Successful re-challenge of PD-1 inhibitors in combination with bevacizumab and pemetrexed for multiple primary NSCLC progressing on prior PD-1 inhibitor therapy:one case report

Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumor therapies,such as chemotherapy,radiotherapy,and targeted therapy,have limited efficacy in the treatment of advanced synchronous multiple primary NSCLC.Immunotherapy is considered the standard of care for advanced or recurrent NSCLC,however,approximately 60%of patients develop primary or secondary resistance to treatment.There are no standard recommendations for overcoming immune resistance.We describe a case of simultaneous multiple primary NSCLC in a patient who received programmed death factor-1(PD-1)inhibitor monotherapy and developed brain metastases.After receiving second-line treatment with a combination of another PD-1 inhibitor,pemetrexed,and bevacizumab,the patient achieved complete remission,although they experienced grade 3 immune-related adverse reactions.Immune re-challenge is safe and feasible,and choosing a synergistic combination regimen is one of the options to overcome immune resistance.A larger sample size is needed to confirm the effectiveness and safety of this strategy in patients with NSCLC resistant to prior PD-1 inhibitors.

抗肿瘤新药pemetrexed治疗乳腺癌的研究

pemetrexed是一种新型抗叶酸药,能够抑制叶酸代谢途径中的多种酶,从而抑制嘧啶和嘌呤生物的合成,达到抑制肿瘤的作用。Ⅱ期临床结果显示,pemetrexed单药对于初治和复治的进展期乳腺癌均有较高的疗效。毒副作用主要为中性粒细胞减少、食欲减退、乏力和皮疹。补充叶酸和Vit B12可显著减少pemetrexed的血液学毒性,预防性给予皮质激素可减轻皮疹的发生。

First-line pemetrexed-platinum doublet chemotherapy with or without bevacizumab in non-squamous non-small cell lung cancer: A real-world propensity score-matched study in China

Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified.Results: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy.Conclusions: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.

Clinical observation of pemetrexed on advanced non-small-cell lung cancer

Objective： The aim of our study was to observe the efficacy and toxicity of 50 cases of advanced non-small cell lung cancer （NSCLC） patients treated by pemetrexed. Methods： Fifty patients, including 29 females and 21 males, with a median age 62 years （35–82 years）, 13 of whom were treated with pemetrexed only and the left 37 cases were treated with pemetrexed combined with platinum in the Department of Oncology, Renmin Hospital of Wuhan University from June 2006 to March 2009. Single agent regimen： patients received pemetrexed 500 mg/m2 on day 1 with every 21 days. Combination regimen： patients received pemetrexed 500 mg/m2 on day 1 and carboplatin 300 mg/m2 on day 1 or cisplatin 35 mg/m2 on day 1 to day 3 or nedaplatin 80 mg/m2 on day 1 by intravenous infusion with 21 days as one cycle. RECIST 1.0 standard was used to evaluate the clinical efficiency, and the WHO toxicity standard was used to evaluate toxic reaction, and the QOL was used to evaluate the quality of life. Results： All patients were given 162 cycles （at least 2 cycles, at most 6 cycles） and the response rate of all the patients were evaluated. There were 2 complete remission （CR）, 7 partial remission （PR）, 22 stable disease （SD） and 19 progressive disease （PD） in the group, the overall response rate was （RR） was 18.0% and disease control rate （DCR） 62.0%. The quality of life improvement rate reaches 58.0%. The major toxic reaction included neutropenia, thrombocytopenia, hypemia, nausea, and vomiting. Most of the severity of these effects was grade I–II and well tolerated. Conclusion： Chemotherapy with pemetrexed or pemetrexed combined with platinum in the treatment of advanced non-small cell lung cancer is effective, safe and well-tolerable, which can improve quality of life of the patient.

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective： The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor（EGFR） mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.Patients and methods： One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin（GP） chemotherapy and second-line EGFR tyrosine kinase inhibitor（TKI） or with first-line EGFR-TKI and second-line GP chemotherapy.Results： The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups（P=0.04）. Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups（P=0.001）. Among 61 cases with thirdline pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different（P=0.001）.Conclusions： Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.

