Novel Tropomyosin Receptor Kinase Inhibitor Yields High Response Rates Across Tumor Types


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Larotrectinib, an oral inhibitor of tropomyosin receptor kinase, showed “striking” activity in adult and pediatric patients with the genetic aberrations known as tropomyosin receptor kinase (TRK) fusion, researchers reported at the 2017 ASCO Annual Meeting.1 Of 55 patients treated with larotrectinib in phase I and II trials, 76% responded, and the majority of responses were ongoing at 12 months, according to David Hyman, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center, New York.


The efficacy [of larotrectinib] exceeds almost any existing standard of care for solid tumors.
— David Hyman, MD

“To me, this is striking. Three out of four patients responded…. The efficacy exceeds almost any existing standard of care for solid tumors. There is hardly any chemotherapy or targeted therapy that has a response rate or durability that looks like larotrectinib in these patients,” Dr. Hyman said at a press briefing. 

Tropomyosin receptor kinase fusions are rare in common cancers but frequently observed in some uncommon cancers, in both adults and children. Fusion of the tropomyosin receptor kinase gene with an unrelated “partner” gene leads to uncontrolled signaling in the tropomyosin receptor kinase pathway that triggers tumor proliferation. As many as 5,000 cancers diagnosed in the United States each year (or even more) could harbor these mutations, Dr. Hyman said. 

“One of the defining features of tropomyosin receptor kinase fusions is the fact that they are not just found in one cancer type, but in dozens of different cancer types, and in both children and adults,” Dr. Hyman noted. Should larotrectinib be approved by the U.S. Food and Drug and Drug Administration, it will be the first targeted therapy developed in a “tumor-agnostic” manner and the first developed simultaneously for the adult and pediatric populations. 

Study in 17 Different Malignancies 

Dr. Hyman and his colleagues analyzed data from 55 patients with advanced cancer of 17 discrete tumor types and tropomyosin receptor kinase fusions. Patients were enrolled in an adult phase I trial, a pediatric phase I/II trial (SCOUT), or an adult and adolescent phase II basket trial, NAVIGATE. The most common malignancies were salivary gland cancer, sarcoma, infantile fibrosarcoma, thyroid cancer, lung cancer, colon cancer, and melanoma. Less common malignancies treated included cholangiocarcinoma (n = 2), gastrointestinal stromal tumors (n = 2), and other (n = 4).

The tropomyosin receptor kinase fusions in these patients were identified by 15 different local laboratories, “so this, in a sense, really represents the real-world identification [tropomyosin receptor kinase fusion–positive] patients,” Dr. Hyman commented.

LAROTRECTINIB IN TROPOMYOSIN RECEPTOR KINASE FUSION TUMORS

  • Tropomyosin receptor kinase is a rare genetic aberration found in a number of different tumor types.
  • The tropomyosin receptor kinase inhibitor larotrectinib was evaluated in 55 adults and children with this mutation, showing robust activity and good tolerability.
  • The objective response rate was 76%, with 12% complete responses and the majority of responses ongoing at 12 months.
  • Larotrectinib has received Orphan Drug and Breakthrough Therapy designations.

The overall rate of confirmed response as assessed by investigators was 76%, with complete responses in 12% of patients. Most patients were “not just meeting partial response criteria, but had deep tumor regressions,” he added. Three pediatric patients thus far were able to be downstaged for potentially curative surgery. Efficacy was consistent regardless of tumor type, the particular tropomyosin receptor kinase gene, or fusion partner gene.

Median time to response was 1.8 months, with many patients reporting “dramatic improvement of their symptoms within days of beginning therapy,” he said.

After a median follow-up of 5.8 months, median duration of response was not yet reached. At 12 months, 79% of responses were ongoing. Median progression-free survival was also not reached, and at 12 months, 63% of patients had not shown disease progression. The first tropomyosin receptor kinase fusion–positive patient treated with larotrectinib continues to respond on treatment past 2 years. 

In addition to their robust responses, patients tolerated the drug well. The most common treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). Only 13% of patients required dose modifications, and no patient discontinued treatment due to adverse events. 

In total, six patients have developed resistance and five were found to have an identical resistance mechanism known as a solvent front mutation. Two of these patients were subsequently responded to LOXO-195, a next-generation tropomyosin receptor kinase inhibitor that appears to retain activity in the presence of this mutation, and both responded.

Tropomyosin Receptor Kinase Testing Encouraged

Tropomyosin receptor kinase fusions can be identified by some, but not all, gene-sequencing tests that oncologists order. Dr. Hyman advised practitioners to find out whether the test they are ordering includes tropomyosin receptor kinase fusion detection, “and if it’s an option, to select it.” 

Oncologists should also be aware that obtaining test results can take weeks, Dr. Hyman added. “My personal opinion is that testing should be more broadly adopted… and I would generally advocate early testing.” 

“I believe these data support larotrectinib as a potential new standard of care for these patients,” he concluded. “However, I want to emphasize that recognizing this benefit in the community will require that we test patients more universally for the presence of tropomyosin receptor kinase fusions.”

On the basis of these promising data, larotrectinib has been granted both Orphan Drug and Breakthrough Therapy designations. A randomized trial comparing larotrectinib to other therapies is unlikely for several reasons, one being the drug’s impressive performance, according to Dr. Hyman. ■

DISCLOSURE: Dr. Hyman has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics; he also receives research funding from AstraZeneca and Puma Biotechnology.

REFERENCE

1. Hyman DM, Laetsch TW, Kummar S, et al: The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase inhibitor, in adult and pediatric TRK fusion cancers. 2017 ASCO Annual Meeting. Abstract LBA2501. Presented June 3, 2017.


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