Advanced Non-small Cell Lung Cancer Research Articles

Very Early Health Technology Assessment for Potential Predictive Biomarkers in the Treatment of Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI)-containing treatment is currently prescribed as first-line treatment for all patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, only 30-45% of patients show no progression within 12 months after treatment start. Various biomarkers are being studied to save costly and potentially harmful treatment in non-responders. We evaluated the cost-effectiveness of implementing a hypothetical predictive biomarker for ICI-containing treatment response compared with standard of care (e.g., no implemented biomarker) for pembrolizumab-containing treatment in patients with advanced NSCLC in the Netherlands. Standard-of-care-based and predictive-biomarker-based strategies were compared using Markov models for three first-line pembrolizumab-containing treatments depending on a patient's tumor programmed cell death ligand-1 (PD-L1) expression and histology. A Dutch healthcare system perspective was adopted. Assuming a receiver operating characteristic-area under the curve of 1.0 in identifying responders, alternative treatments were offered for non-responders in the predictive-biomarker-based strategy. Parameters and assumptions were based on real-world data from surveys, literature using a targeted search, expert opinion, and registries. Outcomes included differences in costs, survival (life years (LYs)), and survival corrected for health-related quality of life (QoL) quality-adjusted life-years (QALYs) between the predictive-biomarker- and standard-of-care-based strategy. Implementing a predictive biomarker in pembrolizumab-carboplatin-paclitaxel treatment led to a mean survival reduction of 24 days (- 0.067 LYs) (18 days corrected for QoL (- 0.049 QALYs)), with cost savings of €22,606 compared with standard of care. Pembrolizumab monotherapy and pembrolizumab-pemetrexed-platinum treatments showed survival reductions of 4.5 and 3.9 months, respectively (3.6 and 2.8 months corrected for QoL), with cost savings of €24,345 and €28,456. Sensitivity analyses confirmed consistent cost savings and survival reductions. Survival losses were mainly observed due to the lower survival rates associated with the alternative first-line treatment options available for non-responders in the predictive-biomarker-based strategy within each pembrolizumab-containing treatment regimen. Pembrolizumab-carboplatin-paclitaxel treatment also showed survival gains under certain conditions related to QoL and survival estimates. Our study highlights the importance of careful de-implementation of ICI-treatments in advanced NSCLC, balancing costs reductions and side effects without comprising survival. In the pembrolizumab-carboplatin-paclitaxel treatment regimen, the survival loss could be considered negligible. Future research should define acceptable tradeoffs and thresholds for de-implementation, considering factors such as survival of alternative treatments and responder classification to guide predictive biomarker implementation and optimize health resource allocation.

Remote symptom monitoring with patient-reported outcomes and nudges during lung cancer immunotherapy in China (PRO-NET): protocol for a randomised controlled trial

IntroductionLung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) comprising the majority of cases. For advanced NSCLC, immunotherapy offers substantial survival benefits but...

Real‑world therapeutic strategies and survival outcomes in advanced HER2-mutant non-small cell lung cancer.

Limited information is available regarding the clinical features and outcomes of advanced human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) in Taiwan, despite expanding treatment options for this distinct subtype. The present study explored the clinical features and outcomes of HER2-mutant NSCLC in a real-world setting. Relevant data were collected from patients with advanced or recurrent HER2-mutant NSCLC who received systemic therapy between 2011 and 2021 and were followed up until 2022 at two medical centers in Taiwan. Clinical features, treatment responses, and survival-associated factors were analyzed. This study included 45 patients (median age: 59.7 [range: 41.3-78.7] years). A775_G776insYVMA was the most common NSCLC subtype (57.8%), followed by G778_P780dup (11.1%). Approximately 53.3% of the patients received first-line platinum-based chemotherapy (PC) alone, whereas 13.3% received PC combined with an immune checkpoint inhibitor (ICI). The median overall survival (OS) and progression-free survival (PFS) after first-line therapy were 25.8 and 4.4 months, respectively. The objective response rate was generally higher in patients receiving first-line PC + ICI than in those receiving PC alone (33.3% vs. 12.5%; p = 0.269). Furthermore, patients receiving PC + ICI had longer PFS than did those receiving PC alone (9.5 vs. 4.4 months; p = 0.131) and those receiving tyrosine kinase inhibitor/ICI monotherapy (9.5 vs. 0.5 months; p = 0.015). Compared with patients having other NSCLC subtypes, those carrying HER2 exon 20 insertion mutations had shorter median PFS (17.3 vs. 2.9 months; p = 0.043) and OS (not reached vs. 19 months; p = 0.031). This study highlights the clinical features and outcomes of advanced HER2-mutant NSCLC in Taiwan. PC + ICI may be more effective than other regimens as first-line therapy. The prognostic role of HER2 exon 20 insertion mutations warrants further investigation.

