Larotrectinib Elicits Rapid, Durable Responses in TRK Fusion-Positive Solid Tumors

Larotrectinib (Vitrakvi) demonstrated rapid and durable as treatment of patients with TRK fusion-positive solid tumors, as well as a favorable long-term toxicity profile, according to an expanded pooled analysis from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687).

Among all patients, the objective response rate (ORR) was 78% (95% CI, 71-84), with 33 (19%) patients achieving a complete response (CR), 103 (59%) achieving a partial response (PR), 23 (13%) stable disease (SD), and 12 progressive disease (PD). The study included both pediatric and adult patients.

The study evaluated patients with non-primary central nervous system (CNS) TRK fusion-positive cancer with measurable disease who had been treated with larotrectinib (n = 175). Patients were required to have locally advanced or metastatic disease and had progressed on or were non-responsive to available treatments or have no available standard treatments. Larotrectinib was administered at 100 mg twice daily for adult patients and 100 mg/m2 twice daily for most pediatric patients. Treatment was administered until disease progression, withdrawal, or unacceptable toxicity but could be continued beyond progression if the patient was still receiving benefit from the therapy.

The median age of patients in the study was 43.0 years (range, 0.1-84.0), which included 59 (34%) pediatric patients. The majority of patients were female (51%), but males made up 49% of the population as well. The ECOG performance status was 0 in 49% of patients, 1 in 38%, 2 in 11%, and 3 in 2%. Eight percent of patients had known CNS metastases at the time of enrollment. Overall, the number of prior lines was 1 in 29% of patients, 3 or more in 26%, 0 in 25%, and 2 in 20%.

The most common tumor types included soft tissue sarcoma (23%), infantile fibrosarcoma (19%), thyroid (16%), salivary gland (13%), and lung (8%). Overall, 55% of patients had NTRK gene fusions, 41% NTRK1 gene fusions, and 3% NTRK2 gene fusions. The most common fusion partners of the 33 observed in this study were ETV6-NTRK3 in 49% of patients, TPM3-NTRK1 in 18%, and LMNA-NTRK1 in 9%.

The primary end point of the study was ORR, while secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. All patients enrolled in 1 of the studies who received at least 1 dose of larotrectinib were included in the safety population, regardless of TRK fusion status (n = 279). Overall, 55 patients were included from the primary dataset and 120 in the supplementary dataset.

The ORR was 71% (95% CI, 62-79) among adults, with CRs in 10% and PRs in 60%. SD was observed in 16% of patients and PD in 9%. Among the pediatric population, the ORR was 92% (95% CI, 81-97), which included 36% CRs, 56% PRs, 7% SD, and 2% PD. The median DOR at a median follow-up of 13.5 months was 81% (95% CI, 73-89), and the 23-month DOR rate was 61% (95% CI, 51-70).

The median PFS was 36.8 months (95% CI, 25.7-not estimable [NE]) at a median follow-up of 13.8 months, and the 12-month PFS rate was 69% (95% CI, 61-76). The 24-month PFS rate was 61% (95% CI, 51-70). Median OS had not yet been reached at a median follow-up of 15.3 months, but the 12-month OS rate was 90% (95% CI, 85-95). The 24-month OS rate was 83% (95% CI, 75-90).

The median time to response was 1.8 months (range, 0.9-6.6), and the duration of treatment ranges from 0.1 to 5.6+ months.

The investigator-assess ORR among 14 evaluable patients with brain metastases was 71% (95% CI, 42-92), in which 10 patients achieved a PR, 2 had SD, and 2 had PD. At a median follow-up of 9.5 months, the median DOR in this patient population was 14.8 months (95% CI, 3.7-NE). The 12-month DOR rate was 61% (95% CI, 26-96).

One hundred patients (57%) were still receiving the study treatment at the data cut-off date, and 32 patients (18%) had continued treatment post-progression.

With longer follow-up, no new safety signals were identified in a population of patients in which 34 were being treated with larotrectinib for ≥24 months. Adverse events (AEs) were mostly grade 1/2, and treatment-emergent AEs (TEAEs) of grade 3 severity occurred in 41% and grade 4 in 8% of patients. The most common grade 3 or higher TEAEs included anemia (9%) and neutrophil count decreased (7%).

Grade 3/4 treatment-related AEs (TRAEs) occurred as grade 3 in severity in 14% of patients and grade 4 in 2%, and the most common included increased alanine aminotransferase (4%), decreased neutrophil count (3%), and anemia (2%). Serious AEs that were related to larotrectinib were observed in 5% of the patients, and the most common grade 3/4 events included increased alanine aminotransferase, increased aspartate aminotransferase, and anemia, which occurred in 2 patients each.

Treatment-emergent grade 5 AEs were observed in 6% of the safety population and 5% of the efficacy population with TRK fusion-positive cancer. No deaths in the study were found to be related to larotrectinib. Dose reductions due to AEs occurred in 11% of the safety population and 12% of patients with TRK fusion-positive cancer, and discontinuation due to TRAEs occurred in 6 (2%) and 2, respectively.

The findings from this analysis validate the role of TRK fusion proteins as therapeutic targets, further supporting the need for routine screening and testing for NTRK gene fusions in patients with cancer.

_Reference

_{McDermott R, van Tilburg C, Farago AF, et al. Survival benefits of larotrectinib in an integrated dataset of patients with TRK cancer. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1955P.}