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

Sankar, K. Nathan; Nagrath, Sunitha; Ramnath, Nithya

doi:10.3390/cancers13061476

Cited by 27 publications

(26 citation statements)

References 73 publications

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“…Other ALK inhibitors are in development, including repotrectinib (TPX-005), that may represent an effective therapeutic option for patients with ALK-rearranged NSCLC who have progressed on earlier-generation TKIs ( 23 ). Furthermore, the role of immune checkpoint inhibitors in ALK-positive NSCLC resistant to ALK-TKIs and chemotherapy is still under investigation ( 24 ). Finally, questions regarding the efficacy of treatments in sequential use were not investigated and, therefore, remain a subject for further studies.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Peng

Yang

et al. 2021

Front. Oncol.

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BackgroundTargeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.MethodsPubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration’s tool.ResultsNine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.ConclusionsLorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Peng

Yang

et al. 2021

Front. Oncol.

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“…It is obvious that the heterogeneity in data collection may be a drawback in massive assessment of data. In respect to this, it is noteworthy that previous studies concerning the role of some gene fusions, notably according to the partners, in resistance to immunotherapy associated with late‐stage NS‐NSCLC led to discrepant results 14–16 . This will certainly be a crucial issue in the future when making decisions on first‐line treatments targeting a gene fusion (notably in other genes than ALK and ROS1 ), probably for any stage and histological subtype of NSCLC patients.…”

Section: Technical Aspects Of Gene Fusion Detection In Lung Cancer: T...mentioning

confidence: 99%

“…These genomic alterations are sensitive to different molecules, notably to next‐generation TKIs (such as alectinib, brigatinib, and lorlatinib), which if given upfront result in significantly longer survival compared to initial treatment with the first‐generation inhibitor crizotinib or chemotherapy 9,11–13 . Excluding presence of an ALK fusion is also crucial before starting immunotherapy, due to the lack of efficacy and increased toxicity of the immune checkpoints inhibitors (ICIs) in ALK‐ positive NSCLC patients 14–16 . Besides a very low tumor mutational burden of ALK ‐positive tumors, uniquely below 3 mut/MB on average, 17 an immunosuppressive tumor microenvironment also appears to contribute to the inherent ICI resistance of these tumors 18 .…”

Section: Alk Ros1 Ntrk and Ret Fusions: The “Big Four” Fusion Targets...mentioning

confidence: 99%

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Kazdal

Hofman

Christopoulos

et al. 2022

Genes Chromosomes & Cancer

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Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late‐stage non‐small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non‐squamous NSCLC (NS‐NSCLC). Gene fusions can be detected using different approaches, but today RNA next‐generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

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“…A recent retrospective study revealed that approximately 10% of ALK-positive patients responded to immunotherapies [191]. Combination of ALK inhibitors and immunotherapy seems to show efficacy but some patients developed severe hepatotoxicity, and long-term clinical outcomes have not yet been reported [192,193]. Therefore, further studies are needed to identify effective immunotherapy and its combination with chemotherapy to achieve favorable clinical outcome for patients with ALK gene rearrangements.…”

Section: Eml4-alkmentioning

confidence: 99%

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

Glorieux

Xia

Huang

2021

Cancers

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Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.

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

Cited by 27 publications

References 73 publications

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

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