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab

Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC.

Suitability of different cytological preparations for molecular analysis of advanced NSCLC.

Around 85% of non-small cell lung cancers (NSCLCs) are diagnosed at an advanced stage (IIIB to IV), where therapeutic options depend on molecular analysis. However, diagnostic material for molecular testing is often represented by cytological samples which are generally scarce and span a wide range of preparation types. Thus, the primary objective is to efficiently manage materials for molecular profiling. This study aims to evaluate the suitability of different cytological samples to assess morphological and molecular characteristics of advanced NSCLC. Sixty-seven cytological samples obtained from patients with advanced NSCLC were utilized. The series encompassed different procedure types (fine-needle aspiration cytology, transbronchial needle aspiration, effusions) processed by cell blocks in 54% (n=36), direct smears in 33% (n=22), and Liquid Based Cytology (LBC) in 13% (n=9). Cytological diagnoses were routinely performed and molecular analysis were conducted using NGS and RT-PCR methods. Adequate quantity and quality of nucleic acids were obtained from all the samples, allowing molecular profiling. Combined Next Generation Sequencing (NGS) and Real Time-Polymerase Chain Reaction (RT-PCR) analysis showed wild-type profiles in 62.7% (n=42) and mutated profiles in 37.3% (n=25) of the samples. Kirsten Rat Sarcoma Virus (KRAS) mutations were identified in 19.5% (n=13) of samples, Epidermal Growth Factor Receptor (EGFR) mutations in 10.4% (n=7) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in 2.9% (n=2). Identified chromosomal alterations were v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) duplication in 2,9% (n=2). The cytological sample types examined in this study proved to be suitable for molecular testing, in addition to conventional morphologic diagnosis, showing versatility and adaptability to different clinical contexts. Molecular testing on cytological samples is accurate and fast, representing a valid tool for molecular profiling of advanced NSCLC.

Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly half of all patients diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) harness the host immune system to combat malignant cells. ICIs, which target programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and cytotoxic T-cell lymphocyte-4 (CTLA-4), have transformed the treatment landscape for advanced NSCLC. While a subset of patients experiences a long-term durable response, most patients will develop disease progression. New drugs targeting novel pathways are being tested in clinical trials to improve the efficacy of immunotherapy and overcome resistance patterns. This review aims to summarize the currently available ICIs for advanced NSCLC and describe emerging immunotherapies with recently published data from phase I/II clinical trials.

Immunological characteristics of peripheral T cells as prognostic markers for Camrelizumab and Apatinib combination therapy in advanced squamous non-small-cell lung cancer.

To determine the characteristic changes of peripheral blood T cells and identify potential biomarkers that associated with the clinical efficacy of combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous non-small cell lung cancer (NSCLC). We performed a comprehensive immunological assessment of peripheral blood mononuclear cell samples from advanced squamous NSCLC patients before and after combination of immunotherapy (Camrelizumab) and anti-angiogenic therapy (Apatinib) using spectral flow cytometry. Correlations between these immunological features and clinical efficacy were analyzed. Our findings revealed that, following two treatment cycles, the concentration of type 1 T helper (Th1) cells in the peripheral circulation was significantly higher in the responder group than in the non-responder group, correlating with a statistically significant improvement in survival outcomes. Post-treatment, CD137 expression within Th1 cells in the responders, whereas TIM-3 expression was significantly reduced. In the validation cohort, elevated CD4+ CXCR3+ CD137+ cells in the peripheral blood were associated with a positive clinical reaction to the treatment and extended survival. Our findings suggest that peripheral blood circulating CD4+ CXCR3+ CD137+ cells serve as biomarkers of response to combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous NSCLC, providing potential guidance for improving clinical outcomes.

