The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

Scagliotti, Giorgio Vittorio; Hanna, Nasser H.; Fossella, Frank V.; Sugarman, Katherine P.; Blatter, J.; Peterson, Patrick; Simms, Lorinda; Shepherd, Frances A.

doi:10.1634/theoncologist.2008-0232

Cited by 648 publications

(520 citation statements)

References 36 publications

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“…Furthermore, both the PARAMOUNT pemetrexed arm and the JMDB homogeneous group had greater incidence of toxicities than the PARAMOUNT placebo arm. However, the overall incidence of all grades and grade 3/4 toxicities emerging after four cycles of pemetrexed-cisplatin was low for both PARAMOUNT and JMDB (≤16.7% and ≤5.2%, respectively), and the toxicities were consistent with the known safety profile of pemetrexedcisplatin [5], [6] and [21].…”

Section: Discussionsupporting

confidence: 66%

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

et al. 2014

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Highlights•Compared advanced NSCLC phase III trials: pemetrexed-cisplatin with or without pem maintenance.•4 cycles pem-cis followed by pem maintenance improves survival over 6 cycles pem-cis.•Longer exposure to pem-cis or maintenance pem increases some toxicities, but overall incidence low. Abstract ObjectivesTwo phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression. MethodsOverall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. ResultsOutcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. ConclusionsThe across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

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Section: Discussionsupporting

confidence: 66%

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

et al. 2014

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“…Conversely, those with squamous cell carcinoma of the lung did significantly worse when treated with pemetrexed with a median OS of 6.2 versus 7.4 months (HR 1.56, p=0.018). 5 This differential efficacy according to histology was confirmed in other trials in the first-line and maintenance settings. 3,6 Based on these findings, pemetrexed became a standard second-line treatment option for patients with recurrent, advanced NSCLC with non-squamous histology and has been FDA-approved since…”

Section: Pemetrexedmentioning

confidence: 54%

“…This was discovered after an additional analysis of two studies showed pemetrexed to be more effective in non-squamous histologies and less active in squamous tumors. [3][4][5] Based on these findings, the choice of first-line agents in metastatic NSCLC is now strongly based on presenting histology, and this initial choice affects available second-line options.…”

Section: First Line Treatmentmentioning

confidence: 99%

Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer

Durm

Hanna

2017

Hematology/Oncology Clinics of North America

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Keywordsnon-small cell lung cancer, chemotherapy, second-line treatment, docetaxel, pemetrexed, erlotinib Key Points• Docetaxel, pemetrexed, and erlotinib are approved for the second-line treatment of NSCLC.• The discovery of targetable mutations, the increasing use of maintenance strategies, and the introduction of immunotherapies has made the choice of second-line agents much more complicated.• Ramucirumab with docetaxel is the only combination regimen that has shown improved overall survival in the second-line setting.• Erlotinib is the only agent approved in the third-line setting for EGFR wild-type patients. First Line TreatmentIn patients without targetable genetic alterations, the standard first-line therapy for advanced (stage IIIB or IV) NSCLC is chemotherapy with a platinum doublet for 4-6 cycles with or without bevacizumab. 1 Historically, a number of drugs including paclitaxel, docetaxel, gemcitabine, and vinorelbine were considered acceptable platinum partners in the first-line metastatic setting with essentially no differences in progression free survival (PFS) or overall survival (OS). More recently, additional agents have been approved in combination with platinum in this setting including pemetrexed and nab-paclitaxel. [1][2][3] One particular advance in the last decade has been the recognition that histology should be considered in the choice of initial chemotherapy. This was discovered after an additional analysis of two studies showed pemetrexed to be more effective in non-squamous histologies and less active in squamous tumors. 3-5 Based on these findings, the choice of first-line agents in metastatic NSCLC is now strongly based on presenting histology, and this initial choice affects available second-line options. Maintenance TherapyHistorically, patients treated with first-line platinum doublet chemotherapy who had objective responses or stable disease were placed on surveillance following completion of 4-6 cycles. However, over the last decade, new data suggests that there is benefit to the addition of maintenance therapy following initial chemotherapy. There are two maintenance strategies including continuation of an agent used in the first-line setting or switching to a previously unused agent (switch maintenance). There is data supporting the use of bevacizumab, pemetrexed, and erlotinib in the maintenance setting either as single agents or in combination. [6][7][8][9][10][11] Prior maintenance therapy is of particular importance when discussing second-line chemotherapy options as the use of maintenance therapy, particularly when switch maintenance is employed, influences the availability of agents in the second-line setting and beyond. Chemotherapy as Second-Line TreatmentHistorically, nearly all patients received platinum doublet chemotherapy followed by single agent chemotherapy in the second-line setting. However, with the discovery of targetable mutations, the development of tyrosine kinase inhibitors (TKI), the increasing use of maintenance strategies, and the introduction of imm...

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“…39,40 The predictive role for histology for pemetrexed was supported by phase II studies and by a retrospective review of two large, randomized, phase III trial. 38 A recent review of 408 publications reported that 11 single-arm or pooled population studies showed …”

Section: Discussionmentioning

confidence: 99%

“…37 However, few data are available on the influence of tumor histology and gene expression of molecular determinants of gemcitabine and cisplatin activity. 38 Similarly, no data are available about differences in gene expression levels of these target genes that have a critical role in tumor sensitivity or resistance to anticancer drugs in primary and metastatic NSCLC tissues.…”

Section: Introductionmentioning

confidence: 99%

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

et al. 2009

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The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5 0 -nucleotidase (5 0 -NT), cytidine deaminase (CDA) and ribonucleotidereductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.

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The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

Cited by 648 publications

References 36 publications

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

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