Impressive Responses, but How to Find Patients With NTRK Fusion Tumors?

Alexander M. Castellino, PhD

November 02, 2018

MUNICH — The investigational drug larotrectinib (Bayer and Loxo), which targets neurotrophic receptor tyrosine kinase (NTRK), continues to impress with high overall response rates (ORRs) and duration of response across a variety of solid tumors that harbor the NTRK fusion gene.

New data with the drug were reported here at the European Society for Medical Oncology (ESMO) 2018 Congress.

However, another study that was presented at the meeting suggests that identifying patients who have these tumors will be a challenge.

In a poster presentation (abstract 75P), Chinese researchers reported a study in which they used next-generation sequencing (NGS) on tumor samples from 3700 patients with solid tumors. They identified 12 patients with NTRK fusion-positive tumors, which accounts for approximately 0.3% of the Chinese patients with solid tumor in their cohort.

Larotrectinib Approval Expected Soon

Bayer has filed applications for approval of larotrectinib for use in NTRK fusion tumors. In the United States, a decision from the US Food and Drug Administration is expected by November, 26, 2018.

The approval applications contain data from the first 55 patients treated with larotrectinib in clinical trials. These data were published in February 2018 and were reported by Medscape Medical News at the time. In an analysis of data from pediatric and adult patients, the ORR was 75%, as determined on the basis of centrally assessed confirmation using Response Evaluation Criteria in Solid Tumors. The investigator-assessed ORR was 80%.

Those initial 55 patients, who constitute the development program for larotrectinib, were participants in Loxo Oncology's phase 1 adult trial, the phase 2 trial (NAVIGATE), and the phase 2/3 pediatric trial (SCOUT).

At the ESMO meeting, new data for larotrectinib were reported (abstract 409O) by Ulrik Lassen, MD, PhD, of the Rigshospitalet, Copenhagen University Hospital, Denmark.

In the entrectinib study (LBA17), which was reported by George G. Dimitri, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, the ORR was 57% with entrectinib.

Larotrectinib is highly selective for inhibiting TRKA, TRKB, and TRKC, whereas entrectinib is a selective inhibitor of all TRK proteins as well as ROS1 and ALK fusions. Lassen presented supplementary data for another 54 patients. In total, 67 patients have been enrolled in the larotrectinib studies. For 13 patients, the first efficacy evaluation time point has not reached.

Baseline characteristics for the additional patients were similar to those of the first 55 patients, Lassen said, but there were more pediatric patients. The age distribution varied from 2 months to 80 years.

For these additional 54 patients, the investigator-assessed ORR was 81%; 17% of patients showed a complete response (CR), and 65% showed a partial response (PR). These rates are consistent with those seen in the first 55 patients (ORR, 80%; CR, 16%; PR, 64%).

Lassen told Medscape Medical News that as data matured over time, stable responses in some patients evolved to PR or CR.

In the initial cohort of 55 patients, at the new data cutoff of July 30, 2018 (1 year later), the ORR remained at 80%, the CR was 18%, and the PR was 62%.

For the integrated efficacy cohort of 109 patients, the ORR was similar — 81%, with a CR of 17% and a PR of 63%.

Responses were seen regardless of age and tumor type, Lassen said. Responses were seen in 92% of pediatric patients and in 75% of adult patients.

Lassen also noted that responses with larotrectinib are durable. The median time to response was 1.8 months. He reported that 84% of those patients who responded and 73% of all patients remain on treatment or have undergone surgery with curative intent. For a few patients, responses extended to 40 months.

In the primary dataset of 55 patients, the median follow-up was 17.8 months. The median duration of response has not been reached; 88% of patients responded at 6 months, and 75% respnded at 1 year. In the supplemental dataset, median follow-up was 7.4 months. The median duration of response has not been reached; 93% of patients responded at 6 months, and 81% responded at 1 year.

"Dose reductions are rare, and the safety profile is favorable, with most events being low grade (grade 1/2)," Lassen said. The most common events were dizziness and fatigue.

How to Find the Patients

As larotrectinib nears approval, the challenge will be to find patients who will benefit from this targeted agent. Lassen told Medscape Medical News that no companion diagnostic test is available for NTRK. Immunohistochemistry or NGS (DNA- or RNA-based) may be used. "An RNA-based NGS sequencing test will be better, as it is not likely to miss patients," he said.

He suggested that worldwide, up to 5000 patients could be diagnosed with this fusion annually.

In some rare cancers, NTRK fusion occurs frequently. These include infantile fibrosarcoma, secretory breast cancer, and mucosal analogue secretory carcinoma. Physicians who treat these rare cancers are aware of NTRK fusion when present and are likely to try to find patients with the defect. It is likely that these patients would benefit from drugs such as larotrectinib.

"However, in the more common cancers where the fusion is present in a frequency of <1%, it may be an issue," he said.

Medscape Medical News approached Solange Peters, MD, the new ESMO president-elect for 2020-2021, and asked how she envisages the search for potential patients.

She indicated that most academic centers are equipped to perform NGS testing, which can be easily modified to include testing for NTRK. "These are easy to do at academic centers, but the problem arises with how to make this broadly available," she said.

When community oncologists cannot connect to an academic center, it becomes the duty of each company to put a plan of action in place by which the information on the test is made available. "Affordability, reproducibility, and accessibility are key for any test to be used in clinical practice," she said.

Access to education is also important, she pointed out. "It is very difficult to be a general oncologist today," she said, because the expertise of specialists is often needed to deliver the best patient care.

With the approval of each agent especially in the tumor-agnostic setting, guidelines will ensure that the platform is easily accessible. "For example, as soon as NTRK fusion is accepted for treating patients [with larotrectinib] across solid tumors, it will be noted in the guidelines," she said.

Dr Lassen is an advisor to Bayer and Pfizer.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstracts 75P and 409O.


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