Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: where do we stand?

Our plain-English summary of Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: where do we stand?, by V. Agarwal, M.J. Lind, L. Cawkwell (Cancer Treatment Reviews, 2011).

The study

• Authors: V. Agarwal, M.J. Lind, L. Cawkwell
• Journal: Cancer Treatment Reviews
• Published: 2011;37(7):533-42
• Type of article: Review
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The median survival for patients with malignant pleural mesothelioma remains extremely poor and there is a need for the development of more effective treatment modalities. The epidermal growth factor receptor is frequently over-expressed in malignant pleural mesothelioma samples and therefore may be a potential therapeutic target. Targeted EGFR therapy has been successful in non-small cell lung cancer using small molecule tyrosine kinase inhibitors and in colorectal cancer using monoclonal anti-EGFR antibodies. However, phase II clinical trials based on EGFR tyrosine kinase inhibitor therapy have so far not shown promise in mesothelioma. This review includes a background to targeted EGFR treatment strategies, explores putative therapy resistance mechanisms, including the role of predictive biomarkers, and describes the current status of targeted EGFR therapeutic strategies for mesothelioma patients.

Copyright © 2010 Elsevier Ltd. All rights reserved.

In plain English

This article is a review, not a new study. The authors summarized published research on drugs that target the epidermal growth factor receptor (EGFR) as possible treatments for malignant pleural mesothelioma. Citing other work, its introduction states that 80% of cases can be attributed to asbestos fibre exposure. The review itself did not study asbestos. The studies it reviewed found EGFR over-expressed in 44–97% of mesothelioma samples. In one phase II trial of gefitinib in 43 patients, 40% (95% confidence interval, 25–56%) were alive and free of disease progression at 3 months. In another phase II trial, erlotinib produced no responses among 33 patients with measurable disease, and 14 had stable disease. Cited studies found no mutations in the parts of the EGFR gene they examined in 66, 16 and 25 mesothelioma samples. The authors concluded that these drugs may not be clinically effective in pleural mesothelioma. They noted that both trials were small and non-randomised, so definite conclusions cannot be drawn. They suggested possible reasons for resistance and called for laboratory studies of anti-EGFR antibodies. No published laboratory or animal studies of these antibodies in mesothelioma existed.

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 research on EGFR-targeted therapy, focused on malignant pleural mesothelioma
• Who was studied: Published laboratory studies and clinical trials on malignant pleural mesothelioma (MPM). Studies in non-small cell lung cancer and colorectal cancer are included as background.
• Exposure: No exposure was studied. The review concerns drug treatment (EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, and anti-EGFR antibodies). Asbestos appears only as background in the introduction, which cites other work.
• Main results:
  • Across the immunohistochemical studies reviewed, EGFR was over-expressed in 44–97% of MPM samples.
  • In the CALGB 30101 phase II trial (43 chemotherapy-naive patients: 42 pleural and 1 peritoneal mesothelioma), 3-month progression-free survival with gefitinib was 40% (95% CI, 25–56%). That trial's authors concluded that single-agent gefitinib was not active.
  • In a phase II trial of erlotinib in 63 chemotherapy-naive patients with advanced or recurrent MPM, there were no responses. 14 of 33 patients with measurable disease (42%) had stable disease.
  • Three cited studies looked for EGFR mutations in MPM samples. One found no mutations in the EGFR tyrosine kinase domain in 66 samples. The other two found no exon 18–21 mutations, one in 16 samples and one in 25 samples from a Japanese population.
  • In a cited series of 206 MPM tissue samples, PTEN protein expression was lost in 62% of cases.
  • In that same cited series, median survival was longer for patients with PTEN-positive tumours (15.5 months; 95% CI, 3.8–27.2) than for those with PTEN-negative tumours (9.7 months; 95% CI, 7.9–11.7), log rank p = 0.0001.
  • The authors suggested that resistance to EGFR tyrosine kinase inhibitors in MPM may be associated with the absence of activating EGFR mutations. They named loss of PTEN protein and trans-activation of EGFR by COX2/PGE2 as other possible mechanisms.
  • No published laboratory (in vitro) or animal (in vivo) studies had assessed anti-EGFR monoclonal antibodies in MPM. The authors said in vitro studies are required.
• The authors' conclusion: The authors concluded that two small phase II trials showed that the EGFR tyrosine kinase inhibitors gefitinib and erlotinib may not be clinically effective in MPM.
• Limitations the authors state:
  • The authors noted that both mesothelioma drug trials were phase II, non-randomised and small (43 and 63 patients), so definite conclusions cannot be drawn from them.
  • The authors noted that immunohistochemistry, the method used to measure EGFR over-expression in the studies reviewed, is a subjective technique.
  • The authors noted that the two trials did not take into account the mutation status of the EGFR tyrosine kinase domain or of the downstream signalling pathway when enrolling patients.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Median Survival, EGFR, Non-Small Cell Lung Cancer, Tyrosine Kinase Inhibitor, Colorectal Cancer, Monoclonal, Clinical Trial.

Related studies

• Epidermal growth factor receptor overexpression in malignant pleural mesothelioma: prognostic correlations — O. Rena, L.R. Boldorini, et al. (2011)
• Epidermal growth factor receptor (EGFR)-targeted therapies in mesothelioma — P.L. Chia, A.M. Scott, et al. (2019)
• Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma — J. Kurai, H. Chikumi, et al. (2012)
• Pulmonary adenocarcinoma with epidermal growth factor receptor-mutations in asbestos exposed non-smokers: A case series — R.L. Kradin, J. Iafrate, et al. (2017)
• Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody — H. Dazzi, P.S. Hasleton, et al. (1990)
• Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers — J.C. Pache, Y.M. Janssen, et al. (1998)

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