Comparison of intra-pleural injection efficacy between Endostar and Bevacizumab combined with pemetrexed/cisplatin for the treatment of malignant pleural effusion in patients with epidermal growth factor receptor-/anaplastic lymphoma kinase-lung adenocarci

Objective To compare intra-pleural injection efficacy and safety between Endostar and bevacizumab combined with pemetrexed/cisplatin for the treatment of malignant pleural effusion in patients with epidermal growth factor receptor(EGFR)-/anaplastic lymphoma kinase(ALK)-lung adenocarcinoma. Methods Sixty-four pCVatients with EGFR-/ALK-lung adenocarcinoma with malignant pleural effusion(MPE) were admitted to the authors' hospital between January 2016 and June 2017. Patients were randomly divided into two groups: Endostar combined with pemetrexed/cisplatin(Endostar group); and bevacizumab plus pemetrexed/cisplatin(Bevacizumab group). They underwent thoracic puncture and catheterization, and MPE was drained as much as possible. Both groups were treated with pemetrexed 500 mg/m^2, intravenous drip(d1), cisplatin 37.5 mg/m^2 per time, intra-pleural injection(d1, d3). Patients in the Endostar group were treated with Endostar 30 mg per time, intra-pleural injection(d1, 3), and patients in the Bevacizumab group were treated with bevacizumab 5 mg/kg per time, intra-pleural injection(d1). Only one cycle of treatment was applied. MPE was extracted before treatment and on day 7 after treatment. The levels of vascular endothelial growth factor(VEGF) were determined using ELISA. Efficacy and side effects were evaluated according to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1, and National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) version 3.0 criteria. Results The objective response rates in the Endostar and Bevacizumab groups were 50.0% and 56.3%, respectively; there was no statistical difference between the groups(P > 0.05). After one cycle of treatment, the mean VEGF levels in MPE in both groups decreased significantly, and there was no significant difference in the degree of decline between the two groups(P > 0.05). In both groups, pre-treatment VEGF levels for patients achieving complete response were significantly higher than those for patients achieving stable disease + progressive disease(P < 0.05). No specific side effects were recorded. Conclusion Endostar and Bevacizumab demonstrated similar efficacy in controlling MPE in patients with EGFR-/ALK-lung adenocarcinoma through an anti-angiogenesis pathway, with tolerable side effects. The levels of VEGF in MPE could predict the efficacy of intra-pleural injection of anti-angiogenesis drugs.

Efficacy of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer patients during tyrosine kinase inhibitor treatment

Objective We aimed to evaluate the efficacy and safety of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer(NSCLC) patients during tyrosine kinase inhibitor(TKI) treatment. Methods Thirty-two patients with advanced NSCLC were divided into two groups. Patients in the control group received continuous daily epidermal growth factor receptor tyrosine kinase inhibitor(EGFRTKI) treatment, and patients in the experimental group received continuous daily EGFR-TKI along with pemetrexed treatment, which was administered on day 1 at 500 mg/m2. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from day 1 to day 21, with a cycle of every 21 days. Dexamethasone, folic acid, and vitamin B12 were also administered during the treatment. The endpoint of the primary study was the disease control rate. Results The objective response rate was 21.9%(95% CI: 7.6% to 36.3%) in the control group, whereas the disease control rate was 84.4%(95% CI: 71.8% to 97.0%) in the experimental group. The median progression-free survival was 6.2(95% CI: 2.4 to 10.0). Grades 3 or 4 adverse effects of leucopenia(15.6%), neutropenia(12.5%), anemia(3.1%), and nausea or vomiting(3.1%) were found in the experimental group.Conclusion The administration of pemetrexed combined with erlotinib or gefitinib showed a higher efficacy in TKI-resistant NSCLC patients. Further, the adverse effects of this drug combination were well tolerated by the patients. Pemetrexed combined with TKI treatment might provide a satisfactory therapeutic strategy for advanced NSCLC patients after TKI treatment.

