficient treatment strategy is found.

Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma

IntroductionPrevious prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy. MethodsThis single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression. ResultsA total of 191 patients met the study criteria: median age 71 years (range 46–90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (≤450,000 versus >450,000, p < 0.001), initial PS (0–1 versus ≥2), maximum standardized uptake value (≤8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy. ConclusionsOur results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.

440P Association of glucocorticoid receptor expression with the treatment outcome of pemetrexed-based chemotherapy in NSCLC patients

440P Association of glucocorticoid receptor expression with the treatment outcome of pemetrexed-based chemotherapy in NSCLC patients

Clinical efficacy of vitamin support in lung adenocarcinoma patients treated with pemetrexed second-line chemotherapy

To analyze the clinical efficacy and toxicity of vitamin support in lung adenocarcinoma patients treated with pemetrexed second-line chemotherapy. Two hundred and eighty-three patients with stage 3/4 lung adenocarcinoma treated at our hospital from August 2010 to August 2013 were included in this study. The lung adenocarcinomas in all the 283 patients were confirmed by pathology or cytology, all were EGFR-negative, and all patients received pemetrexed second line chemotherapy. The 283 patients were randomly divided into two groups: the improved treatment group (142 cases) and the conventional treatment group (141 cases). The patients of conventional treatment group received 400 µg folic acid per os daily for 7 days before the first dose of pemetrexed, and continued until 21 days after the last dose of pemetrexed. Besides, they received 1000 µg vitamin B12 injection at 7 days before the first dose of pemetrexed, and once per cycle of pemetrexed for 3 cycles after the last dose of pemetrexed. The patients of the improved treatment group took 400 µg folic acid daily per os from the day before the first dose to 21 days after the last dose of pemetrexed. They also received 500 µg vitamin B12 by injection one day before the first dose, and one day before each therapy cycle of pemetrexed therapy. The mean number of cycles of pemetrexed chemotherapy was 4 in both groups. In the 142 patients of improved treatment group, complete response (CR) was observed in two cases, partial remission (PR) in 28, stable disease (SD) in 21, and progressive disease (PD) in 91 cases, with a total effective rate of 21.1%. While in the conventional treatment group, CR was observed in one case, PR in 27 cases, SD in 23 cases, and PD in 90 cases, with a total effective rate of 19.9%. The median progression-free survival (PFS) was 3.8 months in the improved treatment group and 4.2 months in the conventional treatment group (P=0.143). The toxicity of chemotherapy was mild in both groups, with no significant difference between the two groups (P>0.05). The most common side effects of hematological system were leukopenia and neutropenia, and the most common side effects of non-blood system were nausea and vomiting. The most common grade 3-4 toxic reaction in both groups was leukopenia and neutropenia, with no significant difference between the two groups (P>0.05). Multivariate analysis showed that the age of patients was an independent factor of grade 3-4 chemotherapy toxic reaction (P<0.05), while gender, the baseline level of PS score or blood system had no significant effect on the grade 3-4 chemotherapy toxic reaction (P>0.05). Compared with the conventional treatment scheme, the improved treatment scheme has similar therapeutic effects and could be used more conveniently, while the toxic effects of chemotherapy are not increased at the same time. Our results indicate that pemetrexed-based chemotherapy does not need to delay the chemotherapy because of vitamin support treatment.

Abstract B56: An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy

Abstract Background: “In situ vaccination” immune-gene therapy has the ability to induce broad, polyclonal anti-tumor responses directed by the patient's own immune system using standard “off the shelf” agents. In this trial, we activated endogenous tumor immunity by injection of an adenovirus expressing a Type I interferon into the pleural space of patients with malignant pleural mesothelioma (MM). Based on preclinical data showing synergy with chemotherapy, all patients then received standard systemic cytotoxic therapy. Methods: Two doses of intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x1011 viral particles were given concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib) to reduce side effects and to modify the tumor microenvironment by decreasing PGE- 2 levels. This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival. Bio-correlates were measured. Results: Forty patients were treated in this study: 18 patients received first-line Pemetrexed-based chemotherapy; 7 patients who had previously received front-line Pemetrexed-based chemotherapy &amp;gt;6 months prior to enrollment received Pemetrexed-based second-line chemotherapy. Additionally, in the second-line chemotherapy arm, fifteen patients (n=15) received gemcitabine-based chemotherapy. Treatment was well tolerated and adverse events were comparable to historical controls. Follow-up chest CT scans demonstrated an overall response rate of 20% by Modified RECIST criteria and disease control rate (DCR) of 85% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Encouragingly, median survival for all patients with epithelial histology (including both first and second line) was 26 months (95% CI: 15-ND); median overall survival (MOS) for patients with non-epithelial histology (both first and second line) was 6.5 months (95% CI: 5.50 – ND). [See figure] Historical MOS with first line chemotherapy alone is 13.3 months. No clear predictors for response were identified including: baseline immunologic parameters (i.e. activated T cells or number of regulatory T cells); the presence of the immune-gene signature in their biopsies; peak levels of interferon in blood or pleural fluid; or induction of anti-tumor antibodies, activated T cells, or natural killer cells in peripheral blood. Conclusions: The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe in patients with unresectable malignant pleural mesothelioma. Overall survival rates were significantly higher than historical controls, particularly in the second-line groups. The results of this study support proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Citation Format: D. H. Sterman, E. Alley, J. Friedberg, S. Metzger, J. Stevenson, E. Moon, A. R. Haas, A. Vachani, S. I. Katz, G. Cheng, J. Sun, D. F. Heitjan, L. Litzky, K. Cengel, C. B. Simone, II, M. Culligan, M. Culligan, S. M. Albelda. An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B56.

