- |||||||||| Clinical, Journal: Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer. (Pubmed Central) - Feb 20, 2021
The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor.Areas covered: In this review, an unstructured search in Pubmed and SCOPUS was conducted. We summarized the mechanisms of resistance to ALK inhibitors and its consequences in the treatment-decision making in advanced or metastatic NSCLC after failure to a first-line ALK inhibitor.Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencing of agents is crucial to deal with the tumor evolution.
- |||||||||| Avastin (bevacizumab) / Roche, Alecensa (alectinib) / Roche
Trial completion date, Trial primary completion date, Combination therapy, Metastases: Alectinib in Combination With Bevacizumab in ALK Positive NSCLC (clinicaltrials.gov) - Feb 10, 2021 P2, N=40, Recruiting, Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients. Trial completion date: Jan 2021 --> Sep 2022 | Trial primary completion date: Dec 2020 --> Jul 2022
- |||||||||| Trial initiation date, Tumor mutational burden: CRAFT: The NCT-PMO-1602 Phase II Trial (clinicaltrials.gov) - Feb 9, 2021
P2, N=175, Not yet recruiting, Brigatinib appears to be effective and tolerable in real-world clinical practice regardless of prior treatment with first or NG ALK TKIs. Initiation date: Nov 2020 --> Apr 2021
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, Alecensa (alectinib) / Roche
Clinical, Journal, PD(L)-1 Biomarker: Alectinib activity in chemotherapy-refractory metastatic RET-rearranged non-small cell lung carcinomas: A case series. (Pubmed Central) - Feb 5, 2021 Although this is a small single center evaluation, alectinib was well tolerated and demonstrated clinical activity against advanced RET-rearranged NSCLCs, suggesting its potential role in this specific subset of malignancies. Clinical trials addressing its efficacy and the optimal dosing schedule in the present context are underway, and results are eagerly awaited.
- |||||||||| Review, Journal, Tumor Mutational Burden, IO biomarker: Therapeutic Sequencing in ALK NSCLC. (Pubmed Central) - Jan 27, 2021
Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies...The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK tumors.
- |||||||||| Review, Journal: How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC). (Pubmed Central) - Jan 26, 2021
Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity...Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors...Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. Additional studies are underway examining mechanisms of resistance and best treatment options post resistance.
- |||||||||| Alecensa (alectinib) / Roche
Journal: EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer. (Pubmed Central) - Jan 5, 2021 Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.
- |||||||||| Review, Journal: The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer. (Pubmed Central) - Dec 30, 2020
The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research...Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs...In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.
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