Phase II study of pemetrexed in combination with carboplatin in the first‐line treatment of advanced nonsmall cell lung cancer

Zinner, Ralph; Fossella, Frank V.; Gladish, Gregory W.; Glisson, Bonnie S.; Blumenschein, George R.; Papadimitrakopoulou, Vassiliki A.; Pisters, Katherine M.W.; Kim, Edward S.; Oh, Yun; Peeples, Beverly O.; Ye, Zhishen; Curiel, Rafael E.; Obasaju, Coleman K.; Hong, Waun Ki; Herbst, Roy S.

doi:10.1002/cncr.21480

Cited by 85 publications

(68 citation statements)

References 32 publications

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“…Carboplatin may have inferior efficacy when compared with cisplatin-based combinations, although most studies suggest similar efficacy for such doublet combinations (42 -44). We chose carboplatin over cisplatin as it offers a markedly better nonhematologic toxicity profile and showed good activity in combination with pemetrexed in the previously mentioned studies (25,29). Furthermore, our results show activity with four complete responses, which is encouraging, and support phase II testing of this combination of pemetrexed with carboplatin and radiation (CALGB 30407).…”

Section: Discussionsupporting

confidence: 64%

“…Doublet chemotherapy has been shown to prolong survival more than single-agent chemotherapy in metastatic NSCLC (37 -41), and as mentioned earlier, the doses, systemic efficacy, and tolerability of pemetrexed/carboplatin without radiotherapy are substantiated in two phase II trials in stage IIIB and IV NSCLC (25,29). In regimen 1, further dose escalation of pemetrexed beyond 500 mg/m 2 was not pursued.…”

Section: Discussionmentioning

confidence: 99%

“…In two phase II studies [one in Europe (N = 39) and one in the United States (N = 50)] in patients with locally advanced or metastatic NSCLC, the combination of pemetrexed (500 mg/m 2 ) and carboplatin (AUC = 6) given every 3 weeks produced response rates of 32% and 24%, median survival times of 10.5 and 13.5 months, and 1-year survival rates of 44% and 56% (25,29).…”

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confidence: 99%

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A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Seiwert¹,

Connell

Mauer³

et al. 2007

Clinical Cancer Research

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Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non^small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m 2 ); regimen 2 was pemetrexed (500 mg/m 2 ) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m 2 ). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m 2 ; AUC = 6); grade 3/4 leukopenia (4 of12 patients) was the mainhematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed.When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase IIdose-range was established (pemetrexed 500 mg/m 2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m 2 ) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Seiwert¹,

Connell

Mauer³

et al. 2007

Clinical Cancer Research

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“…Pemetrexed plus platinum (cisplatin or carboplatin) doublet chemotherapy has become a standard first-line treatment for non-squamous non-small cell lung cancer (NSCLC) patients who are not eligible for targeted therapies (e.g., tyrosine kinase inhibitors [TKIs]) or immunotherapy (2,3). However, the efficacy of this preferred chemotherapeutic regimen is very limited, with response rates of 30% to 40%, and progressionfree survival (PFS) of about 4-6 months (3)(4)(5). Despite a large number of promising studies demonstrating the expression level of enzymes targeted by pemetrexed (6,7) and enzymes involved in nucleotide excision repair (NER) of DNA-platinum adducts (8) can be used to predict response to pemetrexed plus cisplatin treatment, the translation of these scientific data from bench to the bedside has not yet occurred.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Chemotherapeutic Efficacy in Non–Small Cell Lung Cancer by Serum Metabolomic Profiling

