Advanced Non-small Cell Lung Cancer Research Articles

A retrospective comparison of induction chemoimmunotherapy versus chemotherapy followed by concurrent chemoradiotherapy and consolidation immunotherapy in stage III non-small cell lung cancer.

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) usually bear high tumor burden and are not tolerated well to concurrent chemoradiation therapy (CRT) followed by consolidation immunotherapy. We investigated the feasibility of chemoimmunotherapy as induction therapy before CRT for LA-NSCLC. We retrospectively analyzed data from 91 patients with unresectable stage III NSCLC treated with either induction chemoimmunotherapy or chemotherapy before CRT. Tumor responses, survival statistics, and toxic effects were compared. The dosimetric parameters of the RT protocol were evaluated. The primary endpoint was progression-free survival (PFS). The overall response (ORR), the depth of response (DpR) were accessed at the end of CRT (ORRinduc+CRT, DpRinduc+CRT) and induction therapy (ORRinduc, DpRinduc). The median PFS (mPFS) were significantly longer in the chemoimmunotherapy induction group (13.5 months vs. 11.2 months; HR, 0.56; 95% CI, 0.32-0.97; p=0.036). The ORRinduc+CRT, median DpRinduc+CRT (mDpRinduc+CRT) and mDpRinduc were significantly higher in the chemoimmunotherapy induction group (ORRinduc+CRT, 84.0% vs. 65.9%, p=0.044; mDpRinduc+CRT, 49.5% vs. 39.0%, p = 0.012; mDpRinduc, 38.5% vs. 28.0%, p=0.044). Incidence of treatment-related adverse events (AE) was similar between groups, with myelosuppression being the most common grade ≥ 3 AE. Regarding radiotherapy, adopting a mapping strategy with a 5-8 mm margin for clinical tumor volume resulted in decreased radiation doses to critical organs in the chemoimmunotherapy induction group. Chemoimmunotherapy induction therapy before CRT improves efficacy with comparable incidence of AEs compared to chemotherapy induction in LA-NSCLC patients. Further studies are warranted to validate these findings.

Analysis of the association between immune-related adverse events and the effectiveness in patients with advanced non-small-cell-lung cancer.

Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1-2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6months vs. 34.0 vs. 23.6, P = 0.003). Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management.

Targetable molecular algorithm and training platform development for the treatment of non-small cell lung cancer.

Over the last decade, treatment of patients with advanced non-small cell lung cancer (NSCLC) has become dependent on tissue and/or blood biomarkers to guide treatment decisions. Timely access to comprehensive biomarker and tumor signature information is crucial for diagnostic testing. With the rapid development and implementation of complex biomarker testing, comprehensive molecular profiling with in-depth analysis of DNA, RNA, and proteins can be easily performed. Initial data from the MedStar Health system showed considerable disparities in the use of next generation sequencing (NGS) between hospitals, and there is a clear need to improve education and understanding regarding which cases are appropriate for NGS, as well as the use of protocols to make those decisions in an expeditious manner. Clinical pathways are systems-based tools that aim to create greater transparency around care decision making, therapeutic selection, and care delivery. They enhance quality and efficiency by reducing non-value-added intra-provider variability in care. We aimed to create a comprehensive clinical pathway system, the Targetable Molecular Algorithm (TMA), to increase the understanding and use of NGS in NSCLC by physicians in training, oncology nurse navigators, nurse practitioners, and general oncologists. We provide an overview of the implementation of the platform along with navigation guide. A realistic case study-a typical clinical workflow for a patient requiring NGS testing with an EGFR mutation-is also reviewed, demonstrating how the TMA platform can be applied. Additionally, we highlight the importance of the resource, and discuss its strengths, weaknesses, and potential future applications. This new and innovative pathway system will make decision-making easier for clinicians trying to understand the appropriate tests and treatment algorithms for their patients. Our aim is to increase the appropriate and timely use of NGS among health-system providers with the hope that this system will empower physicians to provide better care by providing a quick, simple, user-friendly tool for comprehensive patient care.

Implementation of Liquid Biopsy in Non-Small-Cell Lung Cancer: An Ontario Perspective.

Lung cancer is the leading cause of cancer-related deaths in Canada, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Timely access to comprehensive molecular profiling is critical for selecting biomarker-matched targeted therapies, which lead to improved outcomes in advanced NSCLC. Tissue biopsy samples are the gold standard for molecular profiling; however, several challenges can prevent timely and complete molecular profiling from being performed, causing delays in treatment or suboptimal therapy selection. Liquid biopsy offers a minimally invasive method for molecular profiling by analyzing circulating tumour DNA (ctDNA) and RNA (cfRNA) in plasma, potentially overcoming these barriers. This paper discusses the outcomes of a multidisciplinary working group in Ontario, which proposed three eligibility criteria for liquid biopsy reimbursement: (1) insufficient tissue for complete testing or failed tissue biomarker testing; (2) suspected advanced NSCLC where tissue biopsy is not feasible; and (3) high-risk patients who may deteriorate before tissue results are available. The group also addressed considerations for assay selection, implementation, and economic impact. These discussions aim to inform reimbursement and implementation strategies for liquid biopsy in Ontario's public healthcare system, recognizing the need for ongoing evaluation as technology and evidence evolve.

