Since scientists first identified the neurotrophic factor receptor tyrosine kinase (NTRK) gene family in the 1980s, this key signaling pathway—which regulates neuronal development and survival—has gradually become an important focus in cancer research.
From Survival Signal to Oncogenic Driver:
The Dual Role of the NTRK "Diamond" Target
NTRK (Neurotrophin Receptor Kinase), standing for neurotrophic factor receptor tyrosine kinase, includes NTRK1, NTRK2, and NTRK3, which encode the TRKA, TRKB, and TRKC proteins of the tropomyosin receptor kinase (TRK) family, respectively. Upon binding to specific neurotrophic factors (such as NGF), these receptors activate downstream signaling pathways (e.g., RAS/MAPK, PI3K/AKT), transmitting normal instructions that promote cell survival.
TRK kinases are closely associated with cell proliferation, differentiation, metabolism, apoptosis, and other processes. Overexpression of TRK kinases has been observed in melanoma, non-small cell lung cancer (NSCLC), thyroid cancer, acute myeloid leukemia (AML), malignant glioma, astrocytoma, colon cancer, and other malignancies. This overexpression is closely linked to the migration of tumor cells.
TRK kinases are activated through various mechanisms in malignant tumors, primarily via structural rearrangements and altered expression, with NTRK gene fusions being the most well-defined oncogenic drivers. These fusion genes produce TRK chimeric proteins (ligand-independent TRK) through transcription and translation, leading to ligand-independent constitutive activation of the TRK kinase domain. This results in the persistent activation of multiple downstream signaling pathways, thereby stimulating tumor initiation and progression.
Schematic Diagram of NTRK Fusion Mechanism
Image Source: Literature
First-Generation Drugs Breaking the Ice:
The Outstanding Achievements and Resistance Challenges of Pan-Cancer Therapies
NTRK fusions have so far been identified in over 25 types of cancer, characterized by the distinctive pattern of being "uncommon in common tumors, yet common in rare tumors." Studies indicate that the overall detection rate of NTRK fusions across all malignant tumors is only about 0.30%. However, in certain rare tumors, they serve as key drivers, with detection rates exceeding 90%. For instance, ETV6-NTRK3 fusion exhibits an extremely high incidence in secretory breast cancer, secretory carcinoma of salivary glands, congenital mesoblastic nephroma, and infantile fibrosarcoma, and has become a molecular hallmark of these diseases[1].
Distribution and Frequency of NTRK Fusions in Adult and Pediatric Tumors
Image Source: Literature [2]
In common cancer types in China—lung cancer, breast cancer, and colorectal cancer—only 1% to 5% of patients harbor this mutation, whereas in some rare cancers, such as infantile fibrosarcoma and secretory breast cancer, the frequency of NTRK fusions can be as high as 90% to 100%. Consequently, NTRK is often referred to as the "diamond" gene.
As a "broad-spectrum" target present across various cancers, NTRK gene fusions have become a focal point in the field of precision oncology. The clinical trials for entrectinib and larotrectinib were initiated in 2012 and 2014, respectively, and their exceptional efficacy ultimately led to their approval by the U.S. FDA in 2018 and 2019. These drugs are now among the main first-generation NTRK inhibitors available globally for treating all solid tumor patients harboring NTRK gene fusions [3].
Larotrectinib exhibits high selectivity for TRKA, TRKB, and TRKC, while entrectinib is a multi-target inhibitor that also effectively inhibits ROS1 and ALK kinases in addition to the TRK family [4]. In terms of efficacy, according to key clinical study data, larotrectinib achieved an objective response rate of 75% in NTRK fusion-positive solid tumor patients, while entrectinib demonstrated an objective response rate of 63.5%, providing unprecedented deep and durable responses for many patients with rare mutations.
Currently, the core eligible population for NTRK inhibitors are patients with advanced solid tumors harboring NTRK gene fusions. Their use is not restricted by the primary tumor site, as long as an NTRK fusion is detected. For instance, larotrectinib has been recommended as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with NTRK gene fusions by multiple authoritative guidelines both domestically and internationally (including NCCN and CSCO). It has also been incorporated into first-line and second-line treatments for colorectal cancer, soft tissue sarcoma, salivary gland carcinoma, and other cancer types.