Abstract P017: Circulating tumor DNA kinetics identify prodynorphin signaling as a target to radiosensitize non-small cell lung cancer

Abstract Introduction: Definitive chemoradiation therapy (CRT) is essential for controlling locoregionally advanced non-small cell lung cancer (NSCLC); however, up to 30% of patients experience local recurrences within the radiation field. Analyzing favorable responders to treatment could enable identification of genetic alterations associated with radiosensitivity, but standard imaging cannot distinguish residual disease from inflammation and fibrosis during treatment to assess treatment response. We hypothesized that circulating tumor DNA (ctDNA) kinetics during CRT could identify genetic alterations associated with radiosensitivity that could be validated in preclinical models and harnessed to develop new combination therapies with radiotherapy (RT). Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) ctDNA analysis to pre-CRT and mid-treatment (mid-CRT) plasma samples from 61 patients with Stage II-III NSCLC. We identified ctDNA rapid responders as the 10 patients with the largest decrease in ctDNA concentration mid-CRT without local progression and determined the prevalence of genetic alterations in rapid responders versus slow responders using Fisher’s exact tests corrected for multiple hypothesis testing. To investigate the therapeutic potential of targeting PDYN during RT, we performed clonogenic assays on isogeneic PDYN CRISPR-Cas9 knockout and wildtype H1299 and SW1573 human NSCLC cell lines and H1299 cells treated with prodynorphin-neutralizing antibodies. Results: Mid-CRT log-fold change in ctDNA concentration was significantly associated with progression-free survival (P=0.02) in Stage II-III NSCLC. Mutations in PDYN, which encodes the opioid peptide precursor protein prodynorphin, were observed in 30% of ctDNA rapid responders and 0% of ctDNA slow responders (adjusted P=0.04). In NSCLC patients from TCGA treated with RT, the cumulative incidence of local failure was significantly lower in tumors with PDYN mutations (0% vs. 17% at 3 years, P<0.001). PDYN knockout (PDYNNULL) radiosensitized human NSCLC cancer cells by clonogenic assay, and extracellular administration of prodynorphin or its cleavage product dynophin A partially restored radioresistance in PDYNNULL cells. Prodynorphin cleavage products have been reported to signal through opioid receptors and to antagonize N-methyl-D-aspartate receptor (NMDAR) signaling. Although treatment of wildtype H1299 cells with opioid receptor antagonists did not affect radiosensitivity, the NMDAR antagonist MK-801 partially restored RT resistance in PDYNNULL cells. Finally, prodynorphin-neutralizing antibodies significantly reduced clonogenic survival of human NSCLC cells. Conclusions: ctDNA kinetics enable the identification of patients responding favorably to treatment and putative targets to enhance the efficacy of RT. Targeting prodynorphin may enhance the radiosensitivity of NSCLC by increasing NMDAR signaling. Citation Format: Ziwei Wang, Angela B. Hui, Ash A. Alizadeh, Maximilian Diehn, Everett J. Moding.Circulating tumor DNA kinetics identify prodynorphin signaling as a target to radiosensitize non-small cell lung cancer.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P017

The association between body composition and overall survival in patients with advanced non-small cell lung cancer

Nutritional status is associated with prognosis in a variety of cancers. Studies analyzing the association between the measurements of skeletal muscle and adipose tissue obtained from Computerized Tomography (CT) images at the time of diagnosis of advanced non-small cell lung cancer (NSCLC) and overall survival (OS) are relatively few. Data from 425 patients diagnosed with advanced NSCLC between January 2016 and December 2017 were retrospectively analyzed, with an average follow-up of 15.3 months. To outline the patient’s chest CT plain image at the time of diagnosis,skeletal muscle and subcutaneous fat at the level of both thoracic vertebrae were quantified in terms of mass and quantity by the pectoral muscle index (PMI), pectoral muscle density (PMD), subcutaneous fat index (SFI), subcutaneous fat density (SFD), paravertebral muscle index (PVMI), and paravertebral muscle density (PVMD). The SFI value in the female survival group is significantly lower than that in the death group (P = 0.049), and the PVMI value in the overall survival group is significantly lower than that in the death group (P < 0.001). After adjusting for clinical variables such as gender, smoking status, clinical staging, degree of differentiation, and radiotherapy history, the multivariable Cox regression analysis showed that an increase in SFI significantly improves the overall survival rate of patients (Hazard Ratio [HR] = 1.410, 95% Confidence Interval [CI]: 1.042–1.908, P = 0.026). Conversely, a decrease in PVMD is significantly associated with improved overall survival and prognosis (HR = 0.762, 95% CI: 0.579–0.982, P = 0.048). No association was found between body mass index (BMI) and chest muscle status indicators and overall survival (P > 0.05). CT-measured body composition parameters provide precise prognostic information and are superior to BMI; an increased OS rate in advanced NSCLC is associated with a greater SFI and a lower PVMD.

