Activity of Pemetrexed (ALIMTA®, Multitargeted Antifolate, LY231514) in Metastatic Breast Cancer Patients Previously Treated with an Anthracycline and a Taxane: An Interim Analysis

doi:10.3816/CBC.2001.n.010

Clinical Breast Cancer

Volume 2, Issue 1, April 2001, Pages 47-51

https://doi.org/10.3816/CBC.2001.n.010 Get rights and content

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 ≤ 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.

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Cited by (45)

Pemetrexed nephrotoxicity
2015, Bulletin du Cancer
Le pemetrexed appartient à une nouvelle génération d’antinéoplasique antifolate multi-cible. Il est de plus en plus utilisé comme traitement de première ligne en association avec le cisplatine dans les adénocarcinomes bronchiques, et comme traitement de deuxième ligne ou de maintenance en monothérapie principalement chez les patients contrôlés par la première ligne jusqu’à progression ou mauvaise tolérance. Dans le mésothéliome, le pemetrexed est indiqué uniquement en première ligne avec un sel de platine. Le principal effet indésirable du pemetrexed est la myélosuppression qui peut être prévenue par la supplémentation en acide folinique. Cette revue fait le point sur la toxicité rénale émergente du pemetrexed, toxicité progressive et cumulative touchant cinq à dix pour cent des patients traités « au long cours » par le pemetrexed.
Pemetrexed belongs to a new generation of multitargeted antifolate cytotoxic agents. It is increasingly used as first-line treatment in combination with cisplatin, and as second-line treatment or maintenance monotherapy mainly in metastatic non-small cell lung cancer and in malignant mesothelioma. It is increasingly used as first-line treatment in combination with cisplatin in lung adenocarcinoma, and as second-line treatment or maintenance monotherapy in patients mainly controlled by the first-line to progression or poor tolerance. In mesothelioma, pemetrexed is indicated only in first-line with a platinum salt. The main side effect of pemetrexed is myelosuppression, which may be prevented by folinic acid supplementation. This review focuses on the progressive and cumulative emerging renal toxicity of pemetrexed, affecting five to ten percent of “long-term” pemetrexed-treated patients.
Brain metastases as the primary site of relapse in two randomized phase III pemetrexed trials in advanced nonsmall-cell lung cancer
2012, Clinical Lung Cancer
Symptomatic brain metastases (BM) frequently occurs after initial treatment of non–small-cell lung cancer (NSCLC). Therefore, 2 large randomized trials that involved pemetrexed were retrospectively analyzed to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence.
Two large phase III studies of pemetrexed in advanced NSCLC were included. One study compared pemetrexed with docetaxel in previously treated patients (n = 571); the other study tested cisplatin plus pemetrexed vs. cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (n = 1725). Patients with known BM at study entry were excluded from this analysis. Each study was analyzed separately, then jointly to determine the rate of BM reported as the only site of progressive disease by treatment group and histology. Logistic regression was used to obtain an odds ratio for the treatment effect on the overall occurrence of BM while controlling for potential confounding factors.
Overall, 71.5% of patients in pemetrexed-containing arms (819 of 1145), and 68.2% of patients in non–pemetrexed-containing arms (785 of 1151) experienced progressive disease. BM recurrence rates were 3.2% (95% confidence interval [CI], 2.1%-4.6%) in the pemetrexed-containing arms vs. 6.6% (95% CI, 5.0%-8.6%) in the non–pemetrexed-containing arms (P = .002). The odds ratio for BM recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32-0.76; P = .001). The beneficial effect of pemetrexed on BM was confined to patients with nonsquamous NSCLC.
Patients with advanced nonsquamous NSCLC treated with pemetrexed either in first-line or second-line therapy may reduce the risk of developing BM as the first site of progressive disease. This retrospective analysis is limited due to the lack of baseline and periodic brain scans, and it reflects symptomatic BM only. Regardless, these findings suggest a potential beneficial effect of pemetrexed-based treatments on the control of BM.
A phase II trial of pemetrexed and gemcitabine in patients with metastatic breast cancer who have received prior taxane therapy
2010, Clinical Breast Cancer
Citation Excerpt :
The addition of pemetrexed to either treatment schedule does not appear to confer an improvement in response rate over gemcitabine alone when used to treat heavily-pretreated patients.22,23,26 Similarly, adding gemcitabine to pemetrexed does not confer an improvement in response rate over pemetrexed alone as first-line therapy36 or in patients who have received anthracyclines and/or taxanes.12–14 A trend toward increased ORR was seen in ER– patients compared with ER+ patients on the 14-day schedule, consistent with previous studies,37 but this was not observed in patients on the 21-day schedule.
This phase II trial assessed efficacy and safety of pemetrexed plus gemcitabine to treat metastatic or locally advanced breast cancer in patients previously treated with taxanes.
Eligible women with advanced breast cancer treated with taxanes in the adjuvant or metastatic setting received pemetrexed 500 mg/m² on day 1 followed by gemcitabine 1000 mg/m² on days 1 and 8 of a 21-day cycle. Hematologic toxicities limiting day 8 gemcitabine dosing were observed in the first 20 patients, prompting a protocol amendment to evaluate pemetrexed 500 mg/m² followed by gemcitabine 1500 mg/m² on day 1 of a 14-day cycle. Patients received folic acid, vitamin B₁₂, and dexamethasone. The primary endpoint was objective response rate (ORR).
