Advanced Non-small Cell Lung Cancer Patients Research Articles

Non-cancerous CT findings as predictors of survival outcome in advanced non-small cell lung cancer patients treated with first-generation EGFR-TKIs.

To identify non-cancerous factors from baseline CT chest affecting survival in advanced non-small cell lung cancer (NSCLC) treated with first-generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs). Retrospective study of 172 advanced NSCLC patients treated with first-generation EGFR-TKIs as a first-line systemic treatment (January 2012 to September 2022). Baseline CT chest assessed visceral/subcutaneous fat (L1 level), sarcopenia, and myosteatosis (multiple levels), main pulmonary artery (MPA) size, MPA to aorta ratio, emphysema, and bone mineral density. Cox regression analyzed prognostic factors at 18-month outcome. Median overall survival was 17.57 months (14.87-20.10) with 76 (44.19%) patients died at 18 months. Deceased had lower baseline BMI (21.10 ± 3.44) vs. survived (23.25 ± 4.45) (p < 0.001). Univariable analysis showed 5 significant prognostic factors: low total adiposity with/without cutoff [HR 2.65 (1.68-4.18), p < 0.001; 1.00 (0.99-1.00), p = 0.006;], low subcutaneous adipose tissue (SAT) with/without cutoff [HR 1.95 (1.23-3.11), p = 0.005; 0.99 (0.98-0.99), p = 0.005], low SAT index (SATI) with/without cutoff [1.74 (1.10-2.78), p = 0.019; 0.98 (0.97-0.99), p = 0.003], high VSR [1.67 (1.06-2.62), p = 0.026], and high MPA size with/without cutoff [2.23 (1.23-4.04), p = 0.005; 1.09 (1.04-1.16), p = 0.001]. MPA size, MPA size > 29 mm, and total adiposity ≤85 cm2 remained significant in multivariable analysis, adjusted by BMI [HR 1.14 (1.07-1.21), p < 0.001; 3.10 (1.81-5.28), p < 0.001; 3.91 (1.63-9.40), p = 0.002]. There was no significant difference of sarcopenic and myosteatotic parameters between the two groups. In advanced EGFR-mutated NSCLC patients, assessing pre-treatment prognosis is warranted to predict the survival outcome and guide decision regarding EGFR-TKI therapy. Enlarged MPA size, low total adiposity, and low subcutaneous fat (lower SAT, lower SATI, and higher VSR) are indicators of poor survival. Large MPA size (>29 mm) or low total adiposity (≤85 cm2) alone predict 18-month death.

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...

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.

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.

Current Status, Challenges, and Prospects of Combining Immune Checkpoint Inhibitors and Chemotherapy in Non-Small Cell Lung Cancer Treatment

In recent years, significant advancements have been made in the use of immune checkpoint inhibitors (ICIs) for treating non-small cell lung cancer (NSCLC). Nevertheless, their efficacy as monotherapy remains limited in certain patient populations, especially in patients with low levels of PD-L1 expression. The combination of ICIs with chemotherapy has gradually emerged as a novel strategy, aiming to leverage the immune-enhancing effects of chemotherapy to synergize with ICIs. This review provides a comprehensive analysis of the synergistic mechanisms, clinical trial outcomes, safety and toxicity issues, resistance challenges, and future directions of ICI-chemotherapy combination therapy for NSCLC. Clinical evidence suggests that this combination notably extends progression-free survival (PFS) and overall survival (OS), demonstrating promising efficacy, particularly in advanced squamous NSCLC patients with low PD-L1 levels. By inducing immune enhancement through chemotherapy and activating immune responses via ICIs, this combined approach effectively overcomes the limitations of single-agent therapies. Despite a range of challenges, this immunotherapy combination offers renewed hope for improving treatment outcomes in NSCLC patients.

Exploring Prognostic Factors and Survival Outcomes in Advanced Non-Small Cell Lung Cancer Patients Undergoing First-Line Chemotherapy in Limited-Resource Settings.