P0054 Maintenance therapy with pemetrexed immediately following induction treatment with pemetrexed plus cisplatin for advanced non-small-cell non-squamous carcinoma of the lung: A single institution’s experience

Background Maintenance therapy with pemetrexed for non-small-cell non-squamous lung cancer following a combination of pemetrexed and cisplatin is a treatment option. We present our experience of such patients at the University Hospital of North Midlands (Stoke-on-Trent, UK). Methods We collected and retrospectively analysed the medical records of all patients locally who had received pemetrexed maintenance therapy for non-small-cell lung cancer between March 2012, and April 2014. Findings 384 patients were diagnosed with lung adenocarcinomas, of whom 80 (20.8%) received pemetrexed-based combination induction chemotherapy. 17 patients subsequently received pemetrexed maintenance therapy, with a mean of 5.9 (range 1–20) maintenance cycles. Mean progression-free survival was 5.2 (range 2–15) months. 1-year progression-free survival was 17.4%. Treatment was discontinued because of disease progression (71%), an adverse event (21%), or death from study disease (7%). Grade 3 and 4 laboratory and non-laboratory adverse events were seen in 11.8% and 17.6% of patients, respectively. Anaemia was the most common adverse event (65% patients grade 1–2; 5.9% patients grade 3–4); 35% of patients required blood transfusion. Neutropenia was seen in 41% of patients (35.3% patients grade 1–2, 5.9% patients grade 3–4). Two patients with neutropenia were withdrawn from treatment due to declining renal function. We noted a significant correlation between performance status and number of maintenance cycles administered (Spearman’s rank; R = −0.511, p = 0.036). Interpretation The mean number of maintenance cycles and the 1-year progression free survival was lower than reported in previous studies; however, the number of cycles was still favourable. Performance status should be carefully considered before this drug regimen is started in patients and haemoglobin levels should be monitored vigilantly between cycles of pemetrexed.

Study of Pemetrexed-based Chemotherapy for Patients with Locally Advanced or Metastatic Cancers.

This study was conducted to observe the efficacy and safety of pemetrexed based chemotherapy in treating patients with locally advanced or metastatic cancers as first-line, second-line or third-line therapy. From May 2011 to January 2015, we recruited 29 patients with advanced breast cancer, 19 patients with advanced ovary cancer, 17 patients with advanced esophageal cancer,5 patients with advanced gallbladder cancer,5 patients with advanced cervical cancer and 1 patient with advanced tongue cancer in Jiangsu Cancer Hospital and Research Institute.All of them were pathologically confirmed and treated with pemetrexed based chemotherapy. After two cycles of treatment,efficacy and safety can be evaluated. For pemetrexed based regimens,including 76 patients with 6 kinds of advanced cancer were considered eligible for inclusion. Complete remission represents CR, partial remission represents PR, stable disease represents SD, progressive disease represents PD. Among 29 patients with advanced breast cancer, 4 patients chose pemetrexed based regimens as second-line treatment,1 of them was PR,the other 3 got SD. The last 25 patients made use of this chemotherapy as third-line treatment, except one patient could not be assessed, 2 of them got PR,6 of them got SD,the remaining 16 of them finally were PD.19 patients with advanced ovary cancer,5 patients used this regimens as second-line treatment, 3 of them got PD,the remaining patients got SD, respectively. The last 14 patients made use of pemetrexed based regimens as third-line treatment,. RR (CR+PR) was 28.5%. Among 17 patients with advanced esophageal cancer, 2 patients made use of pemetrexed based regimens as first-line treatment,both of them got PR.4 of them used this chemotherapy as second-line regimen, except 2 patients could not be assessed,the remaining 2 was PD at last. The last 11 patients was third-line users, RR (CR+PR) was 18.2%. Among 5 patients with advanced gallbladder cancer, pemetrexed based regimens was used in 1 patient as first- line treatment and 1 patient as second-line treatment. The curative effect was SD and PD, respectively. 3 patients accepted pemetrexed based regimens as third-line treatment, 2 of them got PD as results and another was SD. Among 5 patients with advanced cervical cancer, just 1 patient adopted pemetrexed based regimens as first-line treatment, whose curative effect was PR.2 patients chose this chemotherapy regimens as second-line treatment. Both of them got PD as their consequence. The last 2 patients made use of the regimens as third-line treatment, the effect of them was PD and SD, respectively. The one who with advanced tongue cancer, pemetrexed based regimens was used as second-line treatment, and the consequence was PD. About 71.1% patients experienced bone marrow suppression. Among them, 5 patients reached 4 grade. Other toxicity of pemetrexed were neurotoxicity, fatigue, diarrhea, dysphagia and vomiting. No treatment related death occurred with pemetrexed-based treatment. Pemetrexed based chemotherapy has considerable effect in patients with advanced cancers such as breast cancer,esophageal cancer and ovary cancer. More randomly clinical trials are needed to verify the results.