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Larotrectinib exhibits durable activity in adults, children with various cancers
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CHICAGO — Larotrectinib — the first selective small-molecule pan-tropomyosin receptor kinase inhibitor — demonstrated clinical activity in adults and children with various tumors that had neurotrophic tyrosine receptor kinase gene fusions, according to study results presented at the ASCO Annual Meeting.
“This is the first targeted therapy developed simultaneously for adults and pediatric patients,” David M. Hyman, MD, director of developmental therapeutics at Memorial Sloan Kettering Cancer Center, said during a press conference.
Tropomyosin receptor kinase (TRK) gene fusions are found among a variety of tumor types. The abnormality occurs in 0.5% to 1% of common cancers, but in more than 90% of rare cancers like salivary gland cancer, a form of juvenile breast cancer and infantile fibrosarcoma.
“One of the defining features of TRK fusions is they aren’t just found in one cancer type, they are found in dozens of cancer types and span the entire lifetime of a person, adult or child,” Hyman said.
Hyman and colleagues presented an integrated dataset from three clinical studies meant to support a regulatory approval of larotrectinib (LOXO-101, Loxo Oncology).
The FDA in May granted orphan drug designation to larotrectinib for the treatment of solid tumors with TRK fusion proteins.
Researchers analyzed data from 55 patients (12 children, 43 adults; age range, 4 months-76 years) with TRK fusions enrolled in ongoing phase 1 and phase 2 clinical trials with locally advanced or metastatic cancer, including salivary (n = 12), sarcoma (n = 10) infantile fibrosarcoma (n = 7), lung (n = 5), thyroid (n = 5), melanoma (n = 4), colon (n = 4), cholangio (n = 2), gastrointestinal stromal tumors (n = 2) and others (n = 4).
Each patient received 100 mg larotrectinib on a continuous 28-day schedule. TRK fusions consisted of NTRK1 (n = 25), NTRK2 (n = 1) and NTRK3 (n = 29).
Overall response rate served as the primary endpoint. Secondary endpoints included duration of response and safety.
Among 46 evaluable patients, the ORR was 76% (95% CI, 62-87), with responses observed in 12 different tumor types. The 6-month duration of response rate was 91%. Ninety-three percent of patients who responded to treatment and 75% of all patients remained on treatment or underwent surgery with curative intent due to tumor downstaging.
“You would be hard pressed to find a targeted therapy that has results like this,” Hyman said.
Because the majority of responders remained on treatment without progression, median duration of response had not been reached. The longest responder remained on treatment at 25 months, followed by eight patients in response at 1 year and 16 patients in response at more than 6 months.
The most common treatment-emergent adverse events included fatigue (30%), dizziness (28%) and nausea (28%).
“Because larotrectinib was designed to target only TRK, it has been very well tolerated and does not cause many of the side effects associated with chemotherapy and multitargeted therapy,” Hyman said.
No patients discontinued treatment due to adverse events. Thirteen percent of patients underwent dose reductions.
Hyman said he believes larotrectinib could become a standard of care in the future.
“Really recognizing this benefit in the community will require we test patients more universally for the presence of TRK fusions or other biomarkers to really enjoy these benefits,” Hyman said. “We have to change the paradigm by which we test these patients.”
Despite the small number of patients, the study by Hyman and colleagues creates a new path for potential future drugs, according to Sumanta Kumar Pal, MD, co-director of City of Hope’s Kidney Cancer Program, ASCO expert and HemOnc Today Editorial Board member.
“Though the study is small and early, it demonstrates compelling evidence that may pave the way for a new class of drugs for rare tumors that could inform the future of precision medicine,” Pal said in a press release. – by Melinda Stevens
Reference:
Hyman DM, et al. Abstract LBA2501. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Hyman reports consultant roles with Atara Biotherapeutics, Chugai Pharma and CytomX Therapeutics; and receives research funding from AstraZeneca and Puma Biotechnology. Please see the abstract for a list of all other researchers’ relevant financial disclosures.