Background/Objectives: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, especially in limited-resource countries (LRCs) where access to advanced treatments such as targeted therapy and immunotherapy is constrained. Platinum-based chemotherapy remains a cornerstone of first-line therapy. This study aims to identify prognostic factors influencing survival outcomes and evaluate treatment response to chemotherapy in advanced NSCLC patients in LRCs. Methods: A retrospective cohort study was conducted on 200 advanced NSCLC patients treated with first-line platinum-based doublet chemotherapy at Surin Hospital Cancer Center, Thailand. Prognostic factors were assessed through univariate and multivariate Cox regression analyses. Additionally, restricted mean survival time (RMST) was calculated to compare survival outcomes between responders and non-responders. Results: Independent prognostic factors associated with improved survival included good performance status, ECOG 0-1 (HR 0.50, p = 0.012), serum albumin ≥ 3.5 mg/dL (HR 0.60, p = 0.010), and favorable response to chemotherapy (HR 0.57, p = 0.003). Responders demonstrated significantly longer RMST at 12 months (p < 0.001), 24 months (p < 0.001), and 36 months (p = 0.004) compared to non-responders. Conclusions: Identifying prognostic factors and treatment responses is important for improving outcomes in advanced NSCLC patients, particularly in limited-resource settings where access to novel therapies is restricted.

Enhanced detection of actionable mutations in NSCLC through pleural effusion cell-free DNA sequencing: A prospective study.

Inadequate tumour samples often hinder molecular testing in non-small cell lung cancer (NSCLC). Plasma-based cell-free DNA (cfDNA) sequencing has shown promise in bypassing these tissue limitations. Nevertheless, pleural effusion (PE) samples may offer a richer cfDNA source for mutation detection in patients with malignant PE. This prospective study enrolled newly diagnosed advanced NSCLC patients with malignant PE. PE samples were collected for cfDNA NGS analysis. Meanwhile, PE cell pellet RNA was extracted for reverse transcription polymerase chain reaction (RT-PCR) for clinically relevant actionable mutations and then confirmed by Sanger sequencing. The concordance between PE cell pellet RT-PCR and PE cfDNA NGS analyses was analysed. Fifty patients were enrolled. The median age was 68.5 years, and the female-to-male ratio was 29:21. Most patients (74 %) were non-smokers. Notably, 45/50 patients (90 %) had actionable mutations, including EGFR exon 19 deletions (24 %), EGFR L858R mutations (36 %), HER2 exon20 insertions (10 %), ROS1 rearrangements (4 %), EGFR exon20 insertions (2 %), ALK rearrangements (4 %), RET rearrangements (2 %), KRAS G12C mutations (2 %), and CD74-NRG1 fusions (2 %). Among the 50 enrolled patients, actionable mutations were detected in 44 (88 %) by PE cfDNA NGS, 39 (78 %) by PE cell pellet Sanger sequencing, and 33 (66 %) by clinical tissue genetic testing (P = 0.031). The detection of actionable mutations from PE cfDNA NGS remained consistently high across M1a to M1c stages. PE cfDNA genotyping has clinical applicability for NSCLC patients and can serve as an additional source for molecular testing. Incorporating PE NGS cfDNA analysis into genetic testing enhances diagnostic yield and aids in identifying actionable mutations in clinical practice.

Immune Checkpoint Blockade Combined with AbnobaViscum® Therapy Is Linked to Improved Survival in Advanced or Metastatic Non-Small-Cell Lung Cancer Patients: A Registry Study in Accordance with the ESMO Guidance for Reporting Real-World Evidence.