Simultaneously, due to the significantly higher incidence of NTRK gene fusions in pediatric tumors compared to adults, larotrectinib has been recommended by several guidelines/consensuses as the preferred option for pediatric patients with NTRK fusion-positive IFS, NTRK-rearranged spindle cell tumors, primary central nervous system tumors, and thyroid cancer.
However, first-generation NTRK inhibitors also face clear therapeutic limitations, with the most critical challenge being the development of resistance. Resistance mechanisms primarily fall into two categories: first, on-target resistance, where mutations occur within the TRK kinase domain itself (such as TRKA-G595R), directly hindering drug binding to the target; second, off-target resistance, where tumors sustain growth by activating other bypass signaling pathways (such as the MAPK pathway), thereby circumventing the attack of TRK inhibitors [4]. Additionally, first-generation NTRK inhibitors are associated with specific adverse reactions. According to real-world pharmacovigilance analyses, both larotrectinib and entrectinib have clear safety signals related to nervous system disorders. Entrectinib is also linked to cardiac risks, while larotrectinib is associated with hepatobiliary system diseases [3].
Evolution in Progress:
Tackling Resistance, the Rise of Second-Generation Inhibitor Development
As first-generation NTRK inhibitors gain widespread clinical use and their resistance mechanisms become clearly understood, clinical research on second-generation drugs targeting resistant mutations is accelerating. The design of second-generation NTRK inhibitors aims to overcome specific resistance mutations, focusing primarily on the most common "on-target" resistance mechanism—mutations within the TRK kinase itself. By optimizing molecular structures, these inhibitors are engineered to bind more tightly to the ATP-binding pocket of the mutated kinase, thereby restoring effective inhibition of kinase activity.
To date, the development of second-generation NTRK inhibitors has achieved substantial breakthroughs. According to "Yaozh Data," several second-generation TRK inhibitors have now received FDA approval globally, with multiple pipelines advancing into Phase II clinical trials.
Bristol Myers Squibb's repotrectinib is a ROS1 and NTRK inhibitor that binds to the target protein within the ATP-binding pocket, remaining effective against various resistance mutations. In November 2023, the drug was approved by the FDA for the treatment of ROS1-positive, locally advanced, or metastatic NSCLC in adults. In June 2024, it received accelerated FDA approval for the treatment of adult and pediatric patients (12 years and older) with NTRK fusion-positive solid tumors (this indication has not yet been approved in China).
Pharmaceutical companies in China are actively developing NTRK-targeted therapies. Currently, domestically developed second-generation TRK inhibitors are already available on the market in China, with several additional pipelines in advanced clinical stages.
Table: Approved and Investigational NTRK Inhibitors in China (Partial)
Data source: Yaozhi Data (Please notify us if any errors are found).
In December 2025, zurletrectinib, developed by InnoCare Pharma, received official approval from the China National Medical Products Administration (NMPA) for the treatment of adult and adolescent patients with solid tumors harboring NTRK fusion genes, including breast cancer, colorectal cancer, lung cancer, thyroid cancer, and others. It is also indicated for patients resistant to first-generation NTRK inhibitors such as larotrectinib and entrectinib.
n terms of efficacy, zurletrectinib demonstrated an objective response rate (ORR) of 89.1%, a disease control rate (DCR) of 96.4%, and 24-month progression-free survival (PFS) and overall survival (OS) rates of 77.4% and 90.8%, respectively, in patients with NTRK fusion-positive tumors, showing significant clinical benefits. Regarding brain penetration, the cerebrospinal fluid/plasma concentration ratio reached 3.04%, with an intracranial ORR as high as 100%. In terms of safety, most adverse events (AEs) were grade 1-2 and reversible, with a permanent discontinuation rate of only 0.7%. In overcoming resistance, preclinical studies demonstrated significant antitumor effects in both cellular and animal models harboring resistance mutations.
