The role of pemetrexed combined with targeted agents for non-small cell lung cancer

Our plain-English summary of The role of pemetrexed combined with targeted agents for non-small cell lung cancer, by K. Konopa, J. Jassem (Current Drug Targets, 2010).

The study

• Authors: K. Konopa, J. Jassem
• Journal: Current Drug Targets
• Published: 2010;11(1):2-11
• Type of article: Review
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed is a novel third-generation multitargeted antifolate agent used in the first- and second-line treatment of unresectable pleural mesothelioma and advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this compound is a preferred partner in the multidrug regimens. In the last few decades, better understanding of molecular oncology and genetics has allowed for the development of an array of molecular targeted agents, many of which have been found active in NSCLC. It has been hoped that these compounds will disrupt tumor signaling pathways complementary to those targeted by chemotherapy. This review outlines the current preclinical and clinical studies using pemetrexed in combination with targeted agents in advanced NSCLC. Clinical experience with the use of these combinations is still limited and mostly includes phase I and II trials. These investigations have mainly focused on compounds previously shown to be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor (cetuximab and erlotinib). Preliminary results have shown the feasibility of these combinations and their promising activity but large phase III studies are warranted to verify the real value of this strategy. Combinations of pemetrexed with other targeted agents, such as mTOR inhibitors and compounds targeting proteasome are still at early stages of development.

In plain English

This article was a review, not an original study. The authors described preclinical and clinical studies, mostly phase I and II trials, that combined the chemotherapy drug pemetrexed with targeted drugs in advanced non-small cell lung cancer. The article did not study asbestos exposure. It mentions pleural mesothelioma only as a disease pemetrexed treats. The reviewed work focused mainly on anti-angiogenic drugs (bevacizumab and small-molecule tyrosine kinase inhibitors) and EGFR inhibitors (cetuximab and erlotinib). In one reviewed phase II study, patients given first-line pemetrexed, carboplatin and bevacizumab had a 55% response rate. In a phase III trial (ZEAL) of 537 patients whose disease had progressed after earlier chemotherapy, adding vandetanib to pemetrexed raised the response rate (19.1% versus 7.9%), but progression-free survival did not differ significantly. A phase II study that added enzastaurin was closed early over toxicity concerns and because enzastaurin appeared to lack efficacy. The authors considered pemetrexed a preferred partner for targeted drugs. They concluded that early results showed feasibility and promising activity, but that large phase III studies are needed to verify the real value of this strategy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of published and ongoing studies
• Who was studied: No patients were studied directly. The article reviewed preclinical studies and clinical trials, mostly phase I and II, in advanced non-small cell lung cancer.
• Exposure: No asbestos exposure was studied. The 'exposure' was drug treatment: pemetrexed combined with targeted agents, mainly anti-angiogenic agents (bevacizumab and small-molecule tyrosine kinase inhibitors) and EGFR inhibitors (cetuximab and erlotinib).
• Main results:
  • The authors described pemetrexed as considered a preferred chemotherapy partner for targeted therapies.
  • In a reviewed phase II study (Patel et al.), patients given first-line pemetrexed, carboplatin and bevacizumab had an objective response rate of 55%, with median progression-free survival of 7.8 months and median overall survival of 14.1 months.
  • In the reviewed phase III ZEAL trial (537 patients who progressed after previous chemotherapy), the pemetrexed-vandetanib arm had a higher response rate than the pemetrexed-placebo arm (19.1% versus 7.9%), but progression-free survival did not differ significantly.
  • A reviewed randomized phase II study of pemetrexed, carboplatin and bevacizumab with enzastaurin or placebo was closed early because of the apparent lack of enzastaurin efficacy (median progression-free survival 4.3 and 4.2 months, respectively) and toxicity concerns.
  • In a reviewed phase I study of intermittent erlotinib with pemetrexed (42 patients with advanced solid tumors, 16 with NSCLC), 5 patients with NSCLC on the first schedule had a partial response, among 16 patients assessable for response.
  • In a reviewed phase II study of pemetrexed, carboplatin and thoracic radiation in locally advanced NSCLC, adding cetuximab did not give an apparent benefit.
• The authors' conclusion: The authors concluded that preliminary results showed these combinations were feasible and had promising activity, but that large phase III studies are needed to verify the real value of the strategy.
• Limitations the authors state:
  • The authors stated that the optimal choice and sequencing of drugs in these combinations has not yet been worked out.
  • In one reviewed trial (Herbst et al.), patients received either docetaxel or pemetrexed, and results were not analyzed separately for each drug.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Antifolate, Unresectable Pleural Mesothelioma, Chemotherapy, Bevacizumab, Tyrosine Kinase Inhibitor, Cetuximab (Erbitux).

Related studies

• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Toxic epidermal necrolysis related to Cisplatin and pemetrexed for metastatic non-small cell lung cancer — K. Scheinpflug, C. Menzel, et al. (2012)
• Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells — L. Su, G. Liu, et al. (2011)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)
• Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients — P.H. Honoré, S.J. Joensen, et al. (2014)
• Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study — N. Blais, D.R. Camidge, et al. (2013)

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