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Very Few Patients Eligible for Tissue-Agnostic TRK Inhibitors Get Them, Real-World Analysis Shows


NEW YORK – Out of 800 patients identified over a two-year window as having NTRK fusion-positive advanced cancers, only 12 received NTRK inhibitors, according to a real-world data analysis presented at the American Society of Clinical Oncology's annual meeting.

In 2018 and 2019, the US Food and Drug Administration approved Bayer's Vitrakvi (larotrectinib) and Genentech's Rozlytrek (entrectinib), respectively, in a histology-agnostic fashion. Adult and pediatric patients could receive these TRK inhibitors if they had metastatic, refractory solid tumors characterized by NTRK fusions and were out of other treatment options.

The tissue-agnostic availability of these TRK inhibitors, as well as immunotherapies and other targeted drugs, has been celebrated by precision medicine proponents as a paradigm shift in the way cancer is viewed and treated. Many expect that the shift to molecularly classifying cancers, instead of in a histology-specific manner, will broaden patients' access to precision oncology advances.

Health technology firm Diaceutics has been tracking the adoption of precision medicine and identifying gaps in access by drawing on real-world claims, treatment, and laboratory testing data in its DXRX database. In an abstract released at ASCO, researchers from the company and elsewhere described their use of this data to try to understand the extent to which Vitrakvi and Rozlytrek are reaching their intended patient populations.

Researchers led by Susanne Munksted, chief precision medicine officer at Diaceutics, identified approximately 4,250 cancer patients in the DXRX database with NTRK fusions between 2022 and 2023. Out of the 800 patients in that database with metastatic solid tumors who could be linked to treatments they received in the second- or later-line settings, only a dozen, or 1.5 percent, received one of the commercially available TRK inhibitors. Eight patients received Rozlytrek, three got Vitrakvi, and one got both.

Of those who received some other type of treatment, 346 patients, or approximately 43 percent, got a different targeted treatment, likely because they had another targetable molecular aberration in their tumors. Still, that left 442 patients, or around 55 percent, who received just chemotherapy (28 percent), only immunotherapy (21 percent), or a chemo/immunotherapy combination (6 percent).

Based on their analysis, Munksted and colleagues concluded that most patients with advanced NTRK fusion-positive solid tumors aren't getting the chance to benefit from available precision medicines designed to directly inhibit the molecular alteration driving their disease. "These findings may suggest that targeted therapy for rarer and/or tissue agnostic alterations may get deprioritized or overlooked," the researchers wrote in the abstract.

NTRK fusions are extremely rare, showing up in less than 1 percent of all solid tumors. However, these alterations occur more frequently in certain rarer tumor types, such as intrahepatic cholangiocarcinoma (4 percent); papillary thyroid cancer (9 percent); spitz tumors and spitzoid melanoma (16 percent); congenital mesoblastic nephroma (72 percent); mammary analogue secretory carcinoma (89 percent); infantile fibrosarcoma (95 percent); and breast secretory cancer (96 percent).

There may be many reasons why patients eligible for TRK inhibitors aren't getting them, but a big factor could be because an oncologist in a typical community practice used to treating patients with more prevalent lung, breast, and colorectal cancers may encounter the rare patient with an NTRK fusion-positive tumor every few years, and therefore be unaware of the latest treatment advances.

The limited use of TRK inhibitors, "we believe, [is] due to the rarity [of] NTRK [fusions]," leading to "other personalized medicine drugs, chemotherapy, and immunotherapies being prioritized," Diaceutics Chief Data Officer Jordan Clark said in an interview. "The rarity of NTRK [alterations] means that physicians aren't familiar with how to manage those patients, so they revert to what they know."

"Most oncology practices are set up to efficiently deal with common [cancers] in a similar way [based on] how they were dealt with for the past decade," agreed Howard McLeod, director of the Center for Precision Medicine & Functional Genomics at Utah Tech University, who was involved in the data-analysis with Diaceutics. "Many or most are not set up to quickly adapt to new models of care."

The National Comprehensive Cancer Network recommends genomic tumor profiling for patients with many types of advanced cancers and mentions the availability of tissue-agnostic therapies as a potential option. In the NCCN's latest guidelines for cholangiocarcinoma, for example, the group recommends multigene next-generation sequencing that can gauge NTRK fusions in patients with advanced disease and Vitrakvi and Rozlytrek for those who test positive.

In its colon cancer guidelines, the NCCN also recommends tumor profiling for multiple genes, including NTRK, for patients with advanced disease to identify those eligible for TRK inhibitors. However, the group also notes these molecular aberrations are "extremely rare" and that a majority of patients with NTRK fusions are mismatch repair deficient (dMMR), which would also make them eligible for checkpoint inhibitors like Merck's Keytruda (pembrolizumab).

For colorectal cancer patients who have NTRK-fusions and are microsatellite instability-high or mismatch repair deficient, both immunotherapy and TRK inhibitors provide the chance for durable responses that last multiple years, but in the first-line setting, Keytruda has shown a trend toward improved survival compared to chemo. Clark noted that guidelines at present aren't clear on precisely when oncologists should prioritize a TRK inhibitor in a tissue-agnostic fashion over another targeted treatment or immunotherapy and that may be contributing to the limited use of TRK inhibitors captured in the real-world data analysis.

Additionally, because there is such a high demand for immunotherapies like Keytruda, oncology practices have much more experience prescribing them than targeted precision medicines like TRK inhibitors for extremely rare indications. "The rarity of NTRK gene fusions has meant that many oncologists haven't had the positive reinforcement that their presence reveals an option that is superior to most anything they planned to give the patient," McLeod said. Even if some oncologists may know there are available TRK inhibitors for patients with NTRK fusions, "they may not know that it is worth stopping the current therapy, which is usually not normal practice, and starting the NTRK inhibitor," he added.

There are also monetary incentives against prescribing oral therapies like Vitrakvi and Rozlytrek. Oncology practices are focused on "keeping infusion chairs full and efficiently turning them around for the next patient," McLeod said, noting that the intravenous treatments contribute significant revenue to the practice. "This favors an immunotherapy infusion over an oral therapy … [for which patients] may be going to an outside pharmacy and is not contributing to the sustainability of the practice."

Diaceutics believes that new approaches are needed to ensure that patients with rare tumor biomarkers are getting precision medicine opportunities.

In another study spearheaded by Diaceutics and shared at ASCO's annual meeting, researchers identified oncologists with "suboptimal" testing behavior for selected biomarkers and tried to educate them about the need to test for them through digital communication. When Diaceutics looked again at laboratory reports around six months after that digital engagement, a small portion of doctors, 15 percent, had ordered the new biomarker test at least once. The investigators said this shows that data-driven digital engagement could help physicians better discern precision treatment opportunities for their patients.

McLeod in 2020 founded Clarified Precision Medicine, a company that provides oncologists access to experts who review patients' genetic test reports and help decide on the most appropriate treatment strategy based on the latest biomarker evidence, for example, when a tissue-agnostic approach might be warranted. The virtual molecular tumor board company recently raised $1.2 million in seed funding and has been contracting with cancer centers around the country, but McLeod believes the field has a ways to go before precision oncology is widely accessible to patients. 

"There are few places that have MTB-like capabilities, but much less use them for most of their patients," he said. "It makes it more difficult for even a subspecialized medical oncologist to realize when the tissue-agnostic options are superior."