Background: Recent advancements in cancer treatment have shown the potential of immune checkpoint blockade (ICB) plus Viscum album L. therapy in improving survival rates for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to investigate factors associated with improved survival in NSCLC patients treated with a combination of ICB and abnobaViscum®. Methods: Patients with advanced or metastatic NSCLC from the accredited Network Oncology registry were included in this real-world data study adhering to ESMO-GROW criteria with ethics approval. Survival outcomes were compared between patients receiving ICB therapy alone versus those receiving combinational ICB plus abnobaViscum® therapy using Kaplan-Meier and multivariable Cox proportional hazard analysis. Results: Among 300 patients (median age 68 years; male/female ratio 1.19), 222 received ICB alone (CTRL group) and 78 received combinational therapy (COMB group). Overall survival was significantly prolonged in the COMB group by 7 months compared to CTRL (13.8 months vs. 6.8 months, p = 0.005) with a survival rate of 16.5% in the COMB group vs. 8.0% in the CTRL group. In programmed death-ligand 1 positive (≥1%) patients treated with first-line ICB, the addition of abnobaViscum® reduced the adjusted hazard of death by 75% (aHR: 0.25; 95%CI: 0.11-0.60, p = 0.02). Conclusions: The addition of abnobaViscum® to ICB is significantly associated with improved survival in patients with advanced or metastatic NSCLC patients, irrespective of age, stage, Eastern cooperative oncology group status, surgery, or radiation. Potential mechanisms include immune modulation, reduced primary ICB resistance, and tumor microenvironment modifications. The findings warrant further validation in randomized controlled trials or registry-based randomized controlled trials. Trial registration: The study was registered (DRKS00013335).

Immune-related adverse events correlate with the clinical efficacy in advanced Non-Small-Cell Lung Cancer patients treated with PD-1 inhibitors combination therapy

ObjectiveThe potential of immune-related adverse events (irAEs) in predicting the efficacy of PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) has rarely been assessed. This study investigated the associations between irAEs and the clinical efficacy of PD-1 inhibitors combination therapy in patients with advanced NSCLC.MethodsA retrospective analysis was conducted of 73 patients with advanced NSCLC receiving PD-1 inhibitors combination therapy from January 2022 and July 2023. Patients were divided into two cohorts: patients with irAEs and patients without irAEs. We conducted an analysis to investigate the impact of irAEs on these different clinical outcomes.ResultsThere were no significant differences observed in clinical characteristics between the two cohorts, except for smoking status (P = 0.011).The cohort with irAEs exhibited a higher objective response rate (ORR) and disease control rate (DCR) compared to the cohort without irAEs (ORR: 32.5% vs 12.1%, P = 0.040; DCR: 80.0% vs 48.5%, P = 0.010).Moreover, the median progression-free survival (PFS) and overall survival (OS) were significantly better in the cohort with irAEs compared to the cohort without irAEs (PFS: 12.4 months vs 6.8 months, P = 0.009; OS: not reached vs 18.3 months, P = 0.024). Additionally, the multivariate COX regression analysis revealed that mild irAEs (PFS: HR = 0.386, 95% CI: 0.199–0.748, P = 0.005; OS: HR = 0.300, 95% CI: 0.105–0.855, P = 0.024) and single-system irAEs (PFS: HR = 0.401, 95% CI: 0.208–0.772, P = 0.006; OS: HR = 0.264, 95% CI: 0.090–0.776, P = 0.015) were identified as independent prognostic factors for both PFS and OS.ConclusionsIrAEs, especially thyroid irAEs, as well as mild or single-system irAEs, may serve as predictors of improved efficacy in advanced NSCLC patients receiving PD-1 inhibitors combination therapy.

Osimertinib as Second- and ≥Third-Line Treatment in Advanced and Recurrence EGFR-Mutant NSCLC Patients Harboring Acquired T790M Mutation.

Osimertinib is a standard sequential therapy for advanced and recurrent Epidermal Growth Factor Receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients with the T790M mutation, following treatment with first- or second-generation EGFR Tyrosine Kinase Inhibitors (TKIs). This study aims to investigate the differences in clinical outcomes between osimertinib as a 2nd-line treatment and as a ≥3rd-line treatment in this patient population. Between September 2014 and March 2023, we enrolled advanced and recurrent T790M + NSCLC patients who had received osimertinib as sequential treatment for analysis. All patients had previously been treated with gefitinib, erlotinib, or afatinib as first-line therapy. A total of 158 patients who received osimertinib as sequential treatment were included in the final analysis. Of these, 99 patients (62.7%) received osimertinib as a 2nd-line treatment, while 59 patients (37.3%) were treated with osimertinib as ≥3rd-line therapy. The median progression-free survival (PFS) was 10.7 months for the 2nd-line group and 8.9 months for the ≥3rd-line group. The median overall survival (OS) from first-line treatment was 73.2 months in the 2nd-line group and 57.5 months in the ≥3rd-line group. No statistically significant differences in PFS or OS were observed between the two groups. Our research demonstrated that osimertinib is effective not only as a 2nd-line therapy but also as a ≥3rd-line treatment, offering promising clinical benefits for advanced and recurrent EGFR-mutant NSCLC patients with acquired T790M mutations who have developed resistance to first- and second-generation EGFR-TKI therapy.

