NTRK fusion ‘pan-tumour’ drug approval marks new approach to cancer treatment

Wednesday, 16 Sep 2020

The Australian registration of a ‘pan-tumour’ TRK inhibitor to treat patients with a wide range of NTRK fusion-positive cancers signals a new approach to cancer treatment that will become increasingly common, a genomic expert says.

Professor David Thomas, Head of the Genomic Cancer Medicine Laboratory at the Garvan Institute of Medical Research in Sydney, told the limbic the registration of larotrectinib (Vitrakvi) to treat more than 15 types of cancer in infants through to adults was a “major milestone”.

Rather than being based on the tumour’s anatomical location, the drug targets tumours anywhere in the body caused by the genetic mutation NTRK (neutrophic tyrosine receptor kinase) gene fusion, which switches on tumour growth.

Larotrectinib is among the first generation of tropomyosin receptor kinase (TRK) inhibitors, that block the protein produced following the fusion process, thereby halting tumour development.

“The importance of this drug is that it represents … an approach to cancer treatment that will become more and more common,” said Professor Thomas, who is also Director of the Kinghorn Cancer Centre.

On 10 September Bayer announced it had gained TGA approval for larotrecinib to treat adult and paediatric patients with locally advanced or metastatic solid tumours with a diagnosed NTKR gene fusion, that cannot be controlled by other therapies.

NTKR mutations are most common in salivary gland cancer and secretory breast cancer, as well as several paediatric cancers such as infantile fibrosarcoma. However, Professor Thomas said the mutation was found in about 1% of a broad range of common cancers, including lung and pancreatic cancer.

He estimated the drug could potentially benefit several hundred Australian patients each year, with clinical trials showing strong overall response rates of up to 80%.

While it had largely been trialled in advanced, incurable cancers, Professor Thomas said tumour shrinkage had been shown to last for months or years in some cases, while in others, previously inoperable tumours had been reduced to a point where they could be surgically resected.

“I think we will see the drug used earlier and earlier in the patient journey, especially to get cancers to a size where they can be safely resected,” he said.

Lactrectonib is the same class of drugs as entrectinib (Rozlytrek, Roche), which was PBS-listed last month [August] for treating Australian patients with ROS-1 positive non-small cell lung cancer. The US FDA has approved both entrectinib and lacrectinib for treatment of tumours with NTKR gene fusion.

A Bayer spokeswoman said Vitrakvi treatment cost $21,190 per month, and the company had made a submission for a PBS-subsidy for the drug which will be assessed in November,

To date, nine Australian cancer patients have been treated with the drug on compassionate, last resort grounds after tests confirmed the presence of NTKR gene fusion.

Associate Professor Jordan Hansord, paediatric oncologist at the Royal Children’s Hospital, Melbourne, said in a statement that larotrectinib would enable treatment to match the genetic blueprint of the cancer, irrespective of the patients’ age – clinical trials have included infants less than one month old.

Genetic testing of children with cancer to reveal what was driving their particular cancer could help select the best treatment approaches, he said.

A NTKR fusion diagnoses is determined via genetic testing of tissue using RNA or DNA next-generation sequencing or fluorescence in situ hybridisation (FISH).

Professor Thomas said a major hurdle to the introduction of new precision oncology drugs such as TRK inhibitors was that in order to be publicly funded, they required approval from both the Medical Services Advisory Committee (MSAC) for the genetic test, and PBAC for the drug subsidy – known as co-dependent technology.

He suggested the two processes needed to be “uncoupled” as an increasing number of drugs targeting genetic alterations became available.

Professor Thomas heads the MoST IIR trial (Investigator initiated research), for which Bayer Global contributes  funding and provides larotrecinib for use in the trial.

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