Roche’s entrectinib hits the mark in paediatric cancers

Roche’s entrectinib for gene fusion-positive cancers has shown promising results in a range of paediatric cancers in an early-stage trial, earning it a spotlight position at a pre-ASCO press conference.

The phase 1/2 study of the in children with tumours characterised by NKTR 1/2/3, ROS1 or ALK gene fusions isn’t due to be presented at ASCO until 2 June, but was highlighted ahead of time because entrectinib could be “the first treatment for childhood cancers that is effective based on tumour genetics instead of tumour type or location,” according to ASCO President Monica Bertagnolli.

The press conference came as ASCO published the abstracts from the forthcoming annual meeting in Chicago, which gets underway on 31 May.

While only involving 29 patients, the early results show impressive responses even in patients who have failed conventional therapies, according to lead investigator Giles Robinson of St. Jude Children's Research Hospital in Memphis, Tennessee.

The study showed entrectinib shrank tumours in all 11 children and adolescents with the target mutations, with two complete responses to the drug, with less activity in patients without those gene fusions than was expected. It’s estimated that NKTR 1/2/3, ROS1 or ALK are involved in around 1% of all childhood cancers.

Of the 11, five had central nervous system (CNS) cancers that are notoriously hard to treat as many drugs struggle to penetrate the blood brain barrier. Treatment with entrectinib appeared to be just as effective in these children, with one complete response and four partial responses.

“We’ve seen some rapid and durable responses, which is very gratifying,” said Robinson, although he noted some unusual side effects, including weight gain which isn’t often seen with cancer drugs, fatigue and loss of taste (dysgeusia).

“These early findings suggest that this therapy holds great promise for those whose tumours have these specific gene fusions,” he told the press conference.

As with all targeted therapies there are always concerns about the duration of response, and that will have to be tested with longer follow-up. As it stands, patients have been on the drug treatment for around 10 months on average.

Entrectinib isn’t the first drug to target cancers based on genetic profiles rather than location, with checkpoint inhibitors - Merck/MSD’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab) – picking up approvals for cancers based on specific mutations last year.

In fact, entrectinib isn’t even the first to target NKTR, as Bayer already has approval for its Vitrakvi (larotrectinib) drug in TRK fusion cancers. Nevertheless, it is generating some excitement among oncologists as it has broader activity that targets multiple mutations, while others are usually effective against just one mutation.

Roche added entrectinib to its pipeline when it acquired oncology biotech Ignyta for $1.7 billion in 2017 and has already submitted it for approval in adults and children with NKTR fusion cancers, with an FDA verdict due in August.

"We are encouraged by the results we have seen with entrectinib in children with paediatric and adolescent cancers, including those with tumours in the brain," said Sandra Horning, Roche's chief medical officer.

The new study “underscores the importance of combining comprehensive genomic profiling with targeted therapies and supports our approach to providing people with personalised medicines developed specifically for their type of cancer,” she added.