Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer

Pemetrexed (Alimta) is a novel multitargeted antifolate that has activity against non-small-cell lung cancer (NSCLC). As a single agent, the response rate is 16%-23%. As second-line therapy, it has a 5% and 14% response rate with pemetrexed in NSCLC patients who have had prior cisplatin or nonplatinum chemotherapy, respectively. Pemetrexed combined with cisplatin has a response rate of 38.9%-44.8%, with a median survival of 8.9-10.9 months. Pemetrexed plus gemcitabine in NSCLC has a response rate of less than 25%. The major toxicity associated with pemetrexed is neutropenia, which may be reduced with vitamin B12 and folate nutritional supplement. Additional studies with pemetrexed in combination with other agents are needed for the treatment of NSCLC patients.     

Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.     

Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group

BACKGROUND: Pemetrexed disodium (Alimta [Eli Lilly and Company, Indianapolis, IN], LY231514, multitargeted antifolate) is a new multitargeted antifolate agent that inhibits multiple enzymes in the folate pathway. Phase II trials showed single-agent response rates of 16% and 23% in untreated patients with nonsmall cell lung carcinoma (NSCLC). This study was undertaken to determine the response to pemetrexed disodium given in combination with cisplatin. METHODS: Previously untreated patients were eligible if they had Stage IIIB or IV NSCLC, performance status 0, 1, or 2, adequate hematology and biochemistry and bidimensionally measurable lesions. Patients with brain metastases or neuropathy higher than Grade 2 were excluded. Pemetrexed disodium 500 mg/m(2) was given over 10 minutes, and cisplatin 75 mg/m(2) with hydration and mannitol diuresis was administered on Day 1 of each 21-day cycle. Dexamethasone 4 mg was taken orally once every 12 hours starting 24 hours before treatment and continuing for 6 doses after treatment. Four patients had detailed pemetrexed disodium pharmacokinetic analysis performed. RESULTS: Between May 1998 and June 1999, 31 patients were treated on the study. There were 20 males and 11 females; median age was 60 years (range, 35-75 years); there were 5 Stage IIIB, 26 Stage IV, 26 performance status 0 or 1, and 5 performance status 2. In 29 patients evaluable for response, there were 13 partial responses (PRs; overall response rate [ORR], 95%; confidence interval [CI]: 26-64%) of median duration 6.1 months (1.6-7.8 months). Three of four evaluable patients with performance status 2 achieved PR, and 11 of 24 evaluable Stage IV patients responded (ORR, 45.8% in Stage IV). Eighteen patients died. The median survival rate was 8.9 months (range, 1-15+ months). A total of 160 courses were delivered (median, 6 for both cisplatin and pemetrexed disodium). Grade 3 and 4 anemia was observed in 5 and 1 patients, respectively, and Grade 3 and 4 granulocytopenia in 7 and 4 patients, respectively. Grade 3 nausea and emesis occurred in only 2 patients, Grade 3/4 diarrhea in 3 patients, and 2 patients had Grade 3 motor neuropathy. Nine patients had Grade 2 infections, and there was one case of febrile neutropenia. Pharmacokinetic results showed C(max), clearance and V(ss) values to be similar to data from single-agent pemetrexed disodium given in the same dose. CONCLUSIONS: The combination of pemetrexed disodium and cisplatin is active against advanced NSCLC and is a well-tolerated convenient outpatient regimen. It deserves further study to compare it with other standard regimens for NSCLC.     

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

Phase II study of pemetrexed in patients with advanced neuroendocrine tumors

Purpose

In some reports, 5-fluorouracil has been associated with modest activity in patients with neuroendocrine tumors. Pemetrexed is a multitargeted antifolate with activity in tumor types not significantly responsive to other antifolates. We evaluated the efficacy of pemetrexed in a phase II study of patients with advanced neuroendocrine tumors.

Methods

Patients with metastatic neuroendocrine tumors (excluding small-cell carcinoma) were treated with pemetrexed administered intravenously at a dose of 500 mg/m² every 21 days. To reduce potential toxicity, patients also received folic acid, vitamin B12 supplementation, and peri-infusional treatment with dexamethasone. Patients were followed for response, toxicity, and survival.

Results

The study was designed with a total accrual goal of 32 patients. Due to lack of radiographic responses in patients during the study period, accrual was terminated at 17. However, one patient achieved a delayed partial response following discontinuation of pemetrexed. Ten patients were evaluable for biochemical response; five (50%) experienced >50% decrease in plasma chromogranin A. Among the 17 patients, 5 (29%) discontinued therapy due to treatment-related toxicity. The median overall survival was 12.1 months.