Safety and efficacy of pemetrexed in gynecologic cancers: A systematic literature review

Gynecologic cancers represent a significant problem worldwide. Advanced, recurrent gynecologic cancers are often refractory to chemo-therapy, so new treatment regimens are needed. Pemetrexed is a third-generation, multi-targeted antifolate that has been approved for use in non-squamous non-small cell lung cancer and malignant pleural mesothelioma in both the United States and European Union. This paper reviews the safety and efficacy of pemetrexed in gynecologic cancers, which were defined as maligancies of the ovaries (including fallopian tubes and primary peritoneum), uterine endometrium, and uterine cervix. A search of English-language literature via PubMed and American Society of Clinical Oncology proceedings was performed from database inception to June 2012. Thirteen clinical trials involving the use of pemetrexed (alone and in combination with other agents) in gynecologic cancers were identified. These were phase I and phase II trials;there were 9 studies in ovarian cancer, 1 study in endometrial cancer, and 3 studies in cervical cancer. Pemetrexed with vitamin supplementation was tolerable in all clinical trials and had activity in ovarian and cervical cancers. Therefore, it may be reasonable to further explore the use of pemetrexed in ovarian and cervical malignancies.

FDA批准Alimta(pemetrexed disodium)与顺铂联用治疗恶性胸膜间皮瘤(一种罕见的癌症)

FDA批准Alimta(pemetrexed disodium)与顺铂联用治疗恶性胸膜间皮瘤(一种罕见的癌症)Alimta早先已被FDA指定为治疗此罕见病用药,它也是得到FDA批准的第一种治疗此症的药物。

Thymidylate synthase confers pemetrexed resistance of non-small cell lung cancer cells by EGFR/PI3K/AKT pathway

Chemotherapy drug resistance is the main cause leading to the relapse and metastasis of non-small cell lung cancer(NSCLC)patients.Our study aimed to investigate the mechanism of pemetrexed resistance in NSCLC.Firstly,the pemetrexed(PEM)-resistant PC-9 and A549 lung adenocarcinoma cell lines(PC-9/PEM and A549/PEM)were established.The expression of thymidylate synthase(TS)in PC-9/PEM,A549/PEM,A549,and PC-9 cells were analyzed by qRT-PCR and western blot.Then,cell viability,colony formation,migration,and invasion were performed on PEM-resistant cells transfected with TS siRNA.The role of EGFR in PEM resistance of PEM-resistant cells was investigated using EGFR siRNA.The effects of gefitinib and EGFR siRNA on EGFR/PI3K/AKT pathway and downstream signaling Cyclin D1 and E2F1 in PEM-resistant cells were analyzed.Results showed that the protein level of TS was significantly increased in A549/PEM and PC-9/PEM.TS knockdown inhibited the potency of proliferation,colony-forming potential,migration,and invasion in PEM-resistant cells.EGFR knockdown abrogated the resistance to PEM of PEM-resistant cells and suppressed the migration and invasion of PEM-resistant cells.Gefitinib treatment and EGFR knockdown respectively inhibited the EGFR/PI3K/AKT pathway and downregulated Cyclin D1 and E2F1 in PEM-resistant cells.Thus,TS might be a predictive marker for PEM resistance in NSCLC.Inhibition of the EGFR pathway abrogated the resistance to PEM and inhibited the EGFR/PI3K/AKT and downstream signaling of PEM-resistant NSCLC cell lines.

培美曲唑 Pemetrexed disodium

商品名：Alimta 化学式：C20H19N5Na2O6·7H2O 化学名：Glutamicacid，N-[4-[2-amino-4，7-dihydm-4-8oxo-1H-pyrmlo[2，3-d]pyrimidin-5-y1]ethyl]benzoy]-，disodiumsalt，heptahydrate LAS：150399-23-8化学结构：别名：LY231514，MTA 相对分子质量：597．46 类别：抗肿瘤药 开发单位：礼莱公司(Lilly)上市国家：美国 作用机制：胸苷酸合酶(Thymidylate synthase)／二氢叶酸还原酶双重抑制剂，抗代谢类抗癌药。

Pemetrexed Monotherapy and Pemetrexed Plus Platinum Combination Therapy as Non-First-Line Treatments for Advanced Non-Small Cell Lung Cancer

