P2, N=54, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Recruiting --> Active, not recruiting | N=84 --> 54 | Trial completion date: Jan 2026 --> Feb 2027

P1, N=12, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P3, N=36, Not yet recruiting, Guangdong Association of Clinical Trials

To the best of our knowledge, we present the first in-depth application of QBA in the context of MAIC. Despite the real-world data limitations, with this MAIC, we show that it is possible to confirm the robustness of the results by using appropriate statistical methods.

After 5 years of follow-up, lorlatinib efficacy and safety in the Asian subgroup of CROWN continue to be consistent with those in the overall population, with PFS remaining unreached with lorlatinib.

These results identified a critical role of entrectinib in promoting nerve cell damage by downregulating the expression of THBS1 while also inhibiting PI3K-AKT and TGF-β signaling pathways. Our findings will provide potential therapeutic targets for CNS-related toxicities.

P1, N=50, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P1, N=150, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Feb 2025 --> Jan 2028 | Trial primary completion date: Jan 2025 --> Dec 2027

P2, N=26, Recruiting, Pingping Song | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> Apr 2028 | Trial primary completion date: Mar 2025 --> Jan 2026

P=N/A, N=0, Available, Nuvation Bio Inc.

P1, N=6, Completed, Shenzhen TargetRx, Inc. | Not yet recruiting --> Completed

P1, N=15, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Sep 2034 --> Jun 2035 | Initiation date: Sep 2024 --> Jun 2025 | Trial primary completion date: Sep 2027 --> Jun 2028

P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial primary completion date: Dec 2024 --> Dec 2025

The patient developed resistance to Lorlatinib treatment accompanied by mesenchymal-epithelial transition factor (MET) amplification. Effective tumor control was achieved with the combined use of Crizotinib and Lorlatinib, providing a valuable reference for further exploration of treatment strategies following resistance to ALK-TKIs in clinical practice..

No abstract available

P=N/A, N=600, Recruiting, Pfizer | Trial completion date: Aug 2028 --> Mar 2028 | Trial primary completion date: Aug 2028 --> Mar 2028

NRTK+ and RET+ CRC possess significantly higher TMB than other RTK+ CRC or NTRK+/RET+ non-CRC solid tumors. TMB testing should be routinely done in MSI-H CRC, and TMB ≥ 35 mut/MB samples should be screened for NTRK and RET fusions as an enrichment strategy to provide additional treatment for NTRK+ and RET+ CRC patients.

The modeling simulation revealed that the G1202R mutation exerted little effect on the binding of iruplinalkib. Iruplinalkib showed potency to G1202R because of its unique chemical structure and removal of steric clashes, which might be a promising option for ALK-rearranged NSCLC patients with G1202R resistance mutation.

P1, N=260, Recruiting, Wuhan Union Hospital, China | Active, not recruiting --> Recruiting | N=49 --> 260 | Trial completion date: Jul 2025 --> Jul 2026

No abstract available

Combination therapy targeting RET and ROS1 using pralsetinib and lorlatinib achieved a partial response with limited durability of only four months. This is the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers.

Mutations in the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first and second generation ALK inhibitors including crizotinib and ceritinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data providing mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.

In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.

In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability...NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies...However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes.

We present the case of a 65-year-old male patient with anaplastic lymphoma kinase-positive lung cancer and preexisting type 2 diabetes mellitus who developed diabetic ketoacidosis (DKA) after switching from alectinib to lorlatinib. After a 2-week interruption, lorlatinib was resumed at a reduced dose with satisfactory glycemic control. This case highlights the importance of vigilant glucose monitoring for patients receiving lorlatinib, especially those with preexisting diabetes, to prevent life-threatening complications such as DKA.

P=N/A, N=683, Recruiting, Pfizer | Trial completion date: Dec 2025 --> Apr 2026 | Trial primary completion date: Dec 2025 --> Apr 2026

FDA-approved NTRK inhibitors entrectinib and larotrectinib effectively blocked TG::NTRK1 signaling in vitro and inhibited xenograft tumor growth in vivo. In summary, we report a spectrum of TG gene fusions as recurrent oncogenic events in thyroid cancer and NIFTP that drive strong overexpression of partner genes, frequently RTKs. The TG::NTRK1 fusion is prone to dimerization, activates oncogenic signaling, drives tumorigenesis in thyroid cells, and, like other fusions involving RTKs, represents a potential therapeutic target in thyroid cancer.

P=N/A, N=0, Available, Nuvalent Inc.

While ocular side effects such as photopsia, blurred vision, vitreous floaters and diplopia have been documented with another ALK TKI, crizotinib, there are few reports of such effects with lorlatinib [3]. Herein we present a case of bilateral optic neuropathy, initially misdiagnosed as optic nerve metastases and treated with palliative radiotherapy.

We must pay attention to rare dual short and long variants of the MYH9-ROS1 fusions, it may affect the efficacy of ROS1-tyrosine kinase inhibitors targeted therapy.

Our model calculations suggested that the effect of the translocation was to induce the dimerization of ALK into a complex that distorted the binding pocket, which is the same for alectinib, lorlatinib and crizotinib. Our observations suggest that molecular modelling based on artificial intelligence (AI) tools may offer potential predictive information in fusions with rare partner genes. Further retrospective and prospective studies are warranted to demonstrate the predictive robustness of these tools.

P=N/A, N=80, Recruiting, Second Hospital of Shanxi Medical University; Second Hospital of Shanxi Medical University

P4, N=100, Shanghai Pulmonary Hospital; Shanghai Pulmonary Hospital

P4, N=167, Peking University Third Hospital; Peking University Third Hospital

P2, N=20, Not yet recruiting, MedSIR | Initiation date: Nov 2024 --> Feb 2025

We report a case showing that lorlatinib is effective in treating EML4-ALK-positive low-grade serous ovarian cancer (LGSO) with intracranial metastasis. This may be the first clinical evidence of LGSO benefit from ALK inhibitors, to provide evidence for the use of ALK inhibitors in more ovarian cancer patients with EML4-ALK fusion and promoting new ideas for the study of EML4-ALK targets in ovarian cancer.

P2, N=534, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Iruplinalkib (WX-0593), a selective oral ALK/ROS1 tyrosine kinase inhibitor, was approved in China as first-line therapy for ALK-positive non-small-cell lung cancer (NSCLC) and for the treatment of locally advanced or metastatic ALK-positive NSCLC that has progressed following crizotinib therapy. No covariate had a clinically meaningful impact on iruplinalkib exposure. These results indicate that dose adjustment of iruplinalkib is not necessary, based on the aforementioned covariates, for ALK-positive NSCLC patients.

We reported a case of lung adenocarcinoma without driver alteration that developed resistance to pembrolizumab and newly emerged CD74-ROS1 fusion, and achieved a partial response after entrectinib treatment. We propose that new therapeutic targets may emerge for this patient population following long-term immunotherapy. Thus, we advocate for regular monitoring of tumor genetic status, which could yield unexpected benefits.

The treatment has been continued for over 25 months since the initiation of ALK Tyrosine kinase inhibitor (ALK-TKI) therapy. This case suggested that ALK-positive advanced LCNEC patients might benefit from first-line intervention with lorlatinib, particularly for managing brain metastases.

The PEARL study (CTONG2303) will evaluate efficacy of lorlatinib in CNS metastases in ALK+ NSCLC using refined CNS response evaluation criteria, with biomarker analyses providing insights into response and resistance mechanisms.

Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR)...We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.