Pharmacokinetic analysis and simplified uptake measures for tumour lesion [18F]F-AraG PET imaging in patients with non-small cell lung cancer.

The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter. Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals. Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60-70min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01). Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.

Second malignancy in advanced or recurrent non-small cell lung cancer after the advent of molecular targeted drugs and immunotherapy.

This study aimed to investigate the characteristics of patients with recurrent or advanced non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune-checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer. This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April1, 2013, and March 31, 2020, and achieved long-term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation. Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non-significant trend towards a higher incidence of secondary malignancies in smokers compared to non-smokers. This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations.

Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway.

Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug. The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance. ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC. These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

Regularity and correlation analysis of regional lymph node metastasis in nonoperative patients with non-small cell lung cancer based on positron emission tomography/computed tomography images

BackgroundDefinitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced, inoperable non-small cell lung cancer (NSCLC). Previous studies have mainly focused on examining local failure and recurrence patterns after surgery and the principles of lymph node metastasis (LNM) in surgical candidates with NSCLC. However, these studies were just only able to guide postoperative radiotherapy (PORT) and the patterns of LNM in patients with resected NSCLC was inadequate to represent that in locally advanced inoperable NSCLC patients for guiding target volume delineation of CCRT. In this study, we aimed to analyze the metastasis regularities and establish the correlations between different lymph node levels in NSCLC patients without any intervention using positron emission tomography/computed tomography (PET/CT) images.MethodsOverall, 358 patients with N1–N3 NSCLC admitted in our hospital between 2018 and 2022 were retrospectively analyzed. The diagnosis of metastatic lymph nodes was reviewed and determined using the European Organization for Research and Treatment of Cancer standard and the standardized value of the PET/CT examination. Univariate and multivariate analysis were performed to investigate the correlations between the different levels were evaluated by using of the chi-square test and logistic regression model.ResultsThe lymph nodes with the highest metastasis rates in patients with left lung cancer were in order as follows: 10L, 4L, 5, 4R, and 7; while in those with right lung cancer they were 10R, 4R, 7, 2R, and 1R. Notably, we found left lung patients were more likely to have contralateral hilar, mediastinal and supraclavicular lymph nodes involved, and the right lung group exhibited a higher propensity for ipsilateral mediastinum and supraclavicular lymph node invasion. Furthermore, correlation analysis revealed there were significant correlative patterns in the LNM across different levels.ConclusionsThis study elucidated the patterns of primary LNM in patients with NSCLC who had not undergone surgery (without any treatment interventions) and the correlations between lymph node levels. These findings were expected to provide useful reference for target volume delineation in definitive concurrent chemoradiotherapy in locally advanced NSCLC patients.

Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study

IntroductionMany clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms. MethodsEGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30–40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. ResultsBetween January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2–22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease. ConclusionsSelected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.

Can We Offset Local Recurrence in Locally Advanced Non-Small Cell Lung Cancer? The Merry-Go-Round of Radiation Dose Escalation and Stubborn Outcomes.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Plasma EGFR mutation ctDNA dynamics in patients with advanced EGFR-mutated NSCLC treated with Icotinib: phase 2 multicenter trial result

Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients’ ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy.Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27.

Plain language summary: 5-year results from the CROWN study of lorlatinib vs crizotinib in non-small-cell lung cancer.

This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK, in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK-positive NSCLC after 5years. After observing people for an average of 5years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis. The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).

Budget impact analysis of pembrolizumab versus the novel PD-1 inhibitor toripalimab in locally advanced or metastatic nonsquamous non-small cell lung cancer

