^
2d
Successful Treatment With Lorlatinib Monotherapy for Secondary Central Nervous System Oligometastatic Disease in Refractory Anaplastic Lymphoma Kinase Positive Non-small Cell Lung Cancer. (PubMed, Cureus)
While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression. Direct comparison of second and third-generation ALK inhibitors is essential to elucidate their comparative efficacy and adverse event profiles, which could refine current management guidelines. Furthermore, if lorlatinib proves superior in terms of progression-free survival, it may offer the potential to delay or obviate the need for radiation therapy, thus mitigating the risk of neurotoxic adverse events associated with these modalities.
Journal • Metastases
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive • ALK rearrangement • ALK G1202R
|
Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
6d
Treatment of metastatic ALK-positive non-small cell lung cancer: real-world outcomes in a single center study. (PubMed, Transl Lung Cancer Res)
We evaluated crizotinib or 2nd generation ALK-TKI effectiveness in first-line treatment and lorlatinib in subsequent lines. This comprehensive study, spanning over a decade, provides crucial insights into the clinical characteristics, treatment patterns, and resistance mechanisms of advanced ALK-positive NSCLC, where median OS exceeds 5 years. Re-biopsies during treatment are essential for advancing our understanding of resistance mechanisms and the tumor dynamics evolving during ALK-TKI therapy.
Journal • Real-world evidence • Real-world • Metastases
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive • ALK rearrangement • ALK mutation
|
Xalkori (crizotinib) • Lorbrena (lorlatinib)
7d
NTRK-rearranged spindle cell tumor with SPECC1L-NTRK3 fusion in the thoracic spine: a case report. (PubMed, J Cancer Res Clin Oncol)
Following 1 month of entrectinib treatment, the patient experienced considerable tumor shrinkage and symptomatic improvement. For bone-derived NTRK-rearranged spindle cell sarcomas, entrectinib shows promising therapeutic efficacy and should be considered a preferred treatment option.
Journal
|
NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase) • SPECC1L (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1 Like)
|
NTRK3 fusion
|
Rozlytrek (entrectinib)
9d
Repotrectinib: a promising new therapy for advanced nonsmall cell lung cancer. (PubMed, Ann Med Surg (Lond))
Notably, the phase 1/2 TRIDENT-1 study showed impressive progression-free survival and intracranial activity in both TKI-naïve and pretreated patients. With its high response rates and manageable side effects, repotrectinib is set to play a significant role in treating ROS1+ and NTRK+advanced solid tumors, highlighting the ongoing need for research and clinical application.
Review • Journal • Metastases
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
|
ROS1 positive • NTRK positive
|
Augtyro (repotrectinib)
11d
Cognitive and ataxic adverse events following entrectinib treatment in NTRK1 fusion gene-positive intrahepatic cholangiocarcinoma: a case report. (PubMed, Clin J Gastroenterol)
The symptoms were reversible and tended to improve after withdrawal of entrectinib. It is crucial to increase awareness of TRKi-specific adverse events and their proper management.
Journal • Adverse events
|
NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1)
|
NTRK1 fusion • NTRK1 positive
|
Rozlytrek (entrectinib)
15d
Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast (ROSALINE) (clinicaltrials.gov)
P2, N=65, Active, not recruiting, Jules Bordet Institute | Trial completion date: Oct 2024 --> Jan 2025 | Trial primary completion date: Aug 2024 --> Jan 2025
Trial completion date • Trial primary completion date • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • HER-2 negative + ER positive
|
Rozlytrek (entrectinib) • letrozole • goserelin acetate
22d
A Novel Oncogenic and Drug-Sensitive KIF5B-NTRK1 Fusion in Lung Adenocarcinoma. (PubMed, Curr Oncol)
We present a case of a lung adenocarcinoma patient harboring a novel kinesin family member 5B (KIF5B)-NTRK1 gene fusion that responds well to entrectinib...Moreover, in vitro experiments showed that the fusion gene could exert oncogenic properties by activating the MAPK and PI3K/AKT signaling pathways. To summarize, our findings broaden the spectrum of NTRK gene fusions in the context of lung adenocarcinoma.