OBJECTIVE Data on the efficacy profiles of pemetrexed mono- therapy and pemetrexed plus platinum combination therapy in the non-first-line setting for patients with advanced non-small cell lung cancer （NSCLC） are limited, and previous studies have reported contradictory results. This study investigated and compared the efficacy and toxicity profiles of these two regimens to provide a broader understanding of their dynamics. METHODS Previously treated patients with advanced and/or recurrent NSCLC who received pemetrexed monotherapy or peme- trexed plus platinum combination therapy between January 1, 2006, and December 31, 2009, at Sun Yat-sen University Cancer Center were evaluated. The primary endpoint of this study was progres- sion-free survival （PFS）, whereas the secondary endpoints were overall response rate （ORR）, disease control rate （DCR）, overall survival （OS）, and toxicity. Survival was analyzed using the Kaplan- Meier method. Univariate analysis was performed to identify the factors potentially influencing OS, and chi-square analysis was carried out to compare ORR and DCR. RESULTS Forty-six patients with advanced and/or recurrent NSCLC were analyzed; of these patients, 25 were given pemetrexed monotherapy and 21 received pemetrexed plus platinum combina- tion therapy. The following correspond to the rates recorded for the pemetrexed monotherapy group and the pemetrexed plus platinum group： median PFS, 1.97 and 2.3 months （P=0.565）; median OS, 30.93 and 30.33 months （P=0.877）; ORR, 8% （2/25） and 9.5% （2/21） （P=0.857）; and DCR, 32% （8/25） and 57.1% （12/21） （P=0.09）. Univariate analysis revealed that no factor was correlated with OS from NSCLC （P〉0.05 for all）. Gastrointestinal toxicity in the pemetrexed plus platinum group was modestly higher than that in the pemetrexed monotherapy group （P=0.034）, but other adverse events were similar between the groups. CONCLUSION Compared with pemetrexed monotherapy, peme- trexed plus platinum combination therapy causes more gastro- intestinal toxicities and does not exhibit improved efficacy, in terms of ORR, DCR, PFS, and OS, in the non-first-line setting for NSCLC. However, further research with a higher patient population is necessary to validate this finding.

Predictive Factors of Severe Toxicities of Pemetrexed-Containing Chemotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer

Background: Pemetrexed (PEM) is an efficacious multi-targeted antifolate with acceptable toxicities for non-squamous non-small cell lung cancer (non-Sq NSCLC). However, in the clinical setting, PEM has more severe adverse effects than those reported. The aim of this study was to identify the factors for the toxicities of PEM-containing chemotherapy in non-Sq NSCLC patients in the clinical setting. Patients and Methods: We retrospectively evaluated the factors related to PEM toxicities in chemotherapy-naive patients with non-Sq NSCLC from September 2009 to July 2013 at our hospital. Logistic regression model was used in the univariate and multivariate analyses. Results: In total, 104 patients were analyzed. Grades 3 to 5 hematologic toxicities were frequent and included neutropenia (42%), febrile neutropenia (7%), anemia (18%), thrombocytopenia (17%), and disseminated intravascular coagulation (2%). On multivariate analyses, the predictors were poor performance status (PS) [odds ratio (OR): 4.89, 95% confidence interval (CI): 1.22 - 19.4] and low body mass index (OR: 1.44, 95% CI: 1.05 - 1.98) for febrile neutropenia;concomitant chronic infectious disease (OR: 6.63, 95% CI: 1.59 - 27.5) and bevacizumab use (OR: 3.57, 95% CI: 1.36 - 9.32) for neutropenia;poor PS (OR: 3.02, 95% CI: 1.33 - 6.85) for thrombocytopenia;and low serum albumin level (OR: 0.22, 95% CI: 0.08 - 0.63) for non-hematologic toxicities. Conclusions: In addition to the previously reported predictors of PEM toxicities, the presence of concomitant chronic infectious disease was associated with hematologic toxicities. Patient groups who are not sufficiently evaluated in clinical trials should be carefully monitored for the development of more toxicities than expected.

