- |||||||||| Lorbrena (lorlatinib) / Pfizer, Xalkori (crizotinib) / Pfizer, Alecensa (alectinib) / Roche
Journal, Real-world evidence, Circulating tumor DNA: Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients. (Pubmed Central) - Mar 25, 2022
Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.
- |||||||||| Alecensa (alectinib) / Roche
Biomarker, Journal: Is Elevation of Alkaline Phosphatase a Predictive Factor of Response to Alectinib in NSCLC? (Pubmed Central) - Mar 25, 2022
In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification.
- |||||||||| Lorbrena (lorlatinib) / Pfizer
Journal: GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer. (Pubmed Central) - Mar 19, 2022
GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance.
- |||||||||| Review, Journal: Drug-drug interactions of tyrosine kinase inhibitors in treatment of non-small-cell lung carcinoma (Pubmed Central) - Mar 18, 2022
The latter may result in changes in pharmacokinetics or pharmacodynamics of the tyrosine kinase inhibitors or their concomitant treatments, with subsequent risks of increasing their toxicity and/or reducing their effectiveness. This review provides an overview of drug-drug interactions with tyrosine kinase inhibitors targeting EGFR and ALK, as well as practical recommendations to guide oncologists and clinical pharmacists in the process of managing drug-drug interactions during the treatment of non-small cell lung cancer with tyrosine kinase inhibitors.
- |||||||||| Alecensa (alectinib) / Roche
Journal: Alectinib-responsive infantile anaplastic ganglioglioma with a novel VCL-ALK gene fusion. (Pubmed Central) - Mar 17, 2022
This review provides an overview of drug-drug interactions with tyrosine kinase inhibitors targeting EGFR and ALK, as well as practical recommendations to guide oncologists and clinical pharmacists in the process of managing drug-drug interactions during the treatment of non-small cell lung cancer with tyrosine kinase inhibitors. 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.
- |||||||||| Biomarker, Enrollment change, Trial completion date, Trial primary completion date: NAUTIKA1: A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer (clinicaltrials.gov) - Mar 14, 2022
P2, N=80, Recruiting,
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. N=60 --> 80 | Trial completion date: Aug 2028 --> Feb 2029 | Trial primary completion date: Aug 2028 --> Mar 2024
- |||||||||| 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.
- |||||||||| 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.
- |||||||||| 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.
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Vitrakvi (larotrectinib) / Bayer
Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib (Section 32) - Mar 9, 2022 - Abstract #AACR2022AACR_5845;
Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib.Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab...Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab...Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay...We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs.
- |||||||||| Alecensa (alectinib) / Roche
Impact of stromal protection on in vivo response to ALK targeted therapies in NSCLC (Section 13) - Mar 9, 2022 - Abstract #AACR2022AACR_5732;
Specifically, we compared response of tumors to the frontline ALK TKI: alectinib between tumors growing in regular NSG xenografts and those grown in NSG derivate with humanized HGF...Our ongoing efforts are focused on determining what molecular mechanisms underlying stromal protection in-vivo, and on interplay between cell-intrinsic and stromal resistance. Addressing these questions will provide knowledge necessary to the development of more effective therapeutic strategies against ALK+ NSCLC.
- |||||||||| Targeted therapies prime lung cancer cells for macrophage-mediated destruction (Section 35) - Mar 9, 2022 - Abstract #AACR2022AACR_3429;
Overall, we have identified a novel therapeutic strategy to enhance the efficacy of RTK-MAPK pathway inhibitors by combining them with anti-CD47 therapies.Our findings suggest cross-sensitivity occurs such that lung cancer cells that become resistant to targeted therapies also become more sensitive to macrophage attack. Our findings provide rationale for testing this combination approach in patients with lung cancers bearing driver mutations.
- |||||||||| MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_3301;
Our data show that combining targeted therapies with a SHP2 inhibitor synergistically decreases the viability of oncogene-driven NSCLC cell lines, indicating that initial combination therapy may be an appealing approach to improve patient outcomes. The observed delay in the emergence of osimertinib resistance, from combining a MET inhibitor with osimertinib, provides preclinical evidence to support further investigating MET inhibition upfront to improve the long-term therapeutic efficacy of EGFR inhibitors.
- |||||||||| 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.
- |||||||||| AsiDNA (etidaligide) / Onxeo
DNA repair-interfering molecule AsiDNA® overcomes resistance to tyrosine kinase inhibitors in lung cancer (New Orleans Theater C, Convention Center) - Mar 9, 2022 - Abstract #AACR2022AACR_1782;
Inhibition of the DNA repair machinery using AsiDNA efficiently prevented the emergence of resistances to tyrosine kinase inhibitors and point to the therapeutic opportunity of combining AsiDNA and TKI to overcome resistance in clinical situation. These findings should have immediate implications to design drug combination strategies to prevent TKI-induced resistance in lung cancers.
- |||||||||| Xalkori (crizotinib) / Pfizer, Alecensa (alectinib) / Roche
Macrophage mediated resistance to TKI therapy in ALK fusion positive non-small cell lung cancer (New Orleans Theater C, Convention Center) - Mar 9, 2022 - Abstract #AACR2022AACR_1781;
In summary, our work demonstrates TKI therapy may be modulated by the presence of and interaction with specific immune cells within the tumor microenvironment. These data support exploring macrophage targeting therapies to improve TKI responsiveness.
- |||||||||| Xalkori (crizotinib) / Pfizer, Alecensa (alectinib) / Roche
Combining Real-World and Randomized Controlled Trial Survival Data Using Bayesian Methods (Virtual) - Mar 8, 2022 - Abstract #ISPOR2022ISPOR_836;
A Bayesian estimation framework allows for controlling the level of borrowing between RCT and RWD according to one’s prior belief. If sample size from RWD is small, adding prior information from RCTs can provide more stable estimates, whereas prior assumptions may be relaxed as more RWD is accumulated.
- |||||||||| 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.
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