A growing number of targeted kinase inhibitor drugs are being developed to treat cancer. These types of drugs are aimed directly at specific mutations in tumour cells. Although the number of cancers an individual drug will be active against is more limited, the chances of success should be greater because only those patients with a specific genetic mutation who are more likely to respond will be treated.
Another such drug that is in development at biotech company Ariad is ponatinib.1 As well as broad activity against the gene BCR-ABL, it targets the BCR-ABL T315I mutation in chronic myeloid leukaemia. Mutations in the BCR-ABL gene are thought to cause up to half of all treatment failure with currently available tyrosine kinase inhibitors; failure occurs because of the development of resistance. Ponatinib appears to retain activity against drug-resistant CML.
In a pivotal Phase II trial, 444 pretreated patients split into six cohorts, based on disease phase and whether or not they had the T315I mutation, were given oral 45mg doses of ponatinib once a day.2 Of these, 93% had received at least two previous tyrosine kinase inhibitors, and 58% at least three. Of the chronic phase patients, 54% achieved a major cytogenic response, and 44% a complete response. Of the 64 evaluable patients with the mutation, 70% achieved a major cytogenic response, and 66% a complete response.
In the 65 patients with advanced phase CML, half with the mutation achieved a major haematologic response, and just over a third of blast phase patients with the mutation. It also had a favourable safety profile in this group of heavily pretreated patients, with the most common adverse events being thrombocytopoenia, rash, dry skin, abdominal pain and headache. Pancreatitis – previously established as the drug’s dose limiting toxicity in the Phase I trial – was seen in 6% of patients across all patient groups.
The success of this trial has led to the drug recently being submitted for approval in both the US and Europe.
References
1. W.S. Huang et al. J. Med. Chem. 2010, 53, 4701
2. J. Cortes et al. Haematologica 2012, 97 (suppl. 1), Abst 1104
