TRK Fusions Identified in Hematologic Cancers

In rare instances, oncogenic tropomyosin receptor kinase (TRK) gene fusions occur in hematologic cancers, and these malignancies might respond to larotrectinib, according to early preclinical research published in the Journal of Clinical Investigation.

“There have been scattered case reports of patients with TRK fusions in hematologic malignancies, but not a real systematic study,” said senior coauthor Omar I. Abdel-Wahab, MD, of the Human Oncology and Pathogenesis Program and Leukemia Service at the Memorial Sloan Kettering Cancer Center, New York. “So, we analyzed RNA sequencing data for TRK fusions across a cohort of just over 7,000 patients with different hematologic malignancies.”

The team identifiedTRK fusions in only 8 of those patients (0.01%), with acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, histiocytosis, multiple myeloma, and dendritic cell neoplasms.

“The fusions we found were very similar to those found in solid tumors,” Abdel-Wahab noted. “Preclinically, they transformed cells and responded to TRK inhibition in preclinical models. Then we were able to treat an AML patient who had refractory disease and a TRK fusion.”

“We found that he had a [ETV6-NTRK2] TRK fusion,” Abdel-Wahab said. “We treated a xenograft from that patient with larotrectinib, which the FDA (Food and Drug Administration) has granted priority review for children and adults with TRK gene fusions. The xenograft responded beautifully to the larotrectinib.”

The TRK-fusion clones also responded when the patient received larotrectinib, Abdel-Wahab reported. But the patient’s other AML clones did not. The researchers also found previously-unidentified TRK fusions in two patients with multiple myeloma and one with AML.

The neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3 encode the TRK proteins TRKA, TRKB, and TRKC. Normally, they are involved in neurogenesis during embryonic development and subsequently in nerve function for appetite, proprioception, memory formation, and pain regulation.

“Fusions involving those three neurotropic receptor tyrosine kinases are quite rare in hematopoietic malignancies, but the ones identified clearly play a role in the pathology of the disease,”  David Bodine, PhD, senior investigator, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, told Cancer Network.

“The authors showed that simply adding the fusion gene to primary mouse cells increased proliferation and/or transformation of cell lines,” Bodine said. “[They] showed that cells making the fusion protein are amenable to targeted inhibition.”

Larotrectinib is a highly-selective TRK inhibitor. Loxo Oncology and Bayer are collaborating on the clinical development of larotrectinib for solid tumors that harbor TRK gene fusions.

In May 2018, the FDA granted the drug Priority Review and announced an anticipated decision by November 26, 2018. Although TRK fusions are rare, they occur across many cancer types.

“Independent of the histologic subtype of cancer, the tissue type of the cancer, it seems that inhibition of TRK has therapeutic impact” in solid tumors, Abdel-Wahab noted. “It's part of the emerging concept of targeting molecular alterations rather than treating specific tissue locations or tumor types, like breast cancer or colon cancer.”

“As we learn more and more about the genomics of cancer, it's become really clear that a lot of our targetable genetic alterations are not commonly shared across a large number of patients with one specific type of cancer,” Abdel-Wahab said. “There are a lot of people walking around with TRK fusions, but the proportion within any given disease is low.”

“There are a lot of critics of precision medicine right but I’ll tell you: if you ever put a patient on a TRK inhibitor like larotrectinib [for a solid-tumor cancer], you’ll want to test everybody because the responses are just incredible,” said David Hong, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Complete responses in 15%–20% of patients. You just don’t see that in advanced solid tumor cancers.”