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Larotrectinib in Patients With Tumors With NTRK Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131)
Neal Akhave1, Zihe Song2, David S Hong1
1The University of Texas MD Anderson Cancer Center, Houston, TX.
Purpose:
Recurrent chromosomal fusions in neurotrophic tropomyosin receptor kinase (NTRK) have been reported as an oncogenic driver across human cancer. Herein, we report results from subprotocol Z1E of the NCI-MATCH (Molecular Analysis for Therapy Choice) trial investigating the efficacy and safety of larotrectinib, a highly selective inhibitor of all three TRK proteins, in TRK fusion-positive cancers.
Methods:
From August 21, 2017, to July 8, 2021, patients with solid tumors or lymphomas progressing on standard therapy were genomically profiled and enrolled to NCI-MATCH, a genomically driven, signal-seeking, precision medicine platform trial. They were assigned to subprotocol Z1E if a NTRK fusion-positive tumor was identified. Patients received larotrectinib 100 mg twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, overall survival (OS), and safety.
Results:
In total, 12 patients with centrally confirmed NTRK fusion-positive tumors were treated with larotrectinib across six distinct tumor histologies. The ORR was 75% (90% CI, 47.3% to 92.8%) with median PFS and OS of 14.4 (90% CI, 8.48 to not reached [NR]) months and 23.9 (90% CI, 11.1 to NR) months, respectively. Treatment was well tolerated, with adverse events predominantly being grade 1.
Conclusion:
NCI-MATCH subprotocol Z1E demonstrates that larotrectinib offers clinically significant benefit with marked ORR across NTRK fusion-positive tumors with no clinically significant toxicities. These findings support the rationale for the US Food and Drug Administration's tissue-agnostic approval of larotrectinib for NTRK fusion-positive tumors. Our findings demonstrate the necessity of including NTRK1, NTRK2, and NTRK3 within comprehensive molecular assays of cancer to navigate patients to an easily administered and highly effective therapy.
Insights
Larotrectinib demonstrated significant efficacy in treating neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cancers, showing a high objective response rate and favorable safety profile. This supports its use in precision medicine for NTRK-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
- Precision Medicine
Background:
- Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are oncogenic drivers in various human cancers.
- Identifying and targeting these fusions is crucial for effective cancer therapy.
- Larotrectinib is a selective inhibitor of all three TRK proteins (TRKA, TRKB, TRKC).
Purpose of the Study:
- To investigate the efficacy and safety of larotrectinib in patients with NTRK fusion-positive cancers.
- To evaluate larotrectinib's performance in the NCI-MATCH (Molecular Analysis for Therapy Choice) trial, subprotocol Z1E.
Main Methods:
- NCI-MATCH subprotocol Z1E enrolled patients with solid tumors or lymphomas with NTRK fusions.
- Patients received larotrectinib 100 mg twice daily until disease progression or toxicity.
- Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS).
Main Results:
- Twelve patients with NTRK fusion-positive tumors across six histologies received larotrectinib.
- The objective response rate (ORR) was 75%, with a median PFS of 14.4 months and median OS of 23.9 months.
- Treatment was well-tolerated, with predominantly Grade 1 adverse events.
Conclusions:
- Larotrectinib provides significant clinical benefit and a marked ORR in NTRK fusion-positive tumors.
- The drug exhibits a favorable safety profile, supporting its tissue-agnostic approval.
- Comprehensive molecular assays including NTRK1, NTRK2, and NTRK3 are essential for identifying patients who can benefit from larotrectinib.
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