Interstitial Lung Disease due to Tepotinib after Durvalumab in a Patient with Lung Adenocarcinoma Harbouring MET Exon 14 Skipping Mutation: A Case Report

Introduction: Tepotinib is a targeted agent for patients with advanced non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation (METex14). Whereas durvalumab is an immune-checkpoint inhibitor (ICI), which has been administered to those with unresectable stage III NSCLC. The efficacy and safety of sequential treatment in patients with METex14 are unclear. Reports have suggested that the administration of tyrosine kinase inhibitors after ICIs could potentially increase the incidence of drug-induced lung injury. Case Presentation: A 76-year-old female patient was diagnosed NSCLC harbouring METex14 with clinical stage IIIA (cT2aN2M0). Chemoradiotherapy and consolidation therapy with durvalumab were initiated to achieve a cure. Durvalumab was discontinued due to interstitial lung disease (ILD). After systemic disease progression was observed, tepotinib was initiated 7 weeks after the last dose of durvalumab. She developed ILD due to the sequential treatment of tepotinib after durvalumab. Conclusion: It is unclear whether tepotinib is safe in patients with METex14 after durvalumab administration. Considering the residual period of ICIs in the body, caution should be exercised when initiating molecular-targeted drugs after ICI administration in patients with NSCLC with METex14.

Cost-effectiveness analysis of gumarontinib versus savolitinib for the treatment of advanced or metastatic NSCLC with MET exon 14 skipping mutations in China using partitioned survival model

Background and objectivesBoth gumarontinib and savolitinib have demonstrated efficacy in treating non-small-cell lung cancer (NSCLC) with tumors harboring mesenchymal–epithelial transition factor gene exon 14 (METex14) skipping. However, the comparison of their efficacy and pharmacoeconomics profiles remains limited. This study aims to evaluate the cost-effectiveness of gumarontinib versus savolitinib for the treatment of METex14 skipping NSCLC in China.MethodsA 3-state partitioned survival model (PSM) was developed with lifetime horizon from the perspective of Chinese healthcare system. Survival inputs were based on an unanchored matching-adjusted indirect comparison using individual patient data from GLORY trial to adjust for patient characteristics in NCT02897479. Costs and outcomes were discounted at an annual rate of 5%. Sensitivity and scenario analyses were conducted to explore model uncertainty.ResultsGumarontinib gained an additional 0.10 QALYs at an incremental cost of $1,893 compared to savolitinib, resulting in the ICERs of $19,243/QALY, which is below the threshold of 3 times the GDP per capita in China ($35,007 per capita in 2022). Sensitivity and scenario analyses confirmed the robustness of the base-case results.ConclusionGumarontinib is a cost-effective option compared to savolitinib for METex14 skipping NSCLC in China.

Efficacy and safety of first-line nivolumab plus ipilimumab treatment in elderly patients (aged ≥ 75 years) with non-small cell lung cancer

PurposeNivolumab plus ipilimumab (Nivo-Ipi) combination therapy is an effective first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its effectiveness and feasibility in elderly patients (aged ≥ 75 years) remain unclear. This study aimed to investigate the efficacy and safety of first-line Nivo-Ipi therapy in elderly patients with NSCLC.MethodsThis retrospective study included 57 patients with NSCLC (52 men and 5 women), aged ≥ 75 years (range: 75–86) who received first-line Nivo-Ipi therapy from December 2020 to November 2022 at four institutes in Japan. Patient characteristics, therapeutic efficacy, and the incidence and severity of adverse events (AE) were assessed.ResultsThe overall response rate was 42.1%, the disease control rate was 73.6%, the median progression-free survival (PFS) was 7.1 months, and the median overall survival (OS) was 14.1 months. Common Grade ≥ 3 AEs included pneumonitis, elevated aspartate transaminase, elevated alanine transaminase, adrenal insufficiency, and colitis. No treatment-related deaths were reported. PFS and OS were longer in patients who experienced treatment-related AEs. Patients with and without AEs had a median PFS of 11.7 and 2.8 months, respectively. Similarly, the median OS of patients with and without AEs was 20.4 and 9.0 months, respectively.ConclusionFirst-line Nivo-Ipi therapy is effective in elderly patients with NSCLC. Although there was an increased incidence of pneumonitis, the treatment was manageable and presented as a viable treatment option. Notably, the occurrence of treatment-related AEs was associated with improved clinical outcomes, suggesting a potential prognostic value of AEs in this population.

