Pemetrexed Exposure Research Articles

Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients.

The purposes of this study were to identify physiological and genetic factors that contributed to variability of pemetrexed (PEM) exposure and to optimize the dosing regimens for Chinese non-small cell lung carcinoma patients. A prospective population pharmacokinetics (PPK) research was performed in this population. The PEM concentrations of 192 plasma samples from 116 in-hospital patients were detected. All patients were genotyped for polymorphisms. The PPK model of PEM was developed. The pharmacokinetic behavior of PEM was described by a two-compartment model with first-order elimination. The population typical values were as follows: clearance (CL) 8.29 L/h, intercompartmental clearance (Q) 0.10 L/h, central volume of distribution (V1) 18.94 L and peripheral volume of distribution (V2) 5.12 L. Creatinine clearance (CrCl) was identified as a covariate to CL, and ERCC1 (rs3212986) and CYP3A5 (rs776746) gene polymorphisms as covariates to Q. By using empirical body surface area (BSA)-based dosing strategy, PEM exposure decreased with the elevation of CrCl. Contrarily, CrCl-based dosing strategy exhibited a satisfactory efficacy of achieving the target PEM exposure. BSA-based dosing regimen in current clinic practice is not suitable to achieve the target exposure in PEM chemotherapy of Chinese NSCLC patients. Alternatively, renal function-based dosing strategy is suggested.

Hyperhydration with cisplatin does not influence pemetrexed exposure.

Pemetrexed is a cytotoxic drug for first‐line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin‐related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (&gt;CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

1997P The Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis

Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD), and resistance to EGFR tyrosine kinase inhibitors is a major obstacle facing EGFR-mutant LUAD patients. We investigated whether the Akt kinase LANCL2 plays a role in promoting EGFR-mutant LUAD cell proliferation and drug resistance. A gene chip array, qPCR validation, and shRNA-based high content screening identified pro-proliferative genes arising from gefitinib+pemetrexed exposure. In silico clinical correlate analysis was performed with the TCGA-LUAD dataset. Cell proliferation, cell cycle arrest, apoptosis, and caspase-3/7 activity assays were performed in EGFR-mutant LUAD cell lines PC9 and HCC827 with shRNA-mediated LANCL2 knockdown or LANCL2 overexpression. A murine xenograft model was used to measure in vivo tumorigenic effects. Pathway and co-IP/MS analyses were employed to identify LANCL2-associated enriched pathways and interactors. LANCL2 positively correlates with EGFR, and LANCL2 gain-of-function is associated with inferior survival, in LUAD patients. LANCL2 knockdown reduced proliferation, induced cell cycle arrest, and enhanced apoptosis in PC9 and HCC827 cells in vitro and suppressed xenograft tumor growth in vivo. LANCL2 overexpression rescued these effects and promoted gefitinib+pemetrexed resistance. Pathway analyses of DEGs from LANCL2 knockdown revealed significant enrichment for several cancer signaling pathways. FLNA and GSTM3 were identified as two novel protein interactors of LANCL2. LANCL2 promotes tumorigenic proliferation, inhibits cell cycle arrest, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on LANCL2's positive association with EGFR and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.

Abstract 1663: Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies

Abstract Our research aims to develop therapeutically active inhibitors of the human uracil-DNA glycosylase (UNG). UNG, a highly conserved enzyme, plays a pivotal role in preventing abnormal bases, uracil and 5-fluorouracil, from incorporation into DNA as a result of treatment with chemotherapeutic drugs, floxuridine (5-FdU) and pemetrexed (PEM). Our previous publication reports that the depletion of UNG by shRNA causes uracil and 5-FU incorporation into DNA following 5-FdU or PEM exposure, and highly sensitizes certain human cancer cells to these chemotherapeutic drugs. These data suggest that UNG specific inhibitors could improve the anticancer effect of 5-FdU or PEM. However, a few known inhibitors have not been shown to function at therapeutic concentrations in human cells. Therefore, in order to identify a novel, small-molecule compound targeting the human UNG enzymatic activity, we have previously optimized a biochemically high-throughput screening (HTS) assay that measures the removal of uracil from a DNA hairpin based on the un-quenching of fluorescence. This assay has been successfully employed in a pharmacologically active compound collection screen (&amp;gt;3,000 small-molecules+ approved drugs). In 384-well plate runs using control wells in which enzyme is not added, the average assay provides signal to background ratios of 3.0 to 4.0. Typical Z factors range from 0.6-0.7, indicating a robust assay. We have identified five bioactive compounds with IC50 values &amp;lt; 1uM and have selected a nanoMolar inhibitor of the human UNG enzyme termed, UNGi-A. By using an in vitro DNA glycosylase activity assay, this compound displays a significant inhibitory activity towards the purified human UNG enzyme over time, in a dose-dependent manner. Further characterization shows a significant effect of this inhibitor on UNG activity in cellular extract that expresses endogenous UNG from DLD1 human colon cancer cell line. The result suggests that UNGi-A compound diminishes UNG activity in cell extracts. In addition, thermal shift assay (TSA) data suggest that UNGi-A binds directly to the human UNG enzyme. Together, this compound shows potential activity that blocks the human UNG activity and we are currently evaluating the effect of UNGi-A in combination with 5-FdU on UNG activity in human cancer cells. Citation Format: Mya T. Nguyen, Yan Yan, Yuriy Fedorvo, John Pink, Drew Adams, Stanton Gerson. Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1663.