Conclusion

Pemetrexed does not appear to have significant antitumor activity in patients with advanced neuroendocrine tumors. The limited antitumor activity and potential toxicity associated with pemetrexed mirrors experience with the majority of other cytotoxic agents in patients with neuroendocrine tumors. Investigation of novel, molecularly targeted agents may offer more promise in this disease.     

Antimetabolites in the management of non-small cell lung cancer

Opinion statement Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Although chemotherapy has been shown to increase survival for patients with advanced-stage disease, survival benefits have been modest and come at the cost of significant toxicity. Treatment options in the second-line setting have been limited. Pemetrexed, a multitargeted antifolate, has activity as a single agent and as part of combination chemotherapy against NSCLC. As reported in a recent phase III clinical trial, survival outcomes in the second-line setting for patients treated with pemetrexed or docetaxel are similar. More importantly, major toxicity with the use of pemetrexed with vitamin B₁₂ and folate supplementation is far less than with docetaxel. Based on its single agent activity, ease of administration, and favorable toxicity profile, pemetrexed has the potential to be incorporated in various settings against NSCLC, including metastatic disease, as adjuvant therapy, and for locally advanced disease.     

培美曲塞治疗非小细胞肺癌无症状脑转移临床分析

目的:培美曲塞已被确定为晚期非小细胞肺癌(非鳞癌)的标准用药之一。本研究旨在探讨培美曲塞治疗非小细胞肺癌无症状脑转移的近期疗效和不良反应。方法:回顾性分析2008年11月—2010年12月45例非小细胞肺癌无症状脑转移患者的临床资料,评价疗效和不良反应。结果:所有患者颅内转移灶的疗效:部分缓解17例(37.8%),疾病稳定20例(44.4%),疾病进展8例(17.8%),客观缓解率为37.8%,疾病控制率为82.2%。全身病灶的总体疗效:部分缓解5例(11.1%),疾病稳定16例(35.6%),疾病进展24例(53.3%),客观缓解率为35.6%,疾病控制率为46.6%。颅内转移灶与全身病灶的疾病控制率差异有统计学意义(P=0.006),而客观缓解率差异无统计学意义(P>0.05)。颅内转移灶的无进展生存期为3.87个月,全身病灶的中位无进展生存期为2.27个月,差异有统计学意义(P=0.009)。颅内转移灶的近期疗效与患者年龄、性别、吸烟状况、脑转移灶数目、是否接受放疗等临床特征之间无明显相关性(P>0.05)。未观察到严重不良反应。结论:培美曲塞对于非小细胞肺癌脑转移患者颅内转移灶具有较好的疗效,不良反应较小。     

培美曲塞在非小细胞肺癌治疗中的研究进展

培美曲塞（Pemetrexed，Alimta^R）是一种新型的多靶点抗叶酸药物．作为局部晚期或转移性非小细胞肺癌的二线治疗药物，目前已经有多个临床研究表明．培美曲塞单药或与其它药物联合在非小细胞肺癌的治疗中均获得显著疗效。该文对此作一回顾。     

Pemetrexed in small-cell lung cancer: background and review of the ongoing GALES pivotal trial

Pemetrexed is a novel, multitargeted antifolate currently under development for the treatment of a number of solid tumors, including small-cell lung cancer. Pemetrexed/platinum combinations appear to compare favorably with other platinum-based doublets in terms of their efficacy and safety profile. The Global Analysis of Pemetrexed in SCLC Extensive Stage (GALES) trial is a direct comparison of pemetrexed and carboplatin with the standard first-line etoposide and carboplatin chemotherapy in extensive-disease small-cell lung cancer. This randomized, multicenter, open-label Phase III study will enroll 1820 patients in 23 countries, with the final analysis planned after 1270 deaths have occurred. An interim analysis will be conducted after 700 patients have been enrolled. The study will also use pharmacogenomic analysis to evaluate biological predictors of response, in particular to pemetrexed.     

