IMPRESS trial fails to find benefit from more tyrosine kinase inhibitor (TKI) treatment after resistance develops

Patients whose lung cancer has developed resistance to the drug gefitinib experience no statistically significant improvement in progression-free survival from continued treatment with the drug in addition to chemotherapy. These phase III trial results were presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain.

The IMPRESS trial is a randomized phase III study that compared continuation of gefitinib in addition to chemotherapy against chemotherapy alone in patients with lung cancer that carried mutations in the EGFR cell surface receptor.

Gefitinib is a tyrosine kinase inhibitor (TKI), and it targets cells with EGFR mutations. Most patients with EGFR mutation-positive non-small cell lung cancer respond to first-line EGFR tyrosine kinase inhibitors, but later acquire resistance. The primary objective of the trial was to show whether there was a difference in progression-free survival when gefitinib was continued in this situation.

"This study was designed to resolve a greatly debated issue: whether tyrosine kinase inhibitors should be continued beyond progression," said study author Tony Mok, MD, a professor in the Department of Clinical Oncology at the Chinese University of Hong Kong. "As the result demonstrated no difference in progression-free survival, the standard treatment is chemotherapy alone."

This study helps to establish the standard of treatment, and in the future, doctors should not prescribe EGFR tyrosine kinase inhibitors in combination with chemotherapy when cancers have progressed after first-line treatment with an EGFR tyrosine kinase inhibitor, Mok said.

The researchers had hoped that the study would show an improvement in progression-free survival. "I suspected the inhibition of TKI-sensitive cancer cells with continuation of gefitinib and inhibition of resistant cells with chemotherapy would optimize the treatment outcome. However, the study has proved otherwise, " said Mok.

The IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study included 265 patients from 71 centers in Europe and the Asia Pacific region who received chemotherapy plus either gefitinib or a placebo. There was no statistically significant improvement in progression-free survival, which was the primary end point of the study, for gefitinib versus placebo.

The overall survival data is still immature, Mok explained, although there is a suggestion of better overall survival in the placebo group. "This needs to be monitored very closely in future," he said.

Commenting on the study, Marina Garassino, MD, a medical consultant at the Medical Oncology Division of the National Cancer Institute of Milan, Italy, said the results were "very robust and reliable, and they will help clinicians in their daily clinical practice."

"However, when possible, it is important to rebiopsy the patients when their tumors progress after treatment with tyrosine kinase inhibitors to understand the mechanism that underlies the resistance," Garassino noted.

"New generations of agents are now becoming available for specific resistance mutations with very promising results. It is therefore possible in the future that we will be able to personalize the further treatments for these patients."

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