Prognostic value of immunotherapy in advanced NSCLC based on baseline and dynamic changes in HALP.

Immune checkpoint inhibitors (ICIs) enhance the tumor-killing ability of T-cells in non-small cell lung cancer (NSCLC), improving overall survival (OS) and revolutionizing treatment for advanced stages. However, challenges remain, such as low response rates and the lack of effective markers for selecting candidates. This study evaluated the impact of hemoglobin, albumin, and platelet (HALP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the efficacy of immunotherapy and survival outcomes in advanced NSCLC. Additionally, it aimed to develop a nomogram based on these parameters. Clinical and hematological data from NSCLC patients who received immunotherapy were analyzed. Efficacy was assessed using the immune Response Evaluation Criteria in Solid Tumors (iRECIST), and progression-free survival (PFS) and OS were evaluated. Prediction models incorporated baseline and post-treatment HALP, NLR, and PLR values. The 203 patients had a median follow-up of 16 months, a median PFS (mPFS) of seven months (6.0-8.0), while the median OS (mOS) was not reached (24.0-not available). Pretreatment PLR (PLR0) was associated with a higher disease control rate (DCR) (odds ratio [OR] = 0.258), while initial immunotherapy and NLR after four treatment cycles (NLR4C) significantly improved the objective response rate (ORR). Cox regression analysis showed that pretreatment HALP (HALP0), HALP after four cycles of treatment (HALP4C), and pretreatment NLR (NLR0) significantly impacted PFS. Additionally, HALP0, NLR0, and PLR after four treatment cycles (PLR4C) were associated with OS. The C-indices for PFS and OS were 0.823 and 0.878, respectively, indicating good predictive accuracy. HALP, NLR, and PLR at various time points effectively predicted immunotherapy response in advanced NSCLC patients, with low HALP combined with high NLR and PLR indicating a poor prognosis. These findings could serve as the basis for stratified randomized controlled trials (RCTs) in the future.

Dynamic characterization of circulating tumor DNA in HER2-altered advanced non-small cell lung cancer treated with pyrotinib and apatinib: Exploratory biomarker analysis from PATHER2 study.

HER2 mutations are critical drivers of non-small cell lung cancer (NSCLC), affecting 2%-3% of patients and often leads to poor prognosis and limited response to conventional therapies. This study investigates the genomic characteristics and prognostic relevance of dynamic circulating tumor DNA (ctDNA) monitoring in advanced NSCLC patients with HER2 mutations treated with pyrotinib and apatinib. The PATHER2 study included 33 advanced NSCLC patients harboring HER2 mutations or amplification, who received combination therapy of pyrotinib and apatinib. Among them, 27 patients had baseline blood samples available for analysis. Baseline blood samples (n=27), follow-up samples after one treatment cycle (n=13), and samples upon disease progression (n=18) were collected. ctDNA was extracted and sequenced using a 556-gene panel. At baseline, HER2 mutations were detected in 21 of 27 patients through ctDNA, and 19 showed consistent results between tissue and blood sample testing. Patients with TP53 and DNMT3A alterations at baseline had significantly shorter progression-free survival (PFS). Dynamic ctDNA monitoring revealed that patients without detectable HER2 mutations after one treatment cycle had longer PFS and a trend toward longer overall survival (OS) compared to those with persistent HER2 mutations. The newly emerged mutations after resistance were infrequently found in HER2, instead primarily enriched in the chromatin remodeling pathway. ctDNA holds significant value in guiding the treatment of patients with HER2 mutations. Baseline TP53 and DNMT3A alterations, along with persistent HER2 mutations after initial treatment, are associated with poorer prognosis. The primary mechanism of resistance to pyrotinib and apatinib in these patients may be attributed to chromatin remodeling rather than on-target alterations.

