Controversies in NSCLC: which second-line strategy after chemo-immunotherapy?
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ABSTRACT:
SUBMITTER: Moliner L
PROVIDER: S-EPMC9958277 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Controversies in NSCLC: which second-line strategy after chemo-immunotherapy?
Moliner L L Spurgeon L L Califano R R
ESMO open 20230213 2
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Project description:Most patients with lung cancer have non-small cell lung cancer (NSCLC) subtype and have advanced disease at the time of diagnosis. Improvements in both first-line and subsequent therapies are allowing longer survival and enhanced quality of life for these patients. The median overall survival observed in many second-line trials is approximately 9 months, and many patients receive further therapy after second-line therapy. The cytotoxic agents pemetrexed and docetaxel and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are standard second-line therapies. For patients with EGFR mutation, a TKI is the favored second-line therapy if not already used in first-line therapy. For patients without the EGFR mutation, TKIs are an option, but many oncologists favor cytotoxic therapy. The inhibitor of the EML4/ALK fusion protein, crizotinib, has recently become a standard second-line treatment for patients with the gene rearrangement and has promise for patients with the ROS1 rearrangement.
| S-EPMC3755933 | biostudies-literature
Project description:BackgroundThe necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity.MethodsTreated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment.ResultsICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8+ T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1).ConclusionA high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.
| S-EPMC11624766 | biostudies-literature
Project description:ObjectiveOur previous economic assessment found that nivolumab was not cost-effective for Chinese patients with advanced non-small cell lung cancer (NSCLC) and without EGFR mutations or ALK translocations, when compared with the standard second-line drug docetaxel. However, a greater survival benefit with nivolumab was observed for patients with 1% or greater tumor programmed death ligand 1 (PD-L1) expression. In view of this, we designed the present analysis to explore whether it is cost-effective to use the PD-L1 test to guide second-line nivolumab treatment in China.Material and methodsA Markov model was established to project the lifetime costs and quality-adjusted life-years (QALYs) of three second-line treatment strategies: nivolumab and docetaxel (strategies without a PD-L1 test) and PD-L1 test-based strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of our results. Additional price reduction and willingness-to-pay (WTP) threshold scenario analyses were performed to explore the impact of economic and health policies with Chinese characteristics on our results.ResultsThe PD-L1 test-based strategy costs approximately CNY 194,607 (USD 28,210) or more and yielded an additional 0.27 QALYs compared to the docetaxel strategy without a PD-L1 test, equating an incremental cost-effectiveness ratio (ICER) of CNY 731,089 (USD 105,978)/QALY. Deterministic sensitivity analyses showed that the price of nivolumab was the strongest source of variation in the ICERs. Probability sensitivity analysis showed that the probability for the PD-L1 test-based strategy being cost-effective increases with the increase of WTP thresholds.ConclusionFrom the perspective of the Chinese healthcare system, using a PD-L1 test to guide second-line nivolumab treatment was not cost-effective. The National Healthcare Security Administration negotiation on the price reduction of nivolumab was found to be the most effective action to improve its cost-effectiveness in China.
| S-EPMC8710478 | biostudies-literature
Project description:Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.
| S-EPMC4197428 | biostudies-literature
Project description:The composition of the gut microbiome of patients with advanced non-small cell lung cancer is currently considered a factor influencing the effectiveness of treatment with immune checkpoint inhibitors. We aimed to evaluate the baseline gut microbiome composition in patients before receiving first-line immunotherapy alone or combined with chemoimmunotherapy. We performed 16S rRNA sequencing based on hypervariable regions. Stool samples were collected from 52 patients with advanced NSCLC treated with immunotherapy or chemoimmunotherapy before treatment. We found that the Ruminococcaceae family, species Alistipes sp. genus Eubacterium ventriosum group and genus Marvinbryantia may be intestinal, microbiological predictors of response to treatment. Genus Akkermansia and species from the [Clostridum] leptum group predicted the length of PFS (progression-free survival). Longer OS (overall survival) is associated with bacteria from the Ruminococcaceae family genera [Eubacterium] ventriosum group, Marvinbryantia, Colidextribacter and species [Clostridum] leptum. Bacteria that have an adverse effect (shortening of PFS or OS) on the response to treatment using immune checkpoint inhibitors are Rothia genus, Streptococus salivarius, Streptococus, Family XIII AD3011 group and Family XIII AD3011 group, s. uncultured bacterium. The composition of intestinal flora can be a predictive factor for immunotherapy in NSCLC patients. Specific bacteria can be positively or negatively associated with response to treatment, progression-free survival, and overall survival. They can be potentially used as predictive markers in NSCLC patients treated with immunotherapy.
