- |||||||||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Enrollment closed, Trial completion date, Trial primary completion date: Study of Trametinib + Ceritinib in Patients With Unresectable Melanoma (clinicaltrials.gov) - May 9, 2022
P1, N=27, Active, not recruiting,
Recruiting --> Active, not recruiting | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2022 --> Dec 2022
- |||||||||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Trial completion date, Trial primary completion date, Metastases: Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - May 3, 2022
P1/2, N=9, Active, not recruiting,
Recruiting --> Active, not recruiting | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2022 --> Dec 2022 Trial completion date: Mar 2022 --> Jan 2023 | Trial primary completion date: Mar 2022 --> Jan 2023
- |||||||||| Ensacove (ensartinib) / Xcovery
Journal: Expert consensus on ensartinib in the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (Pubmed Central) - Apr 29, 2022
In order to facilitate clinical application and provide patients with more treatment options, under the guidance of the Committee of Cancer Rehabilitation and Palliative Care of China Anti-Cancer Association, this article collects and summarizes the common adverse reactions of ensartinib. Based on the clinical practice, a clear adverse classification and specific treatment plan are formulated, in order to provide a corresponding reference for clinicians to make more comprehensive clinical decisions.
- |||||||||| Review, Journal: Targeting ALK Rearrangements in NSCLC: Current State of the Art. (Pubmed Central) - Apr 26, 2022
Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC...Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.
- |||||||||| Ibrance (palbociclib) / Pfizer, Zykadia (ceritinib) / Novartis, Farydak (panobinostat) / Secura Bio
UTILIZING TRANSCRIPTOME ANALYSIS TO IDENTIFY TARGETED THERAPY FOR EWING SARCOMA () - Apr 20, 2022 - Abstract #ASPHO2022ASPHO_480;
HDAC, ALK, or CDK4 inhibition show a decrease in cell viability in ES cell line models as single agents and may potentiate the effects of chemotherapeutics currently used in patients with ES. Future studies of these agents in combination with chemotherapy will aim to determine efficacy in xenograft models.
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
Journal: Targeting EML4-ALK gene fusion variant 3 in thyroid cancer. (Pubmed Central) - Apr 15, 2022
He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use)...To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.
- |||||||||| Zykadia (ceritinib) / Novartis
Clinical, Journal: Ceritinib in the treatment of an adult patient with advanced neuroblastoma positive to the somatic activating mutation of ALK F1174L. (Pubmed Central) - Apr 14, 2022
Neuroblastoma in adults (NB) is a rare tumor that can present somatic activating mutations in the ALK gene in 8-9% of patients (and up to 14% of high-risk NBs); these mutations occur in the tyrosine kinase domain in three key positions (F1174, F1245 and R1275), which account for approximately 85% of all ALK mutations in NB. In this article, we report the case of an adult patient with advanced mutation-positive NB treated with an ALK inhibitor ceritinib showing a therapeutic opportunity due to the molecular diagnostic techniques now available.
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling. (Pubmed Central) - Apr 1, 2022
Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Review, Journal: Recent advances in, and challenges of, designing OMA1 drug screens. (Pubmed Central) - Mar 23, 2022
OMA1 does not exists in a vacuum and potent OMA1 inhibitors are needed to tease apart OMA1's intricate interactions with the other mitochondrial proteases and enzymes. Furthermore, OMA1 inhibitors hold the promise of becoming a new class of cytoprotective medicines for disorders influenced by dysfunctional mitochondria, such as heart failure or Alzheimer's Disease.
- |||||||||| Journal: An Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Afatinib, Alectinib, Ceritinib, Crizotinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib in Human Serum: Erratum. (Pubmed Central) - Mar 17, 2022
Furthermore, OMA1 inhibitors hold the promise of becoming a new class of cytoprotective medicines for disorders influenced by dysfunctional mitochondria, such as heart failure or Alzheimer's Disease. No abstract available
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Journal: Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation. (Pubmed Central) - Mar 15, 2022
We propose that EML4-ALK foci formation occurs as a result of transient association of stable EML4-ALK trimers mediated through an active conformation of the ALK kinase domain. Our results demonstrate the formation of EML4-ALK cytoplasmic foci that orchestrate oncogenic signalling and reveal that their assembly depends upon the conformational state of the catalytic domain and can be differentially modulated by structurally divergent ALK inhibitors.
- |||||||||| Retrospective data, Review, Journal: A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer. (Pubmed Central) - Mar 12, 2022
For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments...For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25)...Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.