Radiomicsmetabolic signature profiles for advanced non-small cell lung cancer with chemoimmunotherapy by reflecting biological function and survival.

Resistance to chemoimmunotherapy in patients with advanced non-small cell lung cancer (NSCLC) necessitates effective prognostic biomarkers. Although 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has shown potential for efficacy assessment, it has been mainly evaluated in immuno-monotherapy setting, lacking elaborations in the scenarios of immunotherapy combined with chemotherapy. To tackle this dilemma, we aimed to build a non-invasive PET/CT-based model for stratifying tumor heterogeneity and predicting survival in advanced NSCLC patients undergoing chemoimmunotherapy. Meanwhile, we explored the interplay and combined effect between programmed death-ligand 1 (PD-L1) and metabolic parameters and probed into the prognostic differences between patients with similar total metabolic tumor volume (tMTV) but different tumor distribution (lesion locations and numbers). We retrospectively recruited unresectable advanced NSCLC patients receiving immunotherapy in Jinling Hospital from 2018 to 2023 as the training cohort. The Cancer Imaging Archive (TCIA) cohort with early-stage NSCLC patients undergoing surgical resection was used for validation and the assessment of the biological function and tumor microenvironment (TME). PET/CT-based parameters were extracted, including radiomics score (Rad-score), bone marrow to liver ratio (BLR), tMTV, and total lesion glycolysis (TLG). The end-point events included overall survival (OS) and progression-free survival (PFS). Step-wise multivariate Cox regression and the least absolute shrinkage and selection operator (LASSO) were used to identify candidate variables and establish models. A total of 220 patients were identified for analysis, including 139 with unresectable advanced NSCLC receiving immunotherapy and 81 from TCIA. The Radiomicsmetabolicos model for OS encompassing Rad-score >0.705 [hazard ratio (HR) =2.455; 95% confidence interval (CI): 1.324-4.550], squamous cell subtype (HR =1.641; 95% CI: 0.900-2.992), liver metastases (HR =3.496; 95% CI: 1.435-8.517), BLR >0.94 (HR =1.885; 95% CI: 1.013-3.507), and tMTV >105 mL (HR =2.162; 95% CI: 1.134-4.119) exhibited reliable prognostic capacity with a notable 3-year area under the curve (AUC) of 0.837. Patients with Rad-score ≤0.705 demonstrated upregulation of immune-related pathways and favorable survival. Additionally, distant metastases metabolic tumor volume (MTV) and TLG, as well as intrathoracic lymph nodes MTV were associated with survival independently. For patients with similar tMTV (≤105 mL), the number of FDG-avid lesions was an independent protective factor for more-than-1-year OS, which indicated that patients with smaller lesions seemed to have better long-term prognoses than those with larger lesions, even of fewer in number. Our findings proved that PET/CT could reveal survival and tumor heterogeneity in advanced NSCLC patients undergoing chemoimmunotherapy, which might guide the selection of immune-monotherapy for low-risk patients and facilitate the advancement of precision treatment.

Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) among them. The KEAP1 gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The STK11 gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The STK11 gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of STK11 or KEAP1 abnormalities with the KRAS mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of STK11 and KEAP1 genes mutations with the KRAS gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with STK11-, KEAP1- and KRAS-mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.

Revolutionizing NSCLC Treatment: Immunotherapy Strategies for EGFR-TKIs Resistance.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment choice for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. EGFR-TKIs have made significant progress in the treatment of advanced NSCLC patients, but drug resistance issues still inevitably arise. The mechanism of drug resistance and subsequent treatment has been current research challenge and priority. Immune checkpoint inhibitors (ICIs) are a new choice for late-stage NSCLC patients without druggable molecular alterations. Currently, several studies have applied ICIs therapy for NSCLC patients with EGFR-TKIs resistance and explored the potential efficacy of ICIs. This review elaborates on the current status of immunotherapy after EGFR-TKIs resistance, including ICIs monotherapy, combined with EGFR-TKIs, chemotherapy, antiangiogenic drugs, and other therapies.