Journal
|
NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • KIF5B (Kinesin Family Member 5B) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK1 fusion • NTRK expression • NTRK fusion
|
Rozlytrek (entrectinib)
23d
A Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Participants With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
P3, N=121, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2035 --> Sep 2033 | Trial primary completion date: Jun 2029 --> Aug 2032
Trial completion date • Trial primary completion date • Metastases
|
PD-L1 (Programmed death ligand 1) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
RET fusion • ALK fusion • ROS1 fusion
|
PD-L1 IHC 22C3 pharmDx • VENTANA PD-L1 (SP263) Assay
|
Imfinzi (durvalumab) • Rozlytrek (entrectinib) • Alecensa (alectinib)
24d
Entrectinib-Induced Myocarditis and Acute Heart Failure Responding to Steroid Treatment: A Case Report. (PubMed, JTO Clin Res Rep)
His treatment was subsequently changed to crizotinib, which was well tolerated. This case was also associated with concurrent acute heart failure after entrectinib treatment which responded promptly to prednisolone (40 mg). Entrectinib-induced cardiotoxicity is an important adverse event to be aware of, particularly as patients may be asymptomatic for an initial period before significant deterioration.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 positive
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
24d
Brief Report: Final overall survival and long-term safety of lorlatinib in patients with ALK-positive non-small cell lung cancer from the pivotal phase 2 study. (PubMed, J Thorac Oncol)
After a minimum follow-up of 5 years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.
P2 data • Journal
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ALK positive • ALK mutation
|
Xalkori (crizotinib) • Lorbrena (lorlatinib)
26d
Epithelioid inflammatory myofibroblastic sarcoma with exceptionally long response to lorlatinib-a case report. (PubMed, Ther Adv Med Oncol)
In total, the patient was treated with crizotinib, alectinib, and lorlatinib. As a result, after over 4 years since the initial diagnosis, she is still alive with significantly improved clinical condition and quality of life. This paper demonstrates the clinical benefits of sequential therapy of ALK inhibitors and an exceptionally long response to lorlatinib, a third-generation tyrosine kinase inhibitor.
Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK rearrangement
|
Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
27d
A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China (clinicaltrials.gov)
P2, N=109, Completed, Pfizer | Active, not recruiting --> Completed
Trial completion • Metastases
|
EML4 (EMAP Like 4)
|
ALK positive • EML4-ALK fusion • ALK fusion
|
VENTANA ALK (D5F3) CDx Assay • Vysis ALK Break Apart FISH Probe Kit • AmoyDx® EML4-ALK Fusion Gene Detection Kit
|
Lorbrena (lorlatinib)
28d
Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice. (PubMed, Andrology)
Inhibition of ROS1 with lorlatinib suppressed sperm maturation and male fertility reversibly. Future exploration of molecules that specifically target ROS1 and the ROS1 pathway in the epididymis may lead to the development of safe and reversible male contraceptives.
Preclinical • Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • RNASE1 (Ribonuclease A Family Member 1)
|
Lorbrena (lorlatinib)
28d
Lorlatinib-associated weight gain and dyslipidaemia: A retrospective analysis and implications for future care. (PubMed, Lung Cancer)
Weight gain and dyslipidaemia are commonly observed with lorlatinib, highlighting the need for effective pharmacologic and non-pharmacologic strategies to manage these toxicities. Rates were similar to those reported in the CROWN trial. Given the 60 % 5-year progression-free survival (PFS) demonstrated in CROWN, mitigation of treatment-related toxicities is paramount to minimise impact on patient quality of life (QOL) and cancer-independent morbidity in this subgroup of NSCLC patients with favourable outcomes.
Retrospective data • Journal
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ALK positive • ROS1 positive • ALK positive + ROS1 positive
|
Lorbrena (lorlatinib)
29d
TGRX-326 Phase I Oral Pharmacokinetic Study (clinicaltrials.gov)
P1, N=72, Not yet recruiting, Shenzhen TargetRx, Inc.