Phase II Study of Pemetrexed Plus Gemcitabine in Advanced Pancreatic Cancer

Background:Gemcitabine is the standard chemotherapy for the treatment of advanced pancreatic cancer. The novel multitargeted antifolate pemetrexed (Alimta®) has also demonstrated activity in this disease. These two drugs are synergistic in vitro, and a phase I study has demonstrated activity of single-agent pemetrexed in pancreatic cancer. Aim:To evaluate pemetrexed plus gemcitabine in a multicenter phase II study in patients with advanced pancreatic cancer. Patients and methods:Chemonaive patients with advanced pancreatic adenocarcinoma, metastatic or locally advanced, not amenable to curative resection, received intravenous gemcitabine 1250 mg/m² over 30 minutes on days 1 and 8 and intravenous pemetrexed 500 mg/m² over 10 minutes on day 8 every 21 days. The primary endpoint was objective response rate. Patients were evaluated for time-to-event variables including overall survival, time-to progression, time-to-treatment failure, and duration of response. Patients who were symptomatic were evaluated weekly for clinical benefit response. CT scans were obtained every two cycles. Results:Forty-two patients were treated; 41 were evaluable for efficacy. Ninety-five percent of patients had metastatic disease. There were five partial responses (objective response rate 12%), and 44% of patients had stable disease. The 1-year survival rate was 32%; median survival was 6.6 months (95% CI 4.4, 9.9). Of 30 eligible patients, four (13%) had a clinical benefit response. Grade 3 and 4 hematologic toxicities included neutropenia (84%), febrile neutropenia (12%), and thrombocytopenia (33%). Non-hematologic toxicities were minimal. Conclusion:The combination of pemetrexed and gemcitabine is active in advanced pancreatic cancer, and has acceptable toxicity; a 1-year survival rate of 32% is encouraging. A phase III trial comparing pemetrexed plus gemcitabine with gemcitabine has completed accrual. 1 The use of trade names is for product identification purposes only and does not imply endorsement.     

Pemetrexed in small-cell lung cancer: background and review of the ongoing GALES pivotal trial

Pemetrexed is a novel, multitargeted antifolate currently under development for the treatment of a number of solid tumors, including small-cell lung cancer. Pemetrexed/platinum combinations appear to compare favorably with other platinum-based doublets in terms of their efficacy and safety profile. The Global Analysis of Pemetrexed in SCLC Extensive Stage (GALES) trial is a direct comparison of pemetrexed and carboplatin with the standard first-line etoposide and carboplatin chemotherapy in extensive-disease small-cell lung cancer. This randomized, multicenter, open-label Phase III study will enroll 1820 patients in 23 countries, with the final analysis planned after 1270 deaths have occurred. An interim analysis will be conducted after 700 patients have been enrolled. The study will also use pharmacogenomic analysis to evaluate biological predictors of response, in particular to pemetrexed.     

Pemetrexed in the Treatment of Leptomeningeal Metastasis in Patients With EGFR-mutant Lung Cancer

IntroductionLeptomeningeal metastasis (LM), still an area of unmet need, has frequently been observed in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). Because the antitumor efficacy of systemic cytotoxic agents against LM is unclear, we explored the role of pemetrexed in the treatment of patients with LM from EGFR-mutant NSCLC.Patients and MethodsWe retrospectively reviewed the medical records of patients with LM from EGFR-mutant NSCLC treated between 2006 and 2016. Post-LM survival was evaluated as well as clinical factors.ResultsIn our patient cohort with EGFR-mutant NSCLC (n = 631), 17.4% (n = 110) developed LM. Their median post-LM survival was 5.7 months (95% confidence interval, [CI], 0.0-12.0 months). Post-LM survival was significantly longer with pemetrexed use after LM (median, 13.7 months; 95% CI, 4.1-23.2 months) than without pemetrexed use after LM (median, 4.0 months; 95% CI, 2.2-5.7 months; P = .008). In the multivariate analyses, no pemetrexed use after LM (vs. use) and no EGFR tyrosine kinase inhibitor use after LM (vs. use) were independently associated with a poor post-LM survival with a hazard ratio of 3.1 (95% CI, 1.5-6.3; P = .002) and 3.0 (95% CI, 1.6-5.8; P = .001), respectively.ConclusionPemetrexed use after LM was independently associated with a longer post-LM survival in patients with EGFR-mutant NSCLC with LM. Prospective studies are warranted to validate this finding.     

A Randomized Phase II Study of Pemetrexed in Combination With Cisplatin or Carboplatin as First-Line Therapy for Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

BackgroundPemetrexed plus cisplatin was approved for first-line treatment of non–small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.Patients and MethodsThe patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or pemetrexed (500 mg/m²) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety.ResultsSixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]).ConclusionsBoth the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.     

