Larotrectinib Development Course Shows Promise for TRK Fusion–Positive Cancers

The rarity of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in solid tumors has left the field with few options for targeted therapies, because there are few patients to participate in clinical trials. The development of an TRK inhibitor has been impending over the recent years and now larotrectinib (Vitrakvi) is 1 of the 2 FDA approved for the treatment of TRK fusion–positive cancers regardless of patient age or disease subtype.

“Although TRK fusion cancer is rare, there are certain entities in pediatric and adult oncology that have a high NTRK frequency. The best example is in infantile fibrosarcoma. Those tumors can be large and the [patients] need [invasive] surgery. But larotrectinib can induce tumor shrinkage very fast and then patients can receive non-invasive surgery,” Cornelius von Tilburg, MD, senior physician, Pediatric Oncology and Hematology, and head of Early Phase Clinical Trials at KiZ Hopp Childen’s Cancer Center Heidelberg, told Targeted Oncology in an interview.

Looking at the pipeline for larotrectinib, it shows an accelerated course, which can be attributed to the drug’s potential to fulfill an unmet need in oncology. Development for the agent in the United States began in 2014 with a safety evaluation and soon after, the full safety and efficacy of the drug was under investigation.

Mechanism of Action and Preclinical Efficacy

Following larotrectinib’s discovery in 2013, in in vitro models, the agent demonstrated high potency against TRKA, TRKB, and TRKC, which are 3 TRK proteins that are encoded by NTRK1, NTRK2, and NTRK3.

In solid tumors, the agent was preclinically tested on a lung adenocarcinoma cell line harboring an MPRIP–NTRK1 fusion, as well as a colorectal cancer cell line harboring a TPM3-NTRK1 fusion.Larotrectinib also had preclinical evaluation in hematologic malignancies in an acute myeloid leukemia cell line harboring an ETV6-NTRK3 fusion. Administration of larotrectinib in these cell lines led to a significant reduction in tumor growth. Responses to larotrectinib in these preclinical models occurred within 2 weeks of treatment initiation.¹

Larotrectinib works by blocking the adenosine triphosphate binding site. The drug appears to have high binding affinity for all 3 TRK receptors.

In addition, the MAPK, PKC, PI3K/AKT, and STAT-3 signaling pathways were inhibited by larotrectinib in in vivo models. This early result ultimately prompted a phase 1 clinical trial of larotrectinib in adults with cancer (NCT02122913), which is still active but no longer recruiting patients.

First-in-Human Results from Larotrectinib

Seventy-two patients with TRK fusion–positive solid tumors were enrolled into the first-in-human phase 1 study of larotrectinib. Of the patients enrolled, 8 had NTRK gene fusions and the remaining 62 patients had unconfirmed NTRK gene fusions. Larotrectinib was administered to these patients to assess the safety, tolerability, pharmacokinetics, and preliminary activity of the drug in this patient population.²

When the phase 1 results were presented at the 2019 European Society of Medical Oncology (ESMO) Virtual Congress, Ulrik Lassen, MD, PhD explained the need for this study in an interview with Targeted Oncology, stating, “in the prior publications and presentations, the data were not mature enough to show median time to event. We didn’t have any demonstration of the duration of response, progression-free survival, and overall survival.”

At 100 mg twice daily of larotrectinib, 1 of the first 6 treated patients experienced dose-limiting toxicities. At 150 mg twice daily, 1 of 7 patients experienced DLTs, and none at 200 mg once daily. Based on these events, the recommended phase 2 dose of larotrectinib was 100 mg twice daily.

Treatment-emergent adverse events (TEAEs) of any grade occurred in at least 10% of patients. The most common TEAEs included fatigue, dizziness, and anemia. Grade 3 or higher TEAEs were observed in 60%, of which the most common was anemia. No patients in the study experienced grade 4 or 5 TEAEs. Forty-six percent of patients experienced serious AEs, which were mainly related to disease progression.

In the overall population, the objective response rate (ORR) was low at 12%, but responses were more significant in the patients with NTRK gene fusions.

Lassen, professor of Medical Oncology and head of the Department of Oncology at Rigshospitalet, in Copenhagen, Denmark, shared the results, stating, “we could see that the median duration of response was 35 months, the progression-free survival was 28 months, and the median overall survival was 44.4 months.”

The ORR observed in the study in patients with TRK fusion–positive cancers was 88% (95% CI, 47%-100%), which included complete responses (CRs) in 25%, partial responses in 63%, and stable disease in 13% per investigator assessment. The median duration of response was not reached (95% CI, 14.7+ to 33.2+).

The study authors, led by David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center,in Houston, wrote in conclusion, “larotrectinib offers a potential new standard of care for patients with TRK fusion cancer, which is contingent on effective tissue-agnostic routine screening to detect tumors harboring NTRK gene fusions.”

Going forward, larotrectinib was then assessed in patients with TRK fusion–positive cancers.

Pooled Larotrectinib Data

A pooled analysis of 159 patients from 3 clinical trials not only confirmed the uniqueness of the molecular profile associated with patients who harbor TRK fusions, but also showed that larotrectinib continues to be a highly active and safe treatment for these patients.³

The data were pooled from a phase 1 study of larotrectinib in adult patients (NCT02122913); the ongoing phase 1/2 SCOUT study of larotrectinib in children with NTRK fusions (NCT02637687); and the ongoing phase 2 NAVIGATE study, a basket trial of larotrectinib in adults and children with NTRK fusion–positive solid tumors (NCT02576431). Together, the data from these clinical trials showed that the analysis was positive for its primary end point of ORR in the intention-to-treat population. Treatment with larotrectinib led to an ORR of 79% (95% CI, 72%-85%) in the 153 evaluable patients, which included CRs in 16% of patients.

The safety portion of the analysis included 260 patients with or without TRK fusion–positive tumors for whom the most common grade 3/4 AEs were increased alanine aminotransferase (3%), anemia (2%), and decreased neutrophil count (2%). Serious AEs associated with larotrectinib included alanine aminotransferase increase, increased aspartate aminotransferase, and nausea, which all occurred in <1% of patients. There were no treatment-related deaths in the studies.

With positive data observed with larotrectinib across multiple TRK fusion–positive solid tumors early-on in clinical trial patients, the development of this agent was accelerated as regulatory bodies agree upon its ability to fill in a treatment gap for this patient population.

_References:

_{1. Federman N, McDermott R. Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer. Expert Rev Clin Pharmacol. 2019;12(10):931-939. doi: 10.1080/17512433.2019.1661775}

_{2. Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019;30(2):325-331. doi:10.1093/annonc/mdy539}

_{3. Hond DS, DuBois SG, Kummar Shivaani, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3}