Phase II Study of Carboplatin and Pemetrexed Followed by Gefitinib for Patients with Advanced Non-Small Cell Lung Cancer Harboring Sensitive EGFR Mutation

We conducted a phase II study of combination chemotherapy with carboplatin (Cb) and pemetrexed (Pem) followed by gefitinib (Gef) to determine the effects and toxicities in patients with non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutation. Eligible patients received four courses of Cb at a dose corresponding to a target area under the curve equal to 6 mg/mL·min and 500 mg/m2 Pem on day 1 every three to four weeks followed by sequential Gef 250 mg once a day until tumor progression. Sixteen of registered 28 patients responded to Cb and Pem combination. Twenty-seven patients received sequential Gef and 8 non-responders to Cb and Pem achieved PR. The overall response rate was 85.7%. Among the major toxicities, grade 3 SGPT elevation, nausea and thrombosis were observed in 3, 3 and 1 patients, respectively, who received Cb and Pem, and grade 3 SGPT elevation and dry skin were observed in 5 and 1 patients, respectively, who received Gef. There was no febrile neutropenia and no treatment-related death. The median progression-free survival time was 19.1 months. Among 21 patients who were followed up for more than 2 years, 14 survived during that time. Cb and Pem followed by Gef maintenance are recommended for further evaluation for patients with metastatic NSCLC harboring sensitive EGFR mutation.

Experimental research of pulmonary injury on irradiation combined with pemetrexed

Objective: The aim of our study was to examine whether irradiation combined with pemetrexed can exacerbate pulmonary injury. Methods: Two groups of male Wister Rats were subjected to bilateral apex of lungs irradiation(a single dose of 12 Gy), with or without pemetrexed(20 mg/kg) by intraperitoneal injection at the same time; a third group of weightand age- matched animals were treated with pemetrexed alone, as the same dose scheme, time and root of injection. The fourth group served as control. The whole lung mounts were dissected to histological evaluation, while serum cytokine transforming growth factor-β1(TGF-β1) analysis were compared at 1, 7, 21, 35, 49 days post-irradiation after irradiation. Results: Histological examination showed a thickening of alveolar septal, accumulation of inflammatory cells. The irradiation treatment group and the radiation-chemo treatment group showed a statistically significant higher level of TGF-β1(P < 0.05) than other two groups, but there were no differences between these two irradiation groups. Conclusion: These results demonstrated that pemetrexed can not aggravate pulmonary injury and it could be safely used in concurrent or sequential radio-chemotherapy in lung adenocarcinoma.

The Clinical Investigation of Pemetrexed Plus Carboplatin as an Active and Tolerable Treatment Plan in Chinese Elderly Patients with Advanced Lung Adenocarcinoma

The standard chemotherapy for Chinese elderly patients with non-small cell lung cancer (NSCLC) remains undefined. The study was to evaluate the therapeutic effects as well as side effects of pemetrexed plus carboplatin regimen as the first-line therapy for Chinese elderly patients with advanced lung adenocarcinoma. Twenty-three Chinese elderly patients (male 14 and female 9, average age 73.7 years, range 70~81 years) with advanced lung adenocarcinoma received pemetrexed plus carboplatin as the first-line therapy, in detail, pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/ml/m2 were given intravenously on day 1. The treatment was repeated everyday in the 21 days cycle. Therapeutic effects were evaluated at least after two cycles of treatment. The remission rate, disease control rate, time to progression and overall survival were observed. The results showed that all the cases were valid for response evaluation, with the complete remission 0 case, partial remission 8 cases, stabilize disease 9 cases and progression disease 6 cases. The remission rate (including complete remission and partial remission) was 34.8%, disease control rate 73.9%, the time to progression was 5.8 months and the overall survival 13.7 months. There showed the positive relationship between the curative effects (either time to progression or overall survival) and chemotherapy cycles. The main toxicities were bone marrow suppression, nausea and vomiting. There was no chemotherapy-related death. The data suggested that the combination regimen with pemetrexed plus carboplatin is an active and tolerable treatment plan for Chinese elderly patients with advanced lung adenocarcinoma, in which the side effects were tolerable and manageable.