Randomized Evaluation of the PET-Adjusted IMRT for NSCLC Trial (REPAINT).

Standard radiotherapy (RT) for locally advanced NSCLC (LA-NSCLC) employs a uniform dose of approximately 60 Gy. Recent trials demonstrated that radiotherapy dose escalation may not improve outcomes and may cause added toxicity. XXX previously performed a single-arm trial testing a personalized, risk-adapted, and de-intensified RT strategy. We now report findings from a randomized trial testing this novel approach. LA-NSCLC patients with ECOG performance status 0-2 were eligible for this trial. Metabolic tumor volume (MTV) for each pulmonary tumor and involved lymph node was calculated using FDG-PET. Participants were randomized 1:1 to receive standard RT (60 Gy in 30 fractions delivered to pulmonary tumors and involved lymph nodes) versus dose-painted RT (55 Gy delivered to tumors and lymph nodes with metabolic volume exceeding 20 cm3 and 44-48 Gy to other lesions, all in 20 fractions). Concurrent chemotherapy and standard adjuvant therapy were given in both arms. The primary objective was to characterize patient-reported outcomes utilizing PRO-CTCAE. Secondary objectives included comparing outcomes between study arms. Fifty patients were enrolled. The most common grade 3 patient-reported adverse events within 90 days of RT completion were dysphagia (38%), fatigue (38%), cough (32%), and wheezing (28%). The median progression-free survival (PFS) duration is 18 months, and the median overall survival (OS) duration is 42 months. PFS and OS rates are similar across study arms (logrank p=0.562 and 0.765, respectively). There have been three cases of in-field disease progression, with one in the control arm and two in the dose-painted arm. Grade 3-4 lymphopenia was reduced with dose-painted RT (48% v. 81%, chi-square p=0.012). High-grade patient-reported toxicity in LA-NSCLC patients who are treated with concurrent chemoradiotherapy is common. We found no evidence that risk-adapted radiotherapy de-escalation compromises clinical outcomes. Follow-up studies testing the ability of this approach to improve the safety profile of chemoradiotherapy are warranted.

Grade ≥ 3 hematologic adverse events of immunotherapy in advanced NSCLC patients: a systematic review and meta-analysis.

The impact of incorporating immune checkpoint inhibitors (ICIs) into standard chemotherapy on the severity and risk of myelosuppression in advanced non-small cell lung cancer (NSCLC) patients remains uncertain. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) that evaluated ICIs in people with NSCLC. A comprehensive search of four databases, PubMed, Web of Science, Embase, and the Cochrane Library, was carried out from inception to 30 October 2023. Pooled analyses assessed the risk ratios (RR) for treatment-related hematological adverse events greater than or equal to grade 3. The protocol is registered with PROSPERO and has the CRD42024500056 registration number. Twenty-three phase 3 RCTs were contained, involving 15,844 people with NSCLC receiving ICIs with or without chemotherapy. Compared with chemotherapy alone, ICI monotherapy or dual immunotherapy reduced treatment-associated leukopenia (relative risk (RR) 0.03, 95% CI 0.01-0.08), neutropenia (RR 0.02, 95% CI 0.01-0.03), thrombocytopenia (RR 0.05, 95% CI 0.02-0.14), and anemia (RR 0.09, 95% CI 0.05-0.15), with a pooled incidence of 0.07%, 0.08%, 0.14%, and 9.07%. Compared with chemotherapy alone, ICIs in combination with chemotherapy increased the risk of developing treatment-related thrombocytopenia (RR 1.35, 95% CI 1.04-1.77), with a pooled incidence rate of 6.83%; it did not increase leukopenia (RR 0.97, 95% CI 0.70-1.35), neutropenia (RR 1.05, 95% CI 0.90-1.23), and anemia (RR 1.10, 95% CI 0.85-1.43), with pooled incidence rates of 4.47%, 14.67%, and 13.36%, respectively. For patients with advanced or metastatic NSCLC, severe hematological adverse events are uncommon when ICIs are used alone, as opposed to chemotherapy. However, when used in conjunction with chemotherapy, these side effects may be intensified, particularly in the form of an elevated incidence of thrombocytopenia of grade 3 or higher.