Tian

Wang

Liu

et al. 2018

Clinical Cancer Research

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In clinical practice, there are currently no validated biomarkers that can, prior to treatment, reliably indicate the intrinsically sensitive or resistant features of a non-squamous NSCLC patient to pemetrexed plus platinum doublet chemotherapy. In this study, we investigated the metabolic characteristics of a large cohort of pre-chemotherapeutic serum samples (354 cases) and found tight associations between small metabolite subsets and the responses of patients to this cytotoxic drug combination. We developed an effective discriminant model employing a seven-metabolite panel (Hypotaurine, Uridine, Dodecanoylcarnitine, Choline, Dimethylglycine, Niacinamide, L-palmitoylcarnitine) that can predict the efficacy of this chemotherapeutic regimens, prior to treatment, with a sensitivity of 90.8% and specificity of 79.5%. We also identified three one-carbon metabolism-involved metabolites including choline, betaine and DMG that are potentially associated with drug resistance to pemetrexed. This serum-based biomarker study can be easily applied in clinical practice and personalize treatment decisions. Conclusion:This study developed an effective and convenient discriminant model that can accurately predict the efficacy and survival outcomes of pemetrexed plus platinum doublet chemotherapy prior to treatment delivery.

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“…Following a dose-ranging phase I study, two phase II trials have been completed using this combination. Zinner et al [15] looked at the combination of pemetrexed plus carboplatin as a first-line treatment in 50 patients with advanced NSCLC, and reported a response rate of 24%, a 1-year survival rate of 56%, and a median survival time of 13.5 months. The switch from cisplatin to carboplatin did not appear to result in any reduction in efficacy; results compared favorably with those in the Shepherd et al [12] and Manegold et al [13] studies.…”

Section: New Doubletsmentioning

confidence: 99%

Conclusion

Bunn

Thatcher

2008

The Oncologist

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Chemotherapy for non-small cell lung cancer (NSCLC) can prolong survival and improve quality of life, but the majority of advanced stage patients succumb to disease within 2 years, meaning that there is room for improvement. The standard chemotherapy for NSCLC involves one of a number of chemotherapy doublets that have been shown to improve survival when compared with single agents or best supportive care. These doublets are generally comparable in terms of efficacy, differing primarily in their toxicity profiles. However, encouraging new options may be approaching, including therapies targeted to specific patient subpopulations, and the use of combinations of current and new drugs to produce synergistic effects.Targeted therapies include the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, EGFR monoclonal antibody cetuximab, and vascular endothelial growth factor (VEGF) inhibitors such as sorafenib, a small molecule TKI, and bevacizumab, a recombinant monoclonal VEGF antibody. Most attempts to combine EGFR-targeted therapies with standard chemotherapy in NSCLC have produced poor results, possibly as a result of antagonism between EGFR TKIs and chemotherapy. Positive results with bevacizumab suggest that VEGF-rather than EGFR-targeted therapies may produce better results when combined with chemotherapy.Other new drugs being tested include enzastaurin, an oral serine threonine kinase inhibitor; vinflunine, a vinca alkaloid; dihydrofolate reductase inhibitors; and thymidylate synthase inhibitors.Combinations of therapies, especially those acting via different mechanisms, hold promise for improvements in survival, but careful testing is required to determine optimum combinations of available drugs and where new drugs fit into the armamentarium. The Oncologist 2008;13(suppl 1):37-46 IntroductionA major theme that arises from this supplement is that while chemotherapy for non-small-cell lung cancer (NSCLC) prolongs survival and quality of life, the majority of advanced stage patients succumb to disease within 2 years, leaving room for improvement. The main chemotherapy doublets for untreated patients are comparable in terms of efficacy, distinct only in terms of somewhat differing safety profiles. The use of triplet chemotherapy does not result in further increased survival, but instead, increased toxicity. However, encouraging new options do seem to be on the horizon, including the targeting of therapies to specific patient subpopulations, and the use of combinations of current and new drugs to produce additive or synergistic effects. As such, the better we can understand prognostic and therapeutic predictive factors in NSCLC, the clearer the choice of optimum therapy becomes. Current studies are focusing on patient factors such as smoking history, histology, molecular characteristics such as mutation state, gene copy number, protein expression levels, mass spectrometry profiles, and response to any previous lines of therapy [1].Patients previously thoug...

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Phase II study of pemetrexed in combination with carboplatin in the first‐line treatment of advanced nonsmall cell lung cancer

Cited by 85 publications

References 32 publications

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Prediction of Chemotherapeutic Efficacy in Non–Small Cell Lung Cancer by Serum Metabolomic Profiling

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