Larotrectinib Demonstrates Limited Benefit in Patients with NTRK Alterations

In a data analysis presented at the American Association for Cancer Research (AACR) Annual Virtual Meeting, held from April 27-28, 2020, researchers suggested that larotrectinib (Vitrakvi) is highly effective in patients with NTRK gene fusions and has demonstrated durable responses.¹

However, in patients with other non-fusion NTRK alterations, including point mutations and amplifications, larotrectinib offered only limited benefit.

“NTRK gene fusions are found at high frequencies at 90% or more in rare tumor types such as secretory breast carcinoma and infantile fibrous sarcoma, and at lower frequencies, generally less than 1%, in a range of other common tumor types, including lung and colorectal cancers,” David S. Hong, MD, of the University of Texas MD Anderson Cancer Center, said in a poster presentation of the data at AACR.²

Data for the trial were pooled from 3 clinical trials of adult and pediatric patients with TRK fusion cancer treated with larotrectinib. Moreover, NTRK gene status was assessed using local molecular testing from 2 studies which initially enrolled patients regardless of TRK fusion status. 

Efficacy outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Researchers also assessed adverse events (AEs), and the data cut-off was February 19, 2019. 

Overall, 159 patients with NTRK fusions, with 17 different tumor types, were included in the analysis, with 153 evaluable for efficacy. Additionally, 73 non-fusion patients with various genomic alterations, with 25 different tumor types, were also included in the study. NTRK alterations reported in the non-fusion patients included point mutations in 8 patients, amplifications in 7, rearrangements in 4, and deletions in 1. 

The ORR was found to be 79% (95% CI, 72-85) in the fusion group, with complete responses (CR) in 24 (16%), partial responses (PR) in 97 (63%), stable disease (SD) in 19 (12%), and progressive disease (PD) in 9 (6%). Further, median DOR was 35.2 months (95% CI, 22.8-not estimable [NE]).

In the non-fusion group treated with larotrectinib, the only response observed was in 1 patient with NTRK1 amplification who had a PR of short duration (3.7 months). Moreover, 17 non-fusion patients (23%) had SD and 48 (66%) had PD as best response.

Comparably, differences were seen in survival endpoints between patients in the overall fusion and non-fusion groups, with a median PFS of 28.3 months vs 1.8 months and median OS of 44.4 months vs 10.7 months, respectively. Median time of treatment was 7.9 months in the fusion group and 1.7 months in the non-fusion group.

Incidences of grade 3 or 4 AEs were lower in the fusion group (49%) vs the non-fusion group (58%). Notably, discontinuation due to AEs occurred in only 6% of patients in the fusion group vs 25% in the non-fusion group.

“These data strongly support the clinical importance of testing for NTRK gene fusions in order to identify patients who would benefit from larotrectinib treatment,” Hong said.

References:

1. AACR. CT062 - Efficacy and safety of larotrectinib in patients with cancer and NTRK gene fusions or other alterations. AACR website. Published April 28, 2020. abstractsonline.com/pp8/#!/9045/presentation/10962. Accessed April 28, 2020. 

2. AACR. Targeted Therapy. AACR website. Published April 28, 2020. aacr20.onlineeventpro.freeman.com/live-stream/15335397/Targeted-Therapy. Accessed April 28, 2020.