Circulating Tumor DNA and [18F]FDG-PET for Early Response Assessment in Patients with Advanced NSCLC

Background/Objectives: Identifying treatment failure at earlier time points to could spare cancer patients from ineffective treatment and side effects. In this study, circulating tumor DNA (ctDNA) and [18F]FDG-PET/CT were investigated during the first cycle of anticancer therapy in patients with advanced non-small cell lung cancer (NSCLC) to explore their potential for early response evaluation. Methods: Patients with advanced NSCLC receiving first-line therapy with immune checkpoint inhibitors and/or chemotherapy were included. CtDNA and [18F]FDG-PET/CT assessments were conducted before treatment and at weeks 1 and 3 during the first cycle of therapy. ctDNA quantification was performed using a targeted next-generation sequencing (NGS) panel, and the least favorable change in any mutated allele frequency at a given time was used for analysis. [18F]FDG-PET/CT was quantified using sumSULpeak and metabolic tumor volume (MTV4.0). Early changes in ctDNA levels and [18F]FDG-PET parameters were compared with final treatment response, measured by RECIST after 12 weeks, as well as progression-free survival and overall survival. Results: Of the sixteen included patients, eight were non-responders. ctDNA mutations were detected in baseline blood samples in eight patients. Changes in ctDNA level, MTV4.0, and sumSULpeak at week 3 indicated response in 7 out of 8 patients, 13 out of 15 patients, and 9 out of 15 patients, respectively. At week 3, no false increases were seen with ctDNA and MTV4.0. Conclusions: These results suggest that early changes in ctDNA and [18F]FDG-PET/CT at 3 weeks of treatment could be used to early assess treatment response. Increased levels of ctDNA and MTV4.0 at week 3 were only observed in patients with treatment failure.

Brigatinib treatment in a patient with advanced NSCLC with XPO1-ALK fusion: a case report

Patients with ALK-rearranged non-small cell lung cancer (NSCLC) who are treated with ALK tyrosine kinase inhibitors (ALK TKIs) have better prognoses. In this case report, we provide evidence of a novel ALK fusion, XPO1-ALK (intergenic), identified by next-generation DNA sequencing in a patient with advanced lung cancer. After 5 months of brigatinib targeted therapy, the patient clearly experienced tumor disintegration, and this treatment resulted in partial remission. To date, this patient has experienced 5 months of progression-free survival after brigatinib treatment. In addition to reporting the identification of a novel ALK fusion, XPO1-ALK (intergenic), and the sensitivity and safety of brigatinib treatment for lung cancer, this study increased the list of known ALK fusion partners in ALK-positive NSCLC. This case report has a significant clinical reference.

The Impacts of Active and Inactive Ghrelin on Cachexia and Immune Checkpoint Inhibitor Monotherapy in Patients with Non-small Cell Lung Cancer.

Identifying the underlying mechanisms of immune checkpoint inhibitor resistance in patients with cachexia is a current challenge. Ghrelin is a peptide hormone that plays an important role in the metabolism of patients with cancer cachexia. Despite the importance of ghrelin in cancer cachexia, most previous studies on the subject have not distinguished between the forms of ghrelin. We retrospectively screened patients with advanced or recurrent non-small cell lung cancer receiving PD-1/PD-L1 inhibitor monotherapy. Active and inactive ghrelin levels were measured in 100 patients with available plasma samples at immune checkpoint inhibitor initiation. Cancer cachexia was defined as weight loss of at least 5% during the past 6 months or weight loss of at least 2% with a BMI < 20. We analyzed the associations of the active and inactive ghrelin levels and active-to-inactive ghrelin ratio (AIR) with cancer cachexia. The prognostic impact of the active and inactive ghrelin levels and AIR were also analyzed. Among 100 patients, 35 were diagnosed with cancer cachexia. The active ghrelin level and AIR were significantly associated with cancer cachexia, whereas the inactive ghrelin level was not. The active and inactive ghrelin levels and AIR were not associated with patient prognosis. The active ghrelin level and AIR were associated with cancer cachexia but not with patient prognosis. The function of the active and inactive forms of ghrelin may differ in cancer patients. The form of ghrelin should be clearly mentioned in relevant studies on cancer cachexia.

