scholarly journals Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1476
Author(s):  
Kamya Sankar ◽  
Sunitha Nagrath ◽  
Nithya Ramnath
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Anaplastic Lymphoma

Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. Here, we aim to describe the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. We report pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describe the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer.

scholarly journals Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marianne Oulhen ◽  
Patrycja Pawlikowska ◽  
Tala Tayoun ◽  
Marianna Garonzi ◽  
Genny Buson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

Response with pemrbolizumab in a patient with EGFR mutated non-small cell lung cancer harbouring insertion mutations in V834L and L858R

2021 ◽  
pp. 107815522110578
Author(s):  
Matthew J. Hadfield ◽  
Alla Turshudzhyan ◽  
Khalid Shalaby ◽  
Aswanth Reddy
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Durable Response ◽  
Egfr Mutated

Introduction Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial. Case report We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy. Management/Outcome While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition. Discussion From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.

Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 931-940 ◽  
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Michele Ghidini ◽  
Claudia Bareggi ◽  
Donatella Gambini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

Anaplastic lymphoma kinase inhibitors in elderly patients with advanced non-small cell lung cancer

2016 ◽  
Vol 16 (8) ◽  
pp. 877-883
Author(s):  
Mazen Zaarour ◽  
Bassel Nazha ◽  
Chanudi Weerasinghe ◽  
Elias Moussaly ◽  
Terenig Terjanian
Keyword(s):  
Lung Cancer ◽  
Elderly Patients ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

Immune checkpoint inhibitors plus anlotinib versus anlotinib alone as third-line treatment in advanced non-small-cell lung cancer: a retrospective study

2021 ◽  
Author(s):  
Wenjie Zhang ◽  
Chufeng Zhang ◽  
Shengjie Yang ◽  
Qing Chen ◽  
Chen Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Hazard Ratio ◽  
Small Cell Lung

Aim: This study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus anlotinib versus anlotinib alone to provide guidance for clinical treatment of non-small-cell lung cancer. Patients & methods: The records of 139 patients with advanced non-small-cell lung cancer who received at least one dose of ICIs plus anlotinib (IA group) or single-agent anlotinib (AA group) were retrospectively reviewed. The efficacy of the treatments, survival outcomes and adverse events were analyzed. The primary end point was investigator-assessed progression-free survival (PFS). Result: The IA group had a significantly prolonged median PFS (mPFS: 5.8 vs 4.2 months; p = 0.022) compared with the AA group (hazard ratio: 0.68; 95% CI: 0.68–0.97). In patients with brain metastases, the IA group exhibited improved efficacy (mPFS: 6.0 vs 3.8 months; p = 0.034) compared with the AA group (hazard ratio: 0.49; 95% CI: 0.23–1.05). Conclusion: ICIs plus anlotinib significantly improved efficacy compared with anlotinib alone and showed substantial potential for the control of intracranial lesions.

scholarly journals Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Jin Kang ◽  
Xu-Chao Zhang ◽  
Hua-Jun Chen ◽  
Wen-Zhao Zhong ◽  
Yang Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Small Cell ◽  
Fusion Partner ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

BackgroundEchinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.MethodsNinety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Results54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.ConclusionOur results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.

scholarly journals Immunotherapy and Targeted Therapies in the Treatment of Non-small Cell Lung Cancer

2017 ◽  
Vol 13 (01) ◽  
pp. 35
Author(s):  
Tu Nguyen-Ngoc ◽  
Martin Reck ◽  
Daniel SW Tan ◽  
Solange Peters ◽  
◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

In the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti-PD-1 antibodies nivolumab and pembrolizumab. Several other anti-PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient.

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