- |||||||||| Trial completion date, Trial primary completion date, IO biomarker, Metastases: PIKACHU: Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation (clinicaltrials.gov) - Mar 10, 2022
P=N/A, N=100, Recruiting,
All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib. Trial completion date: Mar 2022 --> Dec 2023 | Trial primary completion date: Mar 2021 --> Dec 2022
- |||||||||| Lorbrena (lorlatinib) / Pfizer
LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6828;
We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC.
- |||||||||| Zykadia (ceritinib) / Novartis, Alunbrig (brigatinib) / Takeda
High-throughput CRISPR-Cas9 knockout screens identify loss of miRNA1304-5p targeting the RAS/MAPK pathway as a modulator of resistance to ALK inhibitors in high-risk neuroblastoma (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6821;
miR-1304-5p and NRAS expression, in patient-derived xenografts (PDXs) of high-risk NB harbouring ALK mutations, confirmed the relevance of this regulatory axis in NB and suggested that the reduced ALK TKI response in MYCN-positive PDXs could be due to inhibition of miR-1304-5p, and the combination of ALK and NRAS inhibition showed extraordinary anti-tumor efficacy compared to single agents. These findings suggest that the miR-1304-5p/NRAS axis alters the sensitivity of NB to ALK inhibitors and suggest that the modulation of this pathway in combination with ALK inhibition is a promising approach to improve NB treatment response and ultimately patient survival.
- |||||||||| CLIP1-LTK: A novel druggable gene fusion in non-small cell lung cancer (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6668;
We identified the CLIP1-LTK fusion as a novel oncogenic driver in NSCLC, and the fusion protein can be targeted by lorlatinib. Urgent clinical development of molecular targeted agents and companion diagnostics for this new oncogenic driver are now warranted.
- |||||||||| miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_3296;
All H3122-CR lines lacked ALK kinase mutations and were also cross-resistant to other ALK TKIs including ceritinib and alectinib...Afatinib, a pan-ERBB family inhibitor, or Mig6 overexpression, was able to re-sensitize those resistant cells to ALK inhibition...Herein we presented a novel resistance mechanism to ALK inhibition by which miR205 upregulation attenuates Mig6 expression, releasing EGFR-Shc1 signaling transduction from inhibition to support cell survival. This study also provides additional support for targeting EGFR signaling to overcome ALK TKI resistance to improve patient survival.
- |||||||||| Alunbrig (brigatinib) / Takeda
Clinical, Journal: Brigatinib in the first-line treatment of ALK+ metastatic NSCLC: safety and efficacy. (Pubmed Central) - Mar 4, 2022
Each of these ALK inhibitors has a specific tolerability profile, so that the choice may be also guided by patient preference according to potential side effects. In the future other factors could impact treatment choice, for instance the kind of resistance ALK mutations develop under treatment could influence the sequence of ALK inhibitors.
- |||||||||| Journal: The mechanisms of resistance to second- and third-generation ALK inhibitors and strategies to overcome such resistance. (Pubmed Central) - Mar 4, 2022
Based on clinical trial data, treatment with second- or third-generation ALK inhibitors can be initiated after crizotinib therapy without analyzing resistance mechanisms, and some randomized trials have recently shown the superiority of second- or third-generation ALK inhibitors over crizotinib as the initial treatment; however, the optimal treatment for patients who relapse while on second- or third-generation ALK inhibitors is not well-defined...: The comprehensive elucidation of both ALK-dependent and ALK-independent resistance mechanisms is necessary to improve the prognosis of patients with ALK-rearranged NSCLC. Liquid biopsy to clarify these mechanisms of resistance might play an important role in the near future.
- |||||||||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date, Metastases: Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - Feb 24, 2022
P1/2, N=9, Active, not recruiting,
Part of the study findings were presented as a poster at the NCCN 2020 Virtual Annual Conference, April 9, 2020. Recruiting --> Active, not recruiting | N=69 --> 9 | Trial completion date: Dec 2029 --> Mar 2022 | Trial primary completion date: Dec 2029 --> Mar 2022
- |||||||||| Review, Journal: An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance. (Pubmed Central) - Feb 23, 2022
Crizotinib was the most intensely studied TKI , becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown.
- |||||||||| Alunbrig (brigatinib) / Takeda
PK/PD data, Journal: Effect of severe renal impairment on the pharmacokinetics of brigatinib. (Pubmed Central) - Feb 3, 2022
Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.
- |||||||||| Journal: Recommendations from Experts in the Management of Adverse Reactions to ALK Inhibitors (2021 Version) (Pubmed Central) - Feb 3, 2022
However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions..
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