Long-Term and Low-Grade Safety Results of a Phase III Study (PARAMOUNT): Maintenance Pemetrexed Plus Best Supportive Care Versus Placebo Plus Best Supportive Care Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

IntroductionIn the PARAMOUNT (“A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non–Small-Cell Lung Cancer”) trial, patients with advanced nonsquamous non–small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL. Materials and MethodsPatients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m2, day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed. ResultsA median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms. ConclusionPARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.

Uracil–DNA Glycosylase Expression Determines Human Lung Cancer Cell Sensitivity to Pemetrexed

Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil-DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histologic subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with upregulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed upregulation of BER as a feature of acquired pemetrexed resistance. Cotreatment with the BER inhibitor methoxyamine overrides pemetrexed resistance in chronically exposed cells, underscoring the use of BER-directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double-strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value.

Clinical Benefit From Pemetrexed Before and After Crizotinib Exposure and From Crizotinib Before and After Pemetrexed Exposure in Patients With Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer

BackgroundCrizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated. Patients and MethodsPatients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared. ResultsObjective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed. ConclusionCrizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes.

Safety, Resource Use, and Quality of Life in Paramount: A Phase III Study of Maintenance Pemetrexed Versus Placebo after Induction Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results. After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D). Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment. Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.

Abstract 5490: Mice deficient in uracil DNA glycosylase (UDG) display increased sensitivity to the antifolate pemetrexed

Abstract Pemetrexed, a multi-target antifolate, causes genomic uracil incorporation through inhibition of the enzymes thymidylate synthetase (TS) and dihydrofolate reductase (DHFR). Base excision repair (BER), initiated by uracil DNA glycosylase (UDG), actively recognizes and removes misincorporated uracil from the genome. Mice deficient in UDG have been described and display increased genomic uracil accumulation, elevated spontaneous mutation frequency, and higher incidence of B-cell lymphoma. We have previously reported the in vitro induction of UDG in H460 human lung cancer cells after pemetrexed exposure and have illustrated hypersensitivity to pemetrexed in human colon cancer cell lines lacking UDG expression (DLD1 UDG-/-). Here, we have investigated the role of UDG expression on pemetrexed sensitivity in vivo using gene-targeted UDG-/- mice. Mice received either a single 150mg/kg dose of pemetrexed on day 1 or received 3 consecutive 150 mg/kg doses of pemetrexed on days 1-3 and were sacrificed on day 4 or 5, respectively. Compared to UDG+/+ and UDG+/- littermates, UDG-/- mice were markedly myelosuppressed following pemetrexed treatment, as evidenced by a ∼50% reduction in bone marrow cell numbers and a ∼70% reduction in total colony forming units (CFU). Moreover, marrow from pemetrexed-treated UDG-/- mice expressed higher levels of DNA damage markers γ-H2AX and cleaved-PARP than control samples suggesting the formation of DNA double strand breaks and activation of apoptosis in UDG-/- marrow following pemetrexed exposure. Western blot analysis further evinced Chk-1 phosphorylation (p-Chk1, Ser345) in marrow from UDG-/- mice but not UDG+/+ or UDG+/- samples, suggesting inadequate removal of pemetrexed-induced genomic uracil may stall DNA replication and contribute to the cytotoxicity observed. These data in addition with our novel observations of enhanced pemetrexed sensitivity in UDG-/- mouse embryonic fibroblast (MEFs), UDG mutant human lymphoblastoid cell lines (LCLs), and DLD1 UDG-/- cells, strongly suggest that UDG deficiency potentiates pemetrexed cytotoxicity in in vitro as well as in in vivo models. Additionally, our findings indicate a role for genomic uracil accumulation in the mechanism of cytotoxicity for pemetrexed. Furthermore, our data illustrate a synthetic lethal interaction between TS/DHFR inhibition and UDG deficiency and promote UDG as a target for improving pemetrexed efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2011-5490

