A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer

Cullen, Michael; Zatloukal, Petr; Sörenson, Sverre; Novello, Silvia; Fischer, J. R.; Joy, Anil A.; Zereu, Manuela; Peterson, Patrick; Visseren‐Grul, Carla; Iscoe, Neill

doi:10.1093/annonc/mdm592

Cited by 63 publications

(37 citation statements)

References 32 publications

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“…Results from two recently completed randomized studies showed that higher doses of single-agent pemetrexed confirmed that toxicity remained manageable for higher pemetrexed doses administered with vitamin supplementation. One of these studies, a phase III study for second-line treatment of patients with non-small cell lung cancer that enrolled predominantly Western patients, showed a slightly higher, but manageable, toxicity in the high-dose treatment arm (900 mg/m 2 ) relative to the standard dose (31). The other, a phase II study of pemetrexed for second-line treatment of Japanese patients with non-small cell lung cancer also showed manageable toxicity for the high-dose treatment arm (1,000 mg/m 2 ) relative to the standard dose (32).…”

Section: Discussionmentioning

confidence: 99%

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

Latz

Schneck

Nakagawa

et al. 2008

Clinical Cancer Research

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Purpose: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. Experimental Design: 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 21days. 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. Results: 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 F vitamin supplementation were 2.74 Â 10 9 /L and 1.70 Â 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 Â 10 9 /L. Values for the 1,000 mg/m 2 dose with vitamin supplementation were 1.91 Â 10 9 /L and 1.34 Â 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. Conclusions: 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.

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Section: Discussionmentioning

confidence: 99%

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

Latz

Schneck

Nakagawa

et al. 2008

Clinical Cancer Research

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“…During the pivotal phase III study, in which 500 mg/m 2 pemetrexed in combination with 75 mg/m 2 cisplatin was administered to patients with MPM (1), results from a multivariate regression analysis became available that indicated that an elevated baseline homocysteine level (consistent with subclinical folate deficiency) was highly correlated with more severe pemetrexed toxicities (5). To reduce the more severe drug-induced toxic effects, the protocol was amended to include supplementation of patients with folic acid and vitamin B 12 . For all ongoing and subsequent studies of pemetrexed, supplementation was required.…”

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confidence: 99%

Phase I and Pharmacokinetic Study of Pemetrexed plus Cisplatin in Chemonaive Patients with Locally Advanced or Metastatic Malignant Pleural Mesothelioma or Non–Small Cell Lung Cancer

Dickgreber

Fink

Latz

et al. 2008

Clinical Cancer Research

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Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B 12 to the treatment regimen.We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation. Experimental Design: Patients with malignant pleural mesothelioma or non^small cell lung cancer received pemetrexed doses from 500 to 900 mg/m 2 + 75 mg/m 2 cisplatin once every 21days. Folic acid and vitamin B 12 were administered per label recommendations. Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m 2 + 75 mg/m 2 cisplatin. Based on this study, the recommended dose would be 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m 2 single-agent pemetrexed versus 500 mg/m 2 and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.Pemetrexed is an antifolate cytotoxic agent that has been approved in many countries in combination with cisplatin for first-line treatment of malignant pleural mesothelioma (MPM; ref. 1) and as single-agent therapy for second-line treatment of non-small cell lung cancer (NSCLC; ref. 2). Pemetrexed in combination with cisplatin has also been shown to be effective and well tolerated for first-line treatment of NSCLC (3) and was recently approved in Europe and the United States for that indication.The currently established dose of 500 mg/m 2 pemetrexed in combination with 75 mg/m 2 cisplatin every 21 days was established based on a phase I study of pemetrexed in combination with cisplatin that was conducted without folic acid and vitamin B 12 supplementation (4). During the pivotal phase III study, in which 500 mg/m 2 pemetrexed in combination with 75 mg/m 2 cisplatin was administered to patients with MPM (1), results from a multivariate regression analysis became available that indicated that an elevated baseline homocysteine level (consistent with subclinical folate deficiency) was highly correlated with more severe pemetrexed toxicities (5). To reduce the more severe drug-induced toxic effects, the protocol was amended to include supplementation of patients with folic acid and vitamin B 1...

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“…Only a few agents including docetaxel, pemetrexed, gefitinib and erlotinib have shown to be effective in the second-line and third-line chemotherapy for advanced NSCLC (Shepherd et al, 2005;Thatcher et al, 2005;Barlesi et al, 2006;Cullen et al, 2008;Kim et al, 2008;Scagliotti et al, 2009;Cappuzzo et al, 2010;Douillard et al, 2010;Reck et al, 2010;Vamvakas et al, 2010). Despite an increasing proportion of patients with advanced NSCLC derive prolonged survival with novel chemotherapy regimens; many of them will require salvage chemotherapy after relapse (Kosmas et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Baykara¹,

Coşkun²,

Berk³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Purpose: The aim of this retrospective study was to determine response rates, progression-free survival (PFS), overall survival (OS) and toxicity of gemcitabine and paclitaxel combinations with advanced or metastatic non-small cell lung cancer patients (NSCLC) who have progressive disease after platinum-based first-line chemotherapy. Methods: We retrospectively evaluated the file records of patients treated with gemcitabine plus paclitaxel in advanced or metastatic NSCLC cases in a second-line setting. The chemotherapy schedule was as follows: gemcitabine 1500 mg/m 2 and paclitaxel 150 mg/m 2 administered every two weeks. Results: Forty-eight patients (45 male, 3 female) were evaluated; stage IIIB/IV 6/42; PS0, 8.3%, PS1, 72.9%, PS2, 18.8%; median age, 56 years old (range 38-76). Six (12.5%) patients showed a partial response (PR), 13 (27.1%) stable disease (SD), and 27 (56.3%) progressive disease (PD). The median OS was 6.63 months (95% CI 4.0-9.2); the median PFS was 2.7 months (95% CI 1.8-3.6). Grade 3 and 4 hematologic toxicities, including neutropenia (n=4, 8.4%), and anemia (n=3, 6.3%) were encountered, but no grade 3 or 4 thrombocytopenia. One patient developed febrile neutropenia. There were no interruption for reasons of toxicity and no exitus related to therapy. Conclusion: The combination of two-weekly gemcitabine plus paclitaxel was an effective and well-tolerated second-line chemotherapy regimen for advanced or metastatic NSCLC patients previously treated with platinum-containing chemotherapy. Although the most common and dose limiting toxicities were neutropenia and neuropathy, this regimen was tolerated well by the patients.

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A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer

Cited by 63 publications

References 32 publications

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

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

Phase I and Pharmacokinetic Study of Pemetrexed plus Cisplatin in Chemonaive Patients with Locally Advanced or Metastatic Malignant Pleural Mesothelioma or Non–Small Cell Lung Cancer

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

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