Real-world cost-effectiveness of multi-gene panel sequencing to inform therapeutic decisions for advanced non-small cell lung cancer: a population-based study

Multi-gene panel sequencing streamlines treatment selection for advanced non-small cell lung cancer (NSCLC). Implementation continues to be uneven across jurisdictions, partly due to uncertain clinical and economic impacts. In British Columbia (BC), Canada, the public healthcare system reimbursed a multi-gene panel in September 2016. This study determined the population-level cost-effectiveness of publicly reimbursed multi-gene panel sequencing compared to single-gene testing for advanced NSCLC. Our population-based retrospective study design used patient-level linked administrative health databases. We considered adult BC residents with a panel-eligible lung cancer diagnosis between September 2016 and December 2018. Using a machine learning approach, we conducted 1:1 genetic algorithm matching of recipients receiving multi-gene panel sequencing to controls receiving single-gene testing, maximising balance on observed demographic and clinical characteristics. Following matching, we estimated mean three-year survival time and costs (public healthcare payer perspective; 2021 CAD) and calculated the incremental net monetary benefit (INMB) for life-years gained (LYG) at conventional willingness-to-pay thresholds using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. We matched 858 panel-eligible advanced NSCLC patients to controls, achieving balance for the 16 included covariates. Average test turnaround times were 18.6 days for multi-gene panel sequencing and 7.0 days for single-gene testing. After matching, mean incremental costs were $3529 (95% CI:-$4268, $10,942) and mean incremental LYG were 0.08 (95% CI:-0.04, 0.18). Among the 1000 bootstrap samples, 14.5% had lower costs and increased survival and 78.6% had higher costs and increased survival. The INMB was $523 (95% CI:-$6256, $7023) at $50,000/LYG, with a 57.5% probability of being cost-effective, and $4575 (95% CI:-$5468, $14,064) at $100,000/LYG, with an 84.0% probability of being cost-effective. Using population-based real-world data, we found a moderate to high probability that panel-based testing to inform targeted treatment for NSCLC would be cost-effective at higher thresholds. This research was supported by Genome British Columbia/Genome Canada (G05CHS) and the Terry Fox Research Institute.

Phase Ib/II study of imprime PGG and pembrolizumab in patients with previously treated advanced non-small cell lung cancer (NSCLC): BTCRC LUN 15-017.

Therapeutic strategies to engage anti-tumor innate immunity are still underdeveloped. Imprime PGG (imprime), a pathogen-associated molecular pattern (PAMP), through pattern recognition receptors, successfully illicit a broad-based innate immune response in preclinical models against various cancers. We aimed to study safety and efficacy of imprime in combination with pembrolizumab in advanced stage non-small cell lung cancer (NSCLC). We conducted an investigator-initiated, multi-institutional, single-arm, phase Ib/II trial in previously treated, advanced stage NSCLC patients. Primary endpoints were maximum-tolerated dose (MTD) of imprime for the phase Ib, and progression-free survival (PFS) for the phase II study (NCT03003468). All 33 eligible patients were included in the safety analysis. No dose-limiting toxicity was observed and the imprime dose of 4 mg/kg was determined as the MTD. Thirty patients treated at the MTD (phase Ib, 6; phase II, 24) were included in the efficacy analysis. Median length of follow-up was 10.8 months. Confirmed objective response rate was 10% [95% confidence interval (CI): 2-27%], with one complete and two partial responses. Median PFS was 2.6 months (95% CI: 1.4-7.0), and 6- and 12-month PFS rates were 37% and 17%, respectively. Median overall survival (OS) was 11.1 months, and 6- and 12-month OS rates were 75% and 46%. Univariate analysis was performed to assess the impact of age, sex, race, disease-stage, programmed death-