New P1 trial
|
deulorlatinib (TGRX-326) • TGRX-678
29d
New P2 trial • Metastases
|
CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CD4 (CD4 Molecule) • VCAM1 (Vascular Cell Adhesion Molecule 1) • CRP (C-reactive protein)
|
Qi Xinke (iruplinalkib)
29d
Phase I Study of JYP0322 in ROS1 Fusion-Positive Solid Tumors (clinicaltrials.gov)
P1, N=54, Recruiting, Guangzhou JOYO Pharma Co., Ltd | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Jun 2024 --> Jun 2026
Trial completion date • Trial primary completion date
29d
Young-Onset, ROS1-Rearranged Adenocarcinoma of the Lung With Cardiac Tamponade: A Case Report. (PubMed, Cureus)
Oral administration of entrectinib was highly effective, and his serum carcinoembryonic antigen (CEA) level improved from 247 to 10.8 ng/mL. The present case has clinical significance because a pathological and genetic diagnosis was made from the pericardial effusion fluid, and the clinical manifestations of cardiac tamponade due to lung cancer were well controlled by the administration of entrectinib.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CEACAM5 (CEA Cell Adhesion Molecule 5)
|
ROS1 rearrangement
|
Rozlytrek (entrectinib)
30d
New trial • Real-world evidence • Real-world • Metastases
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
1m
Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial. (PubMed, J Thorac Oncol)
Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.
P1 data • Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive • ROS1 positive
|
Xalkori (crizotinib) • Lorbrena (lorlatinib) • deulorlatinib (TGRX-326)
1m
Entrectinib versus crizotinib in Asian patients with ROS1-positive non-small cell lung cancer: A matching-adjusted indirect comparison. (PubMed, Lung Cancer)
The outcomes in this MAIC study including Asian patients with ROS1-positive NSCLC showed a trend for greater clinical benefit with entrectinib versus crizotinib. These findings may contribute to better-informed treatment decisions.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 positive
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
1m
Complex dyslipidemia induced by Lorlatinib therapy: A case study. (PubMed, J Clin Lipidol)
Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.
Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive
|
Lorbrena (lorlatinib)
1m
Lorlatinib in the second line and beyond for ALK positive lung cancer: real-world data from resource-constrained settings. (PubMed, BJC Rep)
This real-world data confirms the efficacy of Lorlatinib in the second line and beyond with adverse effects matching that of registration studies.
Journal • Real-world evidence • Real-world
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive
|
Lorbrena (lorlatinib)
1m
Lorlatinib overcomes alectinib-induced hemolytic anemia in an ALK fusion positive non-small-cell lung cancer patient with severe tumor-associated liver failure: A case report. (PubMed, Thorac Cancer)
In this case, lorlatinib effectively controlled the tumor and improved the patient's liver function and performance status. This case highlights the importance of adapting treatment strategies to manage adverse effects while ensuring the continued use of ALK inhibitors for optimal patient outcomes.
Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive • ALK fusion
|
Alecensa (alectinib) • Lorbrena (lorlatinib)
1m
COMLORLA: Real-world Study of Local Therapy Changes During 1L Lorlatinib in Unresectable ALK+ NSCLC (clinicaltrials.gov)
P=N/A, N=100, Not yet recruiting, Peking University Cancer Hospital & Institute
New trial • Real-world evidence • Real-world
|
ALK (Anaplastic lymphoma kinase)
|
Lorbrena (lorlatinib)
1m
New P1 trial
|
APG-2449
1m
New P2 trial
|
Lorbrena (lorlatinib)
1m
Study of Lorlatinib In People With ALK-positive Non-small Cell Lung Cancer (clinicaltrials.gov)
P4, N=71, Completed, Pfizer | Active, not recruiting --> Completed
Trial completion
|
ALK (Anaplastic lymphoma kinase)
|
ALK rearrangement
|
Lorbrena (lorlatinib)
1m
Trial initiation date • Real-world evidence • Real-world
|
Lorbrena (lorlatinib)
1m
New trial • Real-world evidence • Real-world effectiveness • Real-world
|
Lorbrena (lorlatinib)
2ms
Long-Term Response of Lorlatinib to Leptomeningeal Metastasis in Patients with Anaplastic Lymphoma Kinase Fusion Positive Non-Small Lung Cancer: A Case Report. (PubMed, Case Rep Oncol)
In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases.
Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive • ALK rearrangement • ALK fusion
|
Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)
2ms
Gene-expression profile analysis to disclose diagnostics and therapeutics biomarkers for thyroid carcinoma. (PubMed, Comput Biol Chem)
Then we detected 6 repurposable drug molecules (Entrectinib, Imatinib, Ponatinib, Sorafenib, Retevmo, and Pazopanib) by molecular docking with KGs-mediated receptor proteins, ADME/T analysis, and cross-validation with the independent receptors. Therefore, these findings might be useful resources for wet lab researchers and clinicians to consider an effective treatment strategy against THCA.
Journal • Gene Expression Profile
|
TOP2A (DNA topoisomerase 2-alpha) • TIMP1 (Tissue inhibitor of metalloproteinases 1) • RUNX2 (RUNX Family Transcription Factor 2)
|
KIM1 expression • TIMP1 expression
|
sorafenib • Rozlytrek (entrectinib) • imatinib • Iclusig (ponatinib) • pazopanib • Retevmo (selpercatinib)
2ms
Trial initiation date
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Augtyro (repotrectinib)
2ms
New trial • Adverse events • Real-world evidence • Real-world • Metastases
|
Lorbrena (lorlatinib)
2ms
Small intestinal metastasis in a lung adenocarcinoma patient with concurrent EML4-ALK V3 and TP53 mutations after distinct responses to tyrosine kinase inhibitors: A case report. (PubMed, Heliyon)
After the initial treatment with ensartinib, the patient experienced intracranial disease progression...Subsequent thoracic RT resulted in a partial response of the primary tumor; however, new brain and bone metastases were detected, prompting a switch to lorlatinib...Despite pembrolizumab treatment, the patient's condition deteriorated, and she passed away...Our findings revealed heterogeneity in ALK mutations and responses to ALK-TKIs, necessitating the close monitoring of genetic subtypes and associated mutations for tailored treatment strategies. Maintaining a heightened awareness of potential intestinal metastasis and vigilance in monitoring intestinal symptoms and abdominal metastases are pivotal for managing advanced lung adenocarcinoma.
Journal • PD(L)-1 Biomarker
|
PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4)
|
TP53 mutation • ALK fusion • ALK mutation • EML4-ALK variant 3 + TP53 mutation • ALK fusion + EML4-ALK variant 3 + TP53 mutation
|
Keytruda (pembrolizumab) • Lorbrena (lorlatinib) • Ensacove (ensartinib)
2ms
Tissue-Agnostic Targeting of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals and Future Directions. (PubMed, Cancers (Basel))
Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases...More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.
Review • Journal • Pan tumor
|
NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK fusion
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
New trial • Metastases
|
Qi Xinke (iruplinalkib)
2ms
In-depth theoretical modeling to explore the mechanism of TPX-0131 overcoming lorlatinib resistance to ALKL1196M/G1202R mutation. (PubMed, Comput Biol Med)
The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.
Journal
|
ALK (Anaplastic lymphoma kinase)
|
ALK mutation • ALK G1202R • ALK L1196M
|
Lorbrena (lorlatinib) • TPX-0131
2ms
Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer. (PubMed, Clin Transl Med)
The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.
Review • Journal
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive • ROS1 rearrangement • ROS1 G2032R
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
Lorlatinib Continuation Study (clinicaltrials.gov)
P4, N=73, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=200 --> 73
Enrollment closed • Enrollment change
|
Lorbrena (lorlatinib)
2ms
Response to Crizotinib After Entrectinib Resistance in ROS1-Rearranged, MET-Amplified Lung Adenocarcinoma. (PubMed, JCO Precis Oncol)
Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.
Journal
|
MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
MET amplification • ROS1 rearrangement • ROS1 amplification
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
2ms
Systematic review and network meta-analysis of lorlatinib with comparison to other anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) as first-line treatment for ALK-positive advanced non-smallcell lung cancer (NSCLC). (PubMed, Lung Cancer)
Our NMA analysis adds to existing findings and supplements data gaps from other published NMAs. Findings from eight published NMAs consistently supported lorlatinib as a clinically effective 1L treatment for ALK + advanced NSCLC patients compared to other TKIs.
Retrospective data • Review • Journal • Metastases
|
ALK (Anaplastic lymphoma kinase)
|
ALK positive
|
Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Alunbrig (brigatinib)