Anruitinib is a second-generation NTRK inhibitor independently developed by Jiangsu Wecare in China. It is clinically intended for the treatment of patients with NTRK fusion-positive solid tumors, characterized by its "tumor-agnostic" approach. In Phase I/II clinical studies, anruitinib exhibited outstanding efficacy and a favorable safety profile. Phase I clinical data showed that in patients who had not previously received NTRK inhibitors, the confirmed ORR in the RP2D dose expansion group was 73.1%. Among three subjects who had progressed after prior TRK inhibitor treatment, two experienced tumor shrinkage, with one achieving a partial response (PR) of 39.6%.The majority of patients achieved rapid responses and long-term survival benefits with anruitinib, with the longest duration of response exceeding 36 months. Among six subjects with baseline brain metastases, intracranial lesions shrank by 61.8% and 25% in two cases, respectively, while non-target lesions disappeared in two other patients after four months of treatment. In terms of safety, treatment-related adverse events (TRAEs) were mostly grade 1-2, with no fatal TRAEs reported. Compared to other drugs in its class, no new safety signals were identified.
In January 2025, anruitinib officially entered the preparation stage for domestic marketing authorization in China.
TL118 is an orally administered second-generation NTRK inhibitor independently developed by Teligenebio. It has the ability to cross the blood-brain barrier, demonstrating therapeutic potential for brain metastases. Phase II clinical data show an objective response rate (complete response + partial response) of 90% in efficacy evaluations. Compared to larotrectinib and entrectinib, the available clinical data indicate clear advantages in both safety and efficacy.
Image source: Teligene
Beyond Monotherapy:
Combination Therapies and Future Prospects
In addition to the development of next-generation drugs, combination therapies represent a crucial direction for addressing the current limitations of NTRK inhibitors.
For "off-target resistance" driven by the activation of alternative signaling pathways (such as MAPK or MET), single-agent NTRK inhibitors are often ineffective. Therefore, one of the key future directions lies in actively exploring combination therapies that pair NTRK inhibitors with other targeted agents. Examples include combining NTRK inhibitors with MEK inhibitors to block parallel oncogenic pathways or pairing them with EGFR or MET inhibitors to counteract bypass activation. Furthermore, investigations are underway to combine NTRK inhibitors with immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies), aiming to harness the power of the immune system for synergistic antitumor effects. This approach holds the potential to further enhance the efficacy of first-line treatments and possibly overcome complex resistance mechanisms.
Summary
The evolution of NTRK-targeted therapy is fundamentally a continuous breakthrough in achieving "pan-cancer precision targeting and overcoming resistance barriers." As first-generation inhibitors have gained widespread clinical application, their resistance mechanisms have gradually become clearer, accelerating the emergence of new therapeutic needs and driving the development of second-generation drugs. Represented by agents such as zurletrectinib and anruitinib, second-generation NTRK inhibitors serve as key solutions to the core challenge of resistance caused by mutations in the TRK kinase domain.
In essence, the advent of new-generation inhibitors does not simply replace their predecessors. Instead, they provide crucial sequential treatment options for patients who have developed resistance after prior therapy, significantly expanding the population that can benefit clinically, with advantages far outweighing the drawbacks.
Looking ahead, strategies such as combination therapies targeting bypass activation, the development of next-generation brain-penetrant compounds, and the exploration of personalized treatment based on resistance mutation profiles are poised to reshape the therapeutic landscape for NTRK inhibitors. These diverse research directions not only open new avenues for survival in patients with resistance but also hold the potential to advance NTRK-targeted therapy into a new era characterized by "high efficacy and durability, precise resistance management, and enhanced safety and accessibility."
References
1.Westphalen, C B et al. “Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population.” NPJ precision oncology vol. 5,1 69. 20 Jul. 2021, doi:10.1038/s41698-021-00206-y
2.Cocco, Emiliano et al. “NTRK fusion-positive cancers and TRK inhibitor therapy.” Nature reviews. Clinical oncology vol. 15,12 (2018): 731-747. doi:10.1038/s41571-018-0113-0
3.Cui, Zhiwei et al. “From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis.” Frontiers in pharmacology vol. 15 1329409. 31 Jan. 2024, doi:10.3389/fphar.2024.1329409
4.Drilon, A. “TRK inhibitors in TRK fusion-positive cancers.” Annals of oncology : official journal of the European Society for Medical Oncology vol. 30 Suppl 8 (2019): viii23-viii30. doi:10.1093/annonc/mdz282