9177 Lipocalin-2 is an important predictor of susceptibility to therapy with pemetrexed in non-small cell lung cancers

The novel folate antimetabolite Alimta (pemetrexed disodium, LY231514) exhibits antitumor activity in a broad array of human malignancies and was recently found to enhance radiation-induced cell killing in vitro. In the present study, a possible cell cycle phase–specific radiosensitization by pemetrexed was assessed.Widr human colon carcinoma cells were synchronized by serum withdrawal/stimulation that yielded about 80% cells with G1 DNA content 6 h after replating and more than 60% S-phase cells after 22 h, as assessed by flow cytometry. The respective cultures were irradiated with doses up to 12 Gy in combination with a subtoxic pemetrexed exposure (1.06 μM for 2 h: about 80% survival), or after mock treatment. Survival curves were generated by the clonogenic assay; apoptosis was measured by sub-G1 DNA flow cytometry.The combination treatment of the G1 cells and of the more radioresistant S-phase cell preparations yielded survival rates that were lower than expected for independent cell killing. Radiosensitization, calculated as the ratio of the mean inactivation doses without or with drug exposure (enhancement ratio), was not significantly different for the two cell preparations (enhancement ratio of 2.1 and 2.3, respectively) and was similar to the previously reported value for log-phase cells. Pemetrexed exposure was unable to stimulate an apoptotic response of these cells to radiation.Radiosensitization by pemetrexed is not cell cycle phase–specific, and the relative radioresistance of S-phase cells is retained. Apoptosis seems to have no influence on radiosensitization in this cell line.

Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.

The relationship between pemetrexed exposure (AUC) and clinical outcome in Japanese NSCLC patients

18041 Background: The efficacy of pemetrexed (PEM) 500 mg/m2 administered with vitamin B12 and folic acid (FS) has been established in previously treated NSCLC. The 500 mg/m2 dose is based on the MTD determined for PEM without FS. Recently completed phase I studies have shown the recommended dose of PEM single agent with FS to be 900–1,000 mg/m2. A randomized phase II study conducted in Japan (ASCO 2007) showed PEM 500 mg/m2 and 1,000 mg/m2 with FS to have similar efficacy for patients with 2nd and 3rd line NSCLC. PEM is renally excreted and a PK model characterizing the relationship between CrCL and PEM AUC has been previously established. The exposure response relationships (ERRs) between AUC and progression free survival (PFS), individual patient’ tumor response, and toxicity were explored in these analyses. Methods: Eligible patients had a histologic or cytologic diagnosis of NSCLC, had been previously treated by 1 or 2 chemotherapy regimens, and were randomized to 500 mg/m2 (N = 108 pts) or 1,000 mg/m2 (N = 108 pts) of PEM once every 3 weeks. A previously established PK model was used to estimate AUC based on patient CrCL and dose administered. AUCs were linked to clinical outcome to identify ERRs. Efficacy models assumed a distribution of events with hazard dependent on prognostic factors and mean AUC at cycle over the treatment period. The AE model assumed probability of toxicity as a function of AUC at each cycle. Results: Median CrCL for patients in 500 mg/m2 and 1,000 mg/m2 groups were 85 ml/min (42–167) and 83 ml/min (38–146), respectively; median estimated PEM AUCs were 158 mg.h/L (107–221) and 318 mg.h/L (215–468). The relationship between model-estimated AUC and PFS was not significant. This is consistent with the clinical findings: PFS for the 500 mg/m2 and 1,000 mg/m2 groups of 3.0 months and 2.4 months, respectively; overall response rate (RR) of 18.5% and 14.8%, respectively. ERR analyses for individual patient tumor response, neutropenia and thrombocytopenia are ongoing at this time. Conclusions: Estimated PEM AUCs, based on CrCL, does not correlate with PFS for pretreated NSCLC at 500 mg/m2 and 1,000 mg/m2. The ERRs for individual tumor response and toxicity are ongoing and will be presented at the meeting. No significant financial relationships to disclose.

Radiosensitization by pemetrexed of human colon carcinoma cells in different cell cycle phases

Purpose The novel folate antimetabolite Alimta (pemetrexed disodium, LY231514) exhibits antitumor activity in a broad array of human malignancies and was recently found to enhance radiation-induced cell killing in vitro. In the present study, a possible cell cycle phase–specific radiosensitization by pemetrexed was assessed. Methods and materials Widr human colon carcinoma cells were synchronized by serum withdrawal/stimulation that yielded about 80% cells with G1 DNA content 6 h after replating and more than 60% S-phase cells after 22 h, as assessed by flow cytometry. The respective cultures were irradiated with doses up to 12 Gy in combination with a subtoxic pemetrexed exposure (1.06 μM for 2 h: about 80% survival), or after mock treatment. Survival curves were generated by the clonogenic assay; apoptosis was measured by sub-G1 DNA flow cytometry. Results The combination treatment of the G1 cells and of the more radioresistant S-phase cell preparations yielded survival rates that were lower than expected for independent cell killing. Radiosensitization, calculated as the ratio of the mean inactivation doses without or with drug exposure (enhancement ratio), was not significantly different for the two cell preparations (enhancement ratio of 2.1 and 2.3, respectively) and was similar to the previously reported value for log-phase cells. Pemetrexed exposure was unable to stimulate an apoptotic response of these cells to radiation. Conclusions Radiosensitization by pemetrexed is not cell cycle phase–specific, and the relative radioresistance of S-phase cells is retained. Apoptosis seems to have no influence on radiosensitization in this cell line.