ABSTRACT Aim To estimate the budget impact of adding a toripalimab regimen to the existing treatment mix of pembrolizumab, both with pemetrexed and carboplatin, in patients with locally advanced or metastatic nonsquamous NSCLC within two price inputs (wholesale acquisition cost (WAC) and average sales price (ASP)). Methods Budget impact analysis comparing a treatment mix “without” versus “with” the toripalimab regimen in the annual US nonsquamous NSCLC population treated with a PD-1 inhibitor, a 3-year time horizon, toripalimab market share of 1% in 2024, increasing to 4% (2025) and 5% (2026), and medication use adjustments for discontinuation or progression to estimate fully-treated-patient-equivalents. Cost inputs included drugs, administration, and grade 3/4 adverse event (AE) management. The models were replicated in a 1-million-member plan to estimate costs per-member-per-month (PMPM) and per-member-per-year (PMPY). One-way (OWSA) and probabilistic sensitivity analyses (PSA) as well as two scenario analyses were performed. Results In the “without” scenario, the 3-year WAC costs for the pembrolizumab regimen total $40,750,234,637 ($39,024,548,745 for treatment and $1,725,685,894 for managing AEs). In the “with” scenario, these costs decline to $39,341,379,081. Corresponding “with” costs for toripalimab are $1,186,027,704 (treatment) and $99,454,471 (AE management) for a total of $1,285,482,175. This yields annual net savings of between $10,779,362 (at 1% market share) in 2024 and $64,858,298 (5% market share) in 2026, for 3-year savings of $123,373,381. The associated savings in a 1-million-member plan are $0.030 PMPM and $0.363 PMPY. The ASP model shows similar patterns. Savings were demonstrated in 68% of PSA simulations; OWSAs and scenario analyses reveal how parameter variability impacts results. Conclusion Significant savings are likely achievable from treating between 1% (year 1) to 5% (year 3) of nonsquamous NSCLC patients with the toripalimab regimen. Projected 3-year savings range from $122 million (ASP) to $123 million (WAC); corresponding to savings of $0.030 PMPM and $0.363 PMPY.

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

Spatial profiling of METex14-altered NSCLC under tepotinib treatment: Shifting the immunosuppressive landscape

MET inhibitors have demonstrated efficacy in treating patients with non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Advancements in spatial profiling technologies have unveiled the complex dynamics of the tumor microenvironment (TME), a crucial factor in cancer progression and therapeutic response.This study uses spatial profiling to investigate the effects of the MET inhibitor tepotinib on the TME in a case of locally advanced NSCLC with a METex14 skipping alteration. A patient with resectable stage IIIB NSCLC, unresponsive to neoadjuvant platinum-based chemotherapy, received tepotinib following the detection of a METex14 skipping alteration. Paired pre- and post-treatment biopsies were subjected to GeoMx Digital Spatial Profiling using the Cancer Transcriptome Atlas and immune-related protein panels to evaluate shifts in the immune TME.Tepotinib administration allowed for a successful lobectomy and a pathological downstaging to stage IA1. The TME was transformed from an immunosuppressive to a more permissive state, with upregulation of antigen-presenting and pro-inflammatory immune cells. Moreover, a marked decrease in immune checkpoint molecules, including PD-L1, was noted. Spatial profiling identified discrete immune-enriched clusters, indicating the role of tepotinib in modulating immune cell trafficking and function. Tepotinib appears to remodel the immune TME in a patient with METex14 skipping NSCLC, possibly increasing responsiveness to immunotherapy.Our study supports the integration of genetic profiling into the management of early and locally advanced NSCLC to guide personalized, targeted interventions. These findings underscore the need to further evaluate combinations of MET inhibitors and immunotherapies.

Immune Checkpoint Inhibitors in the Management of Brain Metastases from Non-Small Cell Lung Cancer: A Comprehensive Review of Current Trials, Guidelines and Future Directions

Background: Brain metastases (BM) are a common, severe complication in patients with non-small cell lung cancer (NSCLC) and are difficult to treat due to their complex tumor biology and the intricate microenvironment of the brain. Objectives: This review examines the current role of immune checkpoint inhibitors (ICIs) in treating NSCLC with BM, focusing on the latest clinical trials, emerging strategies, current guidelines, and future directions. We highlight the efficacy of ICIs as monotherapy and in combination with other treatments such as radiotherapy, stereotactic radiosurgery, chemotherapy, and anti-VEGF agents. Results: While no single treatment sequence is universally accepted, combining ICIs with traditional therapies forms the core of the current treatment protocols. ICIs targeting the PD-1/PD-L1 pathway have significantly advanced NSCLC treatment, demonstrated by improved overall and progression-free survival in various settings. However, optimizing these benefits requires careful consideration of potential side effects, including cognitive decline and radiation necrosis, and the impact of steroid use on ICI efficacy. Conclusion: The review underscores the necessity for a personalized, integrated multidisciplinary treatment approach. Future research should focus on refining combination therapies and understanding the optimal sequence and timing of treatment.