Computed Tomography-Based Radiomics and Genomics Analyses for Survival Prediction of Stage III Unresectable Non-Small Cell Lung Cancer Treated With Definitive Chemoradiotherapy and Immunotherapy.

The standard therapy for locally unresectable advanced non-small cell lung cancer (NSCLC) is comprised of chemoradiotherapy (CRT) before immunotherapy (IO) consolidation. However, how to predict treatment outcomes and recognize patients that will benefit from IO remain unclear. This study aimed to identify prognostic biomarkers by integrating computed tomography (CT)-based radiomics and genomics. Specifically, our research involved 165 patients suffering from unresectable Stage III NSCLC. Cohort 1 (IO following CRT) was divided into D1 (n = 74), D2 (n = 32), and D3 (n = 26) sets, and the remaining 33 patients treated with CRT alone were grouped in D4. According to the CT images of primary tumor regions, radiomic features were analyzed through the least absolute shrinkage and selection operator (LASSO) regression. The Rad-score was figured out to forecast the progression-free survival (PFS). According to the Rad-score, patients were divided into high and low risk groups. Next-generation sequencing was implemented on peripheral blood and tumor tissue samples in the D3 and D4 cohorts. The maximum somatic allele frequency (MSAF) about circulating tumor DNA levels was assessed. Mismatch repair and switching/sucrose non-fermenting signaling pathways were significantly enriched in the low-risk group compared to the high-risk group (p < 0.05). Moreover, patients with MSAF ≥ 1% and those showing a decrease in MSAF after treatment significantly benefited from IO. This study developed a radiomics model predicting PFS after CRT and IO in Stage III NSCLC and constructed a radio-genomic map to identify underlying biomarkers, supplying valuable insights for cancer biology.

Efficacy and Safety of Immunotherapy Combined with Anlotinib as FirstLine Treatment in Older NSCLC Patients with PD-L1 Expression

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression＜50%. We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables. The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS. ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

MOMENT registry: Patients with advanced non-small-cell lung cancer harboring MET exon 14 skipping treated with systemic therapy.

Aim: MET exon 14 (METex14) skipping occurs in 3-4% of non-small-cell lung cancer (NSCLC) cases. Low frequency of this alteration necessitated open-label, single-arm trials to investigate MET inhibitors. Since broad MET biomarker testing was only recently introduced in many countries, there is a lack of historical real-world data from patients with METex14 skipping NSCLC receiving conventional therapies. Given the rarity of this population and limitations of existing real-world data sources, the MOMENT registry aims to prospectively collect uniform, comprehensive, high-quality data from patients with METex14 skipping advanced NSCLC treated in routine clinical practice, which can support clinical and regulatory decision making. Patients & methods: MOMENT is a multinational, non-interventional disease registry collecting data on patients with METex14 skipping advanced NSCLC receiving any systemic anticancer therapy. Newly diagnosed patients and those already receiving treatment are eligible. Patients with previous participation in a clinical trial can be included if they receive at least one subsequent therapy line in a routine clinical setting. Eligible systemic treatment includes all available anticancer therapies (approved, conditionally approved or provided through Early Access). Data collection includes biomarker testing results, demographics, baseline clinical characteristics, treatment details and effectiveness, safety information and imaging. Registry site inclusion is dependent on confirmation that local METex14 skipping detection methods are sufficient to confirm METex14 skipping status. MOMENT is currently active at more than 60 sites across Europe and North America and approximately 700 patients are expected to be enrolled within the next 4years. The first patient was enrolled on 4October 2022. After completion of data collection, MOMENT data can be shared with external parties to conduct non-interventional studies. Discussion/conclusion: The MOMENT registry collects comprehensive, high-quality real-world data from patients with METex14 skipping advanced NSCLC receiving systemic anticancer treatment in a routine clinical setting, to enable future studies informing regulatory decisions and optimal care for this rare population. Clinical Trial Registration: NCT05376891 (ClinicalTrials.gov); EUPAS47602 (EU PAS register no.).