Researchers reveal potential new role for Glivec/Imatinib

Imatinib – or Glivec as it also known – looks as if it may become an effective treatment for yet another type of cancer.

Consultant medical oncologist Dr. Grant McArthur told a news briefing today that a Phase II study by an international team has shown that the drug is active against a rare type of cancer called dermatofibrosarcoma protuberans (DFSP) – a malignant tumour that occurs in the second layer of the skin (the dermis).

He said that complete control of the disease was achieved in eight out of 10 patients in a Phase II trial either through imatinib alone or imatinib plus surgery. The research team are preparing to present their findings to regulatory bodies for approval for imatinib’s use as a treatment for unresectable DFSP when it exhibits a particular genetic profile.

The study, presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, was selected as a proffered paper by the scientific board of the EORTC-NCI-AACR and also won an award from the Fondation Nelia et Amadeo Barletta (FNAB), a foundation devoted to supporting worldwide translational research aimed at individualising therapeutics. The award is being presented today to Dr. McArthur, the lead researcher, by Professor Esteban Cvitkovic, president of the foundation’s scientific board.

Dr McArthur, who is head of the Molecular Oncology and Translational Research Laboratories at the Peter McCallum Cancer Centre in Melbourne, Australia, said that the decision to try imatinib in the treatment of DFSP arose from pioneering research from another team published in 1997 . This had shown that a gene called the platelet-derived growth factor receptor B (PDGFB) was re-arranged in DFSP, involving a translocation between chromosomes 17 and 22.

"It was intuitive to try imatinib in the disease because this translocation results in over expression of PDGFB and imatinib is an inhibitor for the PDGFB receptor," said Dr. McArthur.

He said there had been reports of imatinib’s effectiveness in several cases of metastatic DFSP, so he and colleagues at other centres in the USA, Belgium and Switzerland set out to see whether the cellular genetic and kinase profiles in DFSP would correlate with clinical responses to imatinib.

The ten patients were treated with 800mg of imatinib daily. Of the eight with locally advanced disease, two achieved complete response that was pathologically confirmed through resections of the regions where the tumour was present and two achieved complete response confirmed by tumour assessment. Four had partial response followed by surgery to make them free of disease. So, the disease was controlled in all these patients either by imatinib alone or imatinib plus surgery.

Two patients had metastatic DSFP with a more complex genetic profile. One, with a translocation t(17-22) had a partial response to imatinib but the disease progressed after seven months of treatment. The other did not have a translocation and did not respond to imatinib.

Dr. McArthur explained that over 95% of DFSP tumours have t(17-22). "It’s difficult to be certain based on only one case, which was very high grade and where there was also the possibility that it may not have been a true DFSP, but our patient without the translocation did not respond to imatinib. Nevertheless, our data support the use of imatinib where t(17-22) is detected, although our findings cannot be used to make any definite statements about tumours with other molecular abnormalities.

"The most important outcome of our study is that molecular analysis of the tumour can be used to predict a patient’s response to treatment where the analysis indicates that the pathway targeted by imatinib is activated."

Said Professor Cvitkovic: "These results fit perfectly the FNAB objectives supporting research using tissue sample biopsy for molecular analysis to select more accurately patients who could benefit from targeted therapeutics. We are confident that this approach will first benefit patients by tailoring their treatments and avoiding unnecessary therapy and often toxic ‘trial and error’ probabilistic prescriptions. It will also aid regulatory agencies and pharmaceutical companies by speeding up drug development while helping to implement more rational regulatory policies."

Dr McArthur said that one challenge the oncology community faced was working with industry and regulatory agencies to develop strategies for approving novel agents that displayed significant activity in rare diseases. "Possible approaches include registries," he said, "but ultimately, international cooperation in trials such as ours (the Imatinib Target Exploration Study Team – ImTEST) will provide the best data."

He added that it was possible that imatinib may turn out to be useful in other rare tumours or diseases, or in rare subsets of more common diseases where PDGFR or other targets are activated.