TQB2450 with or without anlotinib as maintenance treatment in subjects with locally advanced/unresectable non-small cell lung cancer that have not progressed after prior concurrent/sequential chemoradiotherapy (R-ALPS): study protocol for a randomized, double-blind, placebo-controlled, multicenter phase III trial.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). TQB2450 (benmelstobart) is a novel humanized immunoglobulin G1 monoclonal antibody against programmed death-ligand 1 (PD-L1). Anlotinib, an oral multitargeted anti-angiogenic agent with potential synergy with ICIs, has shown efficacy in relapsed and advanced NSCLC. Accumulating preclinical data suggest a synergism between immunological and anti-angiogenic therapies through the improvement of the immune microenvironment of the tumor. In this study, we hypothesized that the combination of TQB2450 and anlotinib as maintenance treatment would enable further improvements in the outcomes of patients with locally advanced/unresectable NSCLC without driver mutations that have not progressed after definitive chemoradiotherapy. The Radiotherapy and Anlotinib Let PD-L1 Superb (R-ALPS) study is a randomized, double-blind, placebo-controlled, multicenter phase III study (Clinicaltrials.gov identifier, NCT04325763). A total of 534 eligible participants will be randomized to receive TQB2450 (1,200 mg) plus anlotinib (8 mg), or TQB2450 (1,200 mg) plus placebo, or placebo as maintenance therapy. Progression-free survival (PFS), assessed by the independent review committee is the primary endpoint. The secondary endpoints include additional measures of efficacy, safety, and biomarkers. An interim analysis of the effectiveness will be conducted when 70% (286 cases) of the total PFS events have been reached. The development of the R-ALPS study will contribute to a deeper insight into the interplay between immunotherapy and anti-angiogenic therapy and thus might expand the treatment options available to patients with locally advanced or unresectable NSCLC. Clinicaltrials.gov identifier: NCT04325763. Date of registration: May 27, 2020. Protocol version: Version 4.0, Sep 16, 2022 (https://classic.clinicaltrials.gov/ct2/show/NCT04325763).

Impact of Cachexia and First-Line Systemic Therapy for Previously Untreated Advanced Non-Small Cell Lung Cancer: NEJ050A.

Cancer cachexia complicates advanced non-small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first-line systemic therapy. We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first-line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first-line systemic therapy. A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0-2 who were initiated on first-line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first-line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy-associated emesis affecting early appetite-related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: -3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (-1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression-free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003). Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite-related QOL trends vary based on the type of first-line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.

CtDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer.

DNA methylation plays a regulatory role in the oncogenesis and tumor progression and is valuable in the diagnosis and prognosis of cancer. While circulating tumor DNA (ctDNA) is widely used in the detection of oncogenic mutations and the guidance of treatment in advanced non-small cell lung cancer (NSCLC), studies of ctDNA methylation remains insufficient. We aim to investigate the methylation profiles of ctDNA in patients with advanced NSCLC undergoing EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and to discover novel biomarkers with predictive or prognostic value. We recruited 49 patients with EGFR-mutated advanced NSCLC undergoing EGFR-TKI as first-line treatment. Utilizing next-generation sequencing, we examined the somatic mutations and methylation signatures within the tumor-associated genomic regions of ctDNA from pre-treatment blood. Subsequently, we explored the association of these molecular features with the patients' response to therapy and their progression-free survival (PFS). Genomic mutation profiling revealed no significant association of PFS or best overall response (BOR) and ctDNA status. Evaluation of ctDNA methylation showed a negative correlation between the methylation of small nucleolar RNA (snoRNA) genes and PFS (R=-0.31, P=0.043). Furthermore, high-level methylation of SNORD3F was associated with poorer PFS (mPFS 346d vs 243d, HR 0.49, 95% CI 0.24-0.93, P=0.029). Our study explored the prognostic value of ctDNA methylation in patients with advanced NSCLC undergoing targeted therapies and first revealed the predictive role of SNORD3F.

Impact of docetaxel plus ramucirumab therapy on interstitial lung disease in recurrent advanced non-small cell lung cancer patients.

Few studies have examined the safety and efficacy of docetaxel/ramucirumab (DOC/RAM) therapy in advanced non-small cell lung cancer (NSCLC) complicated by interstitial lung disease (ILD). Given the potential of vascular endothelial growth factor inhibitors to prevent drug-induced pneumonia, we aimed to clarify the role of this therapy in NSCLC with ILD. This retrospective observational study evaluated the incidence of ILD in stage IV NSCLC patients receiving DOC/RAM therapy at our institution, stratified by ILD status. We also assessed the efficacy of this treatment. The primary objective was to investigate the incidence of ILD, while secondary objectives included evaluating the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), stratified by ILD status. Among patients with pre-existing ILD, 7 out of 28 (25%) developed DOC/RAM-induced interstitial pneumonia, while none of the 40 patients without pre-existing ILD developed this condition (P<0.001). Comparing historical controls (DOC only) with the DOC/RAM group, RAM did not significantly alter the incidence of interstitial pneumonia (P=0.33). There were no significant differences in ORR, PFS, or OS between patients with and without ILD. Subgroup analysis of smokers showed a non-significant trend toward worse survival in those with pre-existing ILD (P=0.20). DOC/RAM therapy significantly increased the incidence of interstitial pneumonia in NSCLC patients with pre-existing ILD but did not significantly affect efficacy outcomes such as ORR, PFS, or OS.