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 third-line 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.     

Pemetrexed (Alimta®): a novel multitargeted antifolate agent

Pemetrexed (Alimta^®) is a novel, multitargeted antifolate that inhibits at least three of the enzymes involved in folate metabolism, and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated broad antitumor activity in Phase II trials in a wide variety of solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine (Gemzar^®). A pivotal Phase III study in mesothelioma has been presented. This study indicates the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. The most significant toxicities of pemetrexed, myelossuprresion and mucositis have been significantly ameliorated by folate and vitamin B12 supplementation. More importantly, vitamin supplementation has not demonstrated any adverse efficacy. This review discusses the biochemistry and clinical activity of pemetrexed.     

First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients

BackgroundWe aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma.Patients and MethodsNever-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib.ResultsBetween June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR–wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms.ConclusionsIntercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.     

培美曲塞联合奈达铂一线方案治疗晚期肺腺癌的临床研究

目的 观察和评价培美曲塞联合奈达铂与多西他赛联合奈达铂作为一线化疗方案治疗晚期肺腺癌的临床疗效和不良反应。方法 68例初治的晚期肺腺癌患者,体力状况（PS）评分0～2分,34例培美曲塞 500 mg/m2联合奈达铂80 mg /m2;34例多西他赛75 mg/m2联合奈达铂80 mg /m2治疗。结果 入组的68例患者中有67例可评价疗效。培美曲塞组与多西他赛组比较疾病控制率分别为 45.45%和44.12%,中位生存时间分别为8.5月和8.2月,1年生存率为30.3%和26.5%。两组比较差异均无统计学意义（P >0.05）。在中性粒细胞减少和脱发的发生率上培美曲塞观察组均明显低于多西他赛对照组,差异有统计学意义（P＜0.05）。其余恶心、呕吐、乏力等不良反应,两组比较差异无统计学意义。结论 培美曲塞与多西他赛分别联合奈达铂治疗晚期肺腺癌的疗效相当,但在不良反应的发生率上,培美曲塞组则显示出更好的优势。     

The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy

Pemetrexed (Alimta , LY231514) is a new multitargeted antifolate that inhibits several enzymes involved in the folate pathway. Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer (NSCLC) as well as in a broad array of other solid tumors including mesothelioma and breast, colorectal, bladder, cervical, gastric, and pancreatic cancer. In NSCLC, single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin, vinorelbine, oxaliplatin, carboplatin, and gemcitabine. Low-level dietary supplement of folic acid and vitamin B12 has significantly improved the safety profile of pemetrexed without compromising its antitumor effect. In this review, the pharmacology and clinical activity of pemetrexed in NSCLC cancer is discussed.     

Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non–Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies

BackgroundBefore immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non–small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration.Patients and MethodsData from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration.ResultsBaseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration.ConclusionThere was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.     

Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed

Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are target enzymes of inhibition by pemetrexed, an antifolate for treatment of advanced non-small-cell lung cancer (NSCLC). This study is to evaluate the association of TS and DHFR expressions and the treatment efficacy of pemetrexed in NSCLC patients. From January 2006 to October 2008, patients with advanced NSCLC treated with pemetrexed after prior chemotherapy were included. The TS and DHFR expressions in tumor tissues were examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H-score). The H-score was derived from the degrees of intensity of tumor cells multiplied by the percentage of positive neoplastic cells. The medical records were reviewed and analyzed with respect to patients’ characteristics, histology types, treatment responses and survivals. Among 268 NSCLC patients treated with pemetrexed, 49 had tumor specimens available for TS and DHFR evaluation. The TS expression was positively correlated with DHFR expression (r² = 0.11, p = 0.02). Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p = 0.01). Patients with low DHFR expression (≤120) also had a longer median PFS than patients with high DHFR expression (>120), which was not statistically significant (5.8 vs. 3.6 months; p = 0.33). In patients with adenocarcinoma, the low TS patient group also had a longer median PFS and a longer median overall survival (OS) as compared with patients with high TS expression (PFS, 4.8 vs. 3.8 months, p = 0.03; OS, 21.4 vs. 10.0 months, p = 0.03). Nevertheless, the association of DHFR expression level and median PFS as well as OS were not statistically significant. TS expression, rather than DHFR, may be an important predictive factor for treatment efficacy of pemetrexed in NSCLC patients.