Larotrectinib active, safe in certain fusion-positive cancers

Larotrectinib showed activity in adults and children with tropomyosin receptor kinases, or TRK, fusion-positive cancers, according to findings published in The New England Journal of Medicine.

The drug also appeared to have an acceptable safety profile.

“Recurrent chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and various upstream amino-terminal partners have been identified across diverse cancers that occur in children and adults,” Alexander Drilon, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. Biologic models and early clinical evidence suggest that these fusions lead to oncogene addiction regardless of tissue of origin and, in aggregate, may be implicated in up to 1% of all solid tumors.”

The researchers enrolled 55 patients with TRK fusion-positive cancers into three different studies from March 2015 to February 2017: a phase 1 study of adults, a phase 1 to 2 study of children and a phase 2 study of adults and adolescents. Overall response rate as determined by independent review served as the main outcome. Secondary outcomes included duration of response, PFS and safety.

Patients were aged 4 months to 76 years, and had 17 unique types of TRK fusion-positive cancers. The most common type of tumor was salivary gland tumors (n = 12), followed by other soft-tissue sarcomas (n = 11), infantile fibrosarcoma (n = 7), thyroid (n = 5), colon (n = 4), lung (n = 4), melanoma (n = 4), gastrointestinal stromal tumors, (n = 3), cholangiocarcinoma (n = 2), appendix (n = 1), breast (n = 1) and pancreatic (n = 1).

In a combined analysis, patients had an overall response rate of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) according to investigator review.

Nearly three-quarters (71%) of responses remained ongoing at 1 year. Further, more than half (55%) were progression-free. Median duration of response and PFS had not been reached at 1 year.

Most patients (86%) remained in treatment or had undergone curative surgery after a median follow-up of 9.4 months.

Adverse event were overwhelmingly grade 1 or 2 (93%). The most common grade 3 or 4 adverse events included anemia (11%), increased alanine aminotransferase or aspartate aminotransferase levels (7%), weight gain (7%) and decreased neutrophil count (7%). Investigators did not consider any grade 4 or 5 adverse events to be related to treatment. No treatment-related grade 3 events occurred in more than 5% of patients.

In an accompanying editorial, Fabrice Andre, MD, PhD, of the Institut Gustave Roussy, Universite Paris Sud, Villejuif, France, wrote that the findings illuminated the challenges of genomic-driven drug development.

“To address the challenge of orphan molecular segments such as [neurotrophic TRK] fusions, the oncology community must pursue innovative trial designs, implement new biotechnologies for diagnosis and radically change the current pathways of care,” Andre wrote. “The major unknown factor in this field is how many other orphan molecular entities will meet the same therapeutic success as the one observed with larotrectinib. Finally, since these alterations are rare, there is a need for a global effort. This implies harmonization among regulatory agencies across the world and an expansion of global trials.” – by Andy Polhamus

Disclosures: Drilon reports personal fees from Loxo Oncology during the conduct of the study; personal fees from Foundation Medicine, Ignyta, Pfizer, Roche/Genentech and Takeda/Ariad outside the submitted work. Andre reports grant support from AstraZeneca, Eisai, Lilly, Novartis, Pfizer and Roche outside the submitted work. Please see the study for a full list of all other authors’ relevant financial disclosures.

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Source:

Drilon A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714448.