Between July 2003 and September 2006, 73 evaluable women (median age, 52.1 years; range, 28–73 years) were enrolled (21-day schedule: 21 patients, 52% estrogen receptor—positive, 24% HER2-positive; 14-day schedule: 52 patients, 58% ER-positive, 15% HER2-positive). For patients on the 21-day and 14-day schedules, median number of cycles was 4 (range, 1–8 cycles) and 5 (range, 1–38 cycles), respectively. The ORRs were 23.8% and 19.2%, respectively; median survival times were 16.2 months and 13.4 months. The most common grade 3/4 hematologic toxicities were neutropenia (71% vs. 33%) and leukopenia (24% vs. 14%); febrile neutropenia occurred in 10% and 6%. The most common grade 3/4 nonhematologic toxicity was fatigue (29% vs. 10%).
Pemetrexed/gemcitabine given on a 21-day or 14-day schedule is active in patients with advanced breast cancer previously treated with taxanes. A 14-day schedule appears to result in fewer serious toxicities.
Comparison of patient outcomes according to histology among pemetrexed-treated patients with stage IIIB/IV non-small-cell lung cancer in two phase II trials
2010, Clinical Lung Cancer
Citation Excerpt :
Pemetrexed (Alimta®, Eli Lilly and Company; Indianapolis, IN) is a third-generation antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.1,2 This agent has demonstrated activity in a broad range of tumor subtypes.3–8 Pemetrexed has remarkable activity as a substrate for folylpolyglutamate synthetase, and its higher polyglutamate derivatives have comparable inhibition constants for thymidylate synthase.
Recent phase III studies in advanced non–small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology.
Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m² plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m² plus oxaliplatin 120 mg/m² (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex.
More than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19).
In patients treated with pemetrexed/platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.
Pleural Masses
2010, Medical Management of the Thoracic Surgery Patient
Feasibility study of dose-dense biweekly administered pemetrexed in patients with nonsmall cell lung cancer
2010, Hematology/ Oncology and Stem Cell Therapy
Citation Excerpt :
The clinical benefit of such combinations is implied by early preclinical and clinical studies.21,22 In addition, on the assumption that the maximum tolerated dose of pemetrexed is not the one approved by the regulatory agencies and because even higher doses of 600 mg/m2 every 3 weeks were sufficiently tolerable in early phase 2 studies, our patients received a fixed dose of 1000 mg.23 A typical patient, assuming a 1.8 m2 body surface, receives 900 mg, whereas our smaller patient received the equivalent of 588 mg/m2 deemed to be safe.
Pemetrexed is a multitargeted folate pathway inhibitor with documented activity in non-small cell lung cancer (NSCLC). The presumed maximum tolerated dose is 500 mg/m² every 3 weeks, but pemetrexed-related toxicity is ameliorated when folate and B12 supplementation is provided and therefore a higher dose intensity may be tolerated. The current exploratory study assessed the feasibility of administration of pemetrexed at a fixed dose of 1000 mg every 2 weeks in patients with relapsed or refractory NSCLC.
The first cohort of 12 patients received pemetrexed monotherapy. No dose-limiting grade 4 toxicity was noted after 4 cycles, so the subsequent cohort of 14 patients received additional anticancer agents (bevacizumab, erlotinib, carboplatin, docetaxel, vinorelbine) given along with dose-dense pemetrexed.
Toxicity overall was reversible and manageable. Among 19 patients who received pemetrexed either alone or with non-myelosuppressive targeted agents, there were only 2 instances of grade 4 neutropenia after prolonged treatment. Grade 3-4 hematologic toxicity was eventually noted in 11 of the 26 patients (42%; 95% confidence interval, 23% to 61%) after a median of 4 cycles (range, 2-14 cycles). There was no significant additional toxicity nor any treatment-related deaths.
Our preliminary observations indicate that dose-dense pemetrexed every 2 weeks is feasible and this regimen can be used as monotherapy. These data may serve as a scaffold for combination studies.

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Original ContributionActivity of Pemetrexed (ALIMTA®, Multitargeted Antifolate, LY231514) in Metastatic Breast Cancer Patients Previously Treated with an Anthracycline and a Taxane: An Interim Analysis

Treatment of breast cancer

N Engl J Med

LY231514, a pyrrolo[2,3-d] pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes

Cancer Res

LY231514, a novel pyrolopyrimidine antifolate that inhibits thymidylate synthase (TS)

Proc Annu Meet Am Assoc Cancer Res

5-Fluoropyrimidines

Antimetabolites

Comparative antitumor activity of the multitargeted antifolate LY231514 and the thymidylate synthase inhibitor ZD1694

Ann Oncol

Activity of LY231514 against several enzymes in the folate-dependent pathways

Proc Annu Meet Am Assoc Cancer Res

Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria

Invest New Drugs

Ten-year results of FAC adjuvant chemotherapy trial in breast cancer

Am J Clin Oncol

Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration

J Clin Oncol

Original Contribution
Activity of Pemetrexed (ALIMTA®, Multitargeted Antifolate, LY231514) in Metastatic Breast Cancer Patients Previously Treated with an Anthracycline and a Taxane: An Interim Analysis