by Sylvie Lapostolle
PARIS, June 5 (APM) - Loxo Oncology's TRK inhibitor larotrectinib has induced high-level and lasting anti-tumour responses in various paediatric and adult cancers in early and mid-stage studies presented at the American Society of Clinical Oncology (ASCO) congress.
"This is the first targeted therapy developed simultaneously for adults and paediatric patients," said Dr David Hyman, director of developmental therapeutics at the Memorial Sloan Kettering Cancer Center in New York, at an ASCO press conference.
Hyman explained that the drug targets cancers with tropomyosin receptor kinase (TRK) fusion, an anomaly found in various different kinds of cancer - glioma, cancers of the thyroid, lung, pancreas, colon and salivary glands, GIST, melanoma and sarcoma in adults and glioma, sarcoma, fibrosarcoma and thyroid cancer in children.
Larotrectinib (ex LOXO-101) is the first pan-TRK inhibitor in clinical development. In the U.S., TRK fusion occurs in 1,500 to 5,000 patients each year. This anomaly is infrequent in common cancers and but highly frequent in rare ones;
Of 55 patients treated for 17 kinds of cancer in three Phase I or II studies (a Phase I in adults with eight patients with solid tumours, a Phase I/II in children with 12 patients and a Phase II in adults and adolescents with 35 patients), for 50 patients whose evaluation was confirmed, the response rate was 76% including 12% complete responses, the researcher said. 12% of patients saw disease stabilisation.
At six months, 93% of responders and 75% of all patients were still being treated or had been directed towards curative surgery, said Hyman. Median response duration had not been reached. The longest lasting response so far was 25 months and ongoing.
Response was very rapid (median 1.8 months). Adverse effects were fatigue, dizziness and nausea, generally low-grade. Only 13% of patients needed dose reduction and no patients stopped treatment due to tolerance problems.
"Larotrectinib delivers consistent and durable responses in TRK fusion patients across all ages, regardless of tumour context, and does so with few side effects," said Hyman.
"These data represent the promise of precision medicine fulfilled. TRK fusion-positive cancer may be among the first cancer types that is more appropriate to define on the basis of a shared genetic mutation than by the organ in which it arises," he added.
Development continues in all kinds of tumours for patients of all ages. Hyman said it planned to file in the U.S. at the end of 2017 or the beginning of 2018.
He recommended routine screening for TRK mutation to identify candidates for treatment.
Asked about the appearance of resistances, he said six patients had so far become resistant, five of whom had the same acquired resistance mutation, and that Loxo had already developed a second-generation inhibitor, LOXO-195.
TRK fusion was described for the first time in 1982 but has only been detected systematically since the arrival of new generation sequencing (NGS). It occurs in about 0.5% to 1% of the most common cancers but in more than 90% of rare cancers such as salivary gland cancer, a juvenile form of breast cancer and infantile fibrosarcoma.
TRK fusion occurs relatively early in the development of the cancer and remains present when the tumour increases in size and invades other tissue. This abnormal fusion sends out signals to cancer cells to continue growth and cell division.
Other TRK inhibitors have been described, such as Ignyta's entrectinib, which targets TrkA/B/C, ROS1 and ALK (APMMA 53092), but larotrectinib is the first to selectively inhibit TRK, which makes it very well tolerated. It received breakthrough therapy designation from the U.S. Food and Drug Administration in July 2016.
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