Combinational therapy of crizotinib and afatinib for malignant pleural mesothelioma

Our plain-English summary of Combinational therapy of crizotinib and afatinib for malignant pleural mesothelioma, by L. Huang, M. Cai, X. Zhang, et al (American Journal of Cancer Research, 2017).

The study

• Authors: L. Huang, M. Cai, X. Zhang, F. Wang, L. Chen, M. Xu, K. Yang, Z. Chen, X. Wang, L. Fu
• Journal: American Journal of Cancer Research
• Published: 2017;7(2):203-217
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a relative rare but highly aggressive neoplasm which is associated with asbestos exposure in most patients. The majority of patients are diagnosed in advanced stages so patients neither benefit from chemotherapy (e.g. pemetrexed-platinum combination) nor from surgery. It has been reported that cellular-mesenchymal to epithelial transition factor (MET) and epidermal growth factor receptor (EGFR) were critical for MPM cell proliferation. Moreover, targeting MET and EGFR drugs have gained promising results on anti-tumor therapy. Here, a striking difference in overall survival was observed between the MET and EGFR co-expression group (median survival time = 13.5 months) and non-co-expression group (median survival time = 20.5 months). In addition, treatment with combination of crizotinib and afatinib showed stronger inhibition on cell proliferation of MPM than the treatment by either one in vitro and in vivo. In conclusion, our data illustrated that crizotinib combined with afatinib may be a potentially effective strategy for treating MPM patients with over-expression of MET and EGFR.

In plain English

This laboratory study in China tested two targeted drugs against malignant pleural mesothelioma: crizotinib, which blocks a protein called MET, and afatinib, which blocks a protein called EGFR. It did not study asbestos exposure. The authors stained tumor tissue from 24 patients, collected between 1999 and 2015. Of the 24 tumors, 8 had MET staining graded ++ and 10 graded +++, and EGFR was over-expressed in 87%. Lowering MET or EGFR alone in mesothelioma cells did not significantly reduce their growth, but lowering both did. In two cell lines, the drugs together had a synergistic effect. In mice carrying human mesothelioma tumors (10 per group), mean tumor weight was 0.50 g with the combination, compared with 1.08 g with saline, 0.98 g with crizotinib and 0.96 g with afatinib. In patients, median survival was 13.5 months when both proteins were highly expressed and 20.5 months in all others. The authors concluded that the combination may be a potentially effective strategy for patients whose tumors over-express both proteins. The combination was tested only in cells and mice.

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: Laboratory study combining staining of patient tumor tissue (with a survival comparison), experiments on mesothelioma cell lines, and an animal experiment in mice carrying human tumor cells
• Who was studied: Tumor tissue from 24 malignant pleural mesothelioma patients and 24 normal pleura tissues, collected at Sun Yat-sen University Cancer Center, China, 1999 to 2015. Also five human mesothelioma cell lines (H28, 211H, H226, H2452, H2052), one immortalized normal mesothelial cell line (MeT-5A), and female nude mice (10 per group) injected with 211H cells.
• Exposure: Not asbestos. The exposures studied were the drugs crizotinib (a MET inhibitor) and afatinib (an EGFR inhibitor), alone or combined. In mice each was given at 20 mg/kg by stomach tube, with saline as control. In cells, MET and EGFR were also lowered using siRNA.
• Main results:
  • MET staining grades in the 24 mesothelioma tissues: - in 1 (4.2%), + in 5 (20.8%), ++ in 8 (33.3%) and +++ in 10 (41.7%). The authors reported higher MET in tumor than in normal pleura (P less than 0.001).
  • EGFR was over-expressed in 87% of the mesothelioma specimens.
  • In 211H and H226 mesothelioma cells, lowering MET or EGFR alone did not significantly affect cell proliferation.
  • Lowering MET and EGFR at the same time markedly inhibited proliferation of the mesothelioma cells (P less than 0.001).
  • In 211H and H226 cells, crizotinib and afatinib together showed a significant synergistic killing effect on the cells.
  • In mice with 211H tumors (10 per group), mean tumor weights were 1.08 ± 0.14 g (saline), 0.98 ± 0.08 g (crizotinib), 0.96 ± 0.18 g (afatinib) and 0.50 ± 0.10 g (combination) (P less than 0.01).
  • The tumor growth inhibition rate in the mouse combination group was 53.67%.
  • Mice in the combination group did not have notable body weight loss.
  • In patients, median survival was 14.5 months in the high MET expression group and 21.7 months in the low MET expression group (P = 0.006).
  • In patients, survival showed no relationship with high versus low EGFR expression (P = 0.197).
  • Median survival was 13.5 months in patients whose tumors highly expressed both MET and EGFR, and 20.5 months in all other patients, whose tumors did not highly express both (P less than 0.001).
• The authors' conclusion: The authors concluded that crizotinib combined with afatinib may be a potentially effective strategy for treating malignant pleural mesothelioma patients whose tumors over-express MET and EGFR. They said their work provided a potential strategy for a clinical trial. They also suggested that high expression of both MET and EGFR may be a useful marker of prognosis.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Asbestos Exposure, Chemotherapy, Pemetrexed (Alimta), EGFR, Overall Survival, Median Overall Survival.

Related studies

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• FISH Analysis of Crizotinib Target Genes ROS1/ALK/MET in Malignant Mesothelioma — S. Salvi, S. Varesano, et al. (2017)
• Treatment status and safety of crizotinib in 2028 Japanese patients with ALK-positive NSCLC in clinical settings — N. Ueno, S. Banno, et al. (2019)

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