| S-EPMC11842579 | biostudies-literature
Project description:Glioma remains significant challenging to completely cure by the conventional surgical resection because of its high infiltrative growth properties. Recently, emerging immunotherapy has achieved remarkable success in treating various cancer, but glioma do not benefit from cancer immunotherapy owing to its specific immunosuppressive tumor microenvironment (iTME). Herein, we show the significant improvement of the immunotherapy efficacy for glioma through multifunctional liposome (Lpo@Cu2Se-GOx). After tumor cells endocytosis, the released glucose oxidase (GOx) could oxidize glucose into gluconic acid to achieve starvation therapy and generate H2O2 as byproduct. Meanwhile, these properties might further cause anti-oxidant systems dysfunction and reinforce Cu2+ based Fenton-like reaction, which lead to lipid peroxides accumulation and ferroptosis occur. Moreover, the onset of ferroptosis would trigger the release of damage-associated molecular patterns and induce immunogenic cell death, which contributed to the dendritic cell maturation and cytotoxic T cell infiltration. Besides, in vitro and in vivo experiments verified that Lpo@Cu2Se-GOx had well significant glioma inhibition without adverse reactions. Taken together, our research demonstrates the modulation of iTME through self-amplified chemo-dynamic therapy could be a significant strategy to improve the immunotherapy of glioma.
| S-EPMC11834134 | biostudies-literature
Project description:Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.
| S-EPMC4839329 | biostudies-literature
Project description:BackgroundImmunotherapy (IO)-based strategies have been demonstrated to significantly prolong survival in the perioperative setting of non-oncogene-addicted non-small cell lung cancer (NSCLC). The adoption of such strategies in clinical practice depends on heterogeneous regulatory approvals and on the agreement between medical oncologists and thoracic surgeons on patients' selection.MethodsAn Expert Panel Meeting of medical oncologists and thoracic surgeons was held virtually by the Italian Association of Thoracic Oncology (AIOT) to discuss results of pivotal clinical trials with perioperative chemo-immunotherapy and reach agreement on open issues for the topic, formulating specific statements based on initially proposed discussion questions.ResultsOverall, panelists found agreement on seven statements. With regard to tissue and biomarker analysis, the role of increasing PD-L1 expression in predicting IO efficacy was recognized, whereas ctDNA and pCR were mainly attributed a prognostic role, in the absence of dedicated studies. The panelists acknowledged direct relationship between the benefit of neoadjuvant chemo-immunotherapy approaches and the local burden of disease/mediastinal node involvement, supporting the inclusion of these factors, together with PD-L1, in selecting upfront surgery or induction treatment. The panelists agreed that the current literature data do not answer the issue of assessing the role of the adjuvant phase within a perioperative treatment strategy. Surgical considerations on the role of pneumonectomy and other approaches were also discussed.ConclusionsThis experience highlights the importance of a synergistic approach between oncologists and surgeons to leverage the unmet needs in translating results of IO-perioperative clinical trials into clinical practice in patients with resectable NSCLC.
| S-EPMC11854886 | biostudies-literature
Project description:In contrast to the established role of epidermal growth factor receptor (EGFR) inhibitors for the first-line treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR blockade and of EGFR molecular testing in the second-line treatment remains less clear. The irreversible pan-ErbB family inhibitor afatinib (Gi(l)otrif®) was recently FDA- and EMA-approved for the second-line treatment of NSCLC with squamous cell histology irrespective of the EGFR mutational status (LUX-Lung 8). Contrariwise, results from the TAILOR and DELTA trials among retrospective biomarker analyses show the predictive value of the EGFR mutational status for efficacy of reversible EGFR inhibitors also as a second-line therapy. This mini review critically summarizes the current role of EGFR-targeting strategies in the second-line treatment of NSCLC with special respect to afatinib in light of emerging T790M-specific EGFR and immune check point inhibitors. The review also emphasizes the urgent need for reliable biomarkers to guide therapeutic decision-making and outlines prospective changes to the second-line landscape with some of the current second-line treatment concepts likely to be moved to the first-line.
| S-EPMC5303897 | biostudies-literature
Project description:The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK kinase domain. Alectinib is a second-generation ALK inhibitor capable of overcoming multiple crizotinib-resistant ALK mutations and has demonstrated improved outcomes after crizotinib failure. Favorable toxicity profile and improved intracranial activity have spurred ongoing front-line trials and comparisons to other ALK inhibitors. However, important questions regarding comparability to competitor compounds, acquired alectinib resistance, and ALK inhibitor sequencing remain. Here, we review the key clinical data supporting alectinib in the second-line therapy of ALK+ NSCLC and provide context in comparison to other ALK inhibitors in development.
| S-EPMC5127851 | biostudies-literature