A novel drug designed to specifically target RET has shown high response rates and durable efficacy in patients with RET fusion positive lung and thyroid cancers.

The results from two phase 1-2 trials of selpercatinib (formerly known as LOXO-292) just published in NEJM also show that it is well tolerated and has significant intracranial activity in patients with brain metastases.

Study investigators say the early results suggest that the new class of selective RET fusion  targeted drugs will be a substantial improvement over current multikinase TKIs because they lack the off-target toxic effects that lead to dose reduction and discontinuation.

One study – which included patients at the Peter MacCallum Cancer Centre – enrolled 105 patients with advanced RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and some who were previously untreated.

For the primary endpoint, the percentage of selpercatinib treated patients with an objective response was 64% and the median duration of response was 17.5 months, with 63% of the responses ongoing at a median follow-up of 12.1 months.

In the 39 previously untreated patients, the percentage with an objective response was 85%, and 90% of the responses were ongoing at six months.

An objective intracranial response was seen in 91% of patients with selpercatinib in patient with brain metastases.

Treatment related adverse events of grade 3 or higher were seen in 28% of patients – most commonly hypertension –  and 2% discontinued selpercatinib because of a drug-related adverse event.

In a separate study of selpercatinib in patients with RET-mutant medullary thyroid cancer, the percentage who had a response was 69% in 55 patients who had previously received vandetaniband/or cabozantinib, and 73% in 88 patients who had not.

One-year progression-free survival rates were 82% and 92% for these patient groups respectively.

In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% and 1-year progression-free survival was 64%.

Grade 3 or higher treatment related adverse events were seen in about 30% of patients, and 2% discontinued selpercatinib owing to drug-related adverse events.

The study investigators said the findings suggested that RET fusion targeted drugs would offer a promising advance over multikinase inhibitors such as cabozantinib and vandetanib, which have only weak activity against RET fusion–positive tumours and substantial side effects resulting from non–RET kinase inhibition.

“For example, in a phase 2 trial of cabozantinib, the percentage of patients with an objective response was 28% and the median progression-free survival was only 6 months, and dose modifications were warranted in 73%,” they noted.

They also noted that RET mutations were present in most patients with metastatic medullary thyroid cancer and in 1-2% of patients with NSCLC.

Therefore molecular screening strategies will be essential for identifying the patients who may benefit from RET inhibition, they concluded.