Pemetrexed and Gemcitabine for Chemotherapy Refractory Colorectal Cancer—Results of a Phase II and Translational Research Study

Introduction: We investigated the safety and efficacy of pemetrexed with gemcitabine in heavily pre-treated, chemotherapy refractory, KRAS mutated colorectal cancer (mCRC) and the prognostic value of quantitative levels of cell free DNA (cfDNA) in plasma. Methods: Inclusion criteria comprised;histopathologically verified, KRAS mutant, chemotherapy resistant mCRC, adequate organ function and performance status. Patients received pemetrexed (initially 500 mg/m2 q3w) + gemcitabine (1250 mg/m2 days 1 and 8) until progression or unacceptable toxicity. RECIST version 1.1, NCI-CTCAE version 4.0 and Kaplan-Meier statistics were used for endpoint evaluation. Cell free DNA was quantified from pre-treatment EDTA plasma-samples by an in-house qPCR. Results: Forty patients were included. The median number of cycles was 3 (range 0 - 12). Thirty-six percent obtained disease stabilisation, but?no objective response was observed. Median PFS and OS were 2.8 (range 2.1 - 4.0) and 5.4 (range 4.3 - 7.0) months, respectively. Adverse events caused immediate discontinuation of treatment or delay of the next cycle and consequently discontinuation in 5 patients. Translational research revealed a shorter PFS and OS with increasing levels of cfDNA. The median PFS in patients with cfDNA levels above the 75 percentile was 2 months compared to 4 months in the remaining patients, HR 3.23 (1.05 - 9.89), p = 0.0008. The median OS was 3 and 6 months, respectively, HR 2.9 (95%CI 0.98 - 8.34). Cox regression analysis confirmed that cfDNA remained a significantly independent prognostic factor for both PFS and OS. Conclusion: Pemetrexed and gemcitabine did not prove sufficient benefit and unacceptable toxicity was observed. The potential value of cfDNA should be investigated further.

The Role of Thymidylate Synthase in Pemetrexed-Resistant Malignant Pleural Mesothelioma Cells

We established new pemetrexed-resistant cells originating from malignant pleural mesothelioma MSTO-211H cells to clarify the mechanism involved in pemetrexed resistance in malignant pleural mesothelioma. In the pemetrexed-resistant cells, only thymidylate synthase (TYMS) mRNA was overexpressed among other well-known molecular targets and chemosensitivity determinants of pemetrexed, and the role of the TYMS gene was ascertained by artificial regulation induced by specific siRNA. Silencing the TYMS expression partially restored the cytotoxicity of pemetrexed. The resistant cells did not display other gene alterations related to folate metabolism. We conclude that the primary mechanism imparting resistance to these cells is specific up-regulation of TYMS function. Further, the TYMS gene may serve as a useful biomarker for the prediction of pemetrexed chemosensitivity in patients with malignant pleural mesothelioma. We also investigated the efficacy of 1-(3-C-ethynyl-β-D-ribo-pento furanosyl)cytosine (ECyd) in overcoming pemetrexed resistance;this compound is presently undergoing clinical trials in the USA as TAS-106. ECyd had a similar antitumor effect on the resistant cells as that on the parental cells. In the clinical treatment of malignant pleural mesothelioma, ECyd promises to emerge as a novel drug.

Good Response to Pemetrexed after Treatment Failure with Another Thymidylate Synthase Inhibitor in Lung Adenocarcinoma: A Case Report

Pemetrexed is an antimetabolic agent and is well-known as a potent inhibitor of thymidylate synthase (TS). It also inhibits dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). We reported an intriguing case in which a non-small cell lung cancer patient who was refractory to pretreatment with S-1, a strong TS inhibitor, showed good response to pemetrexed treatment.

Unexpected Dramatic Response of Pretreated Invasive Thymic Malignancies on Pemetrexed-Case Report and Review of Current Treatment Modalities

Thymomas are rare and usually slowly growing tumors, originating from the epithelial layer of the thymus. Prognosis depends on the extent of invasion of adjacent tissues whereby multimodality treatment including surgery with or without adjuvant chemoradiotherapy is the preferred approach for locally advanced thymomas. For metastatic thymomas, only few chemotherapeutic options are available. We report 2 cases of patients with metastatic thymic malignancies with a dramatic response on pemetrexed treatment. The choice for this antifolate therapy is based upon a small series. Because metastatic thymic neoplasm is a rare disease, large randomised trials are not feasible. Case reports on the treatment of these malignancies are very important and can provide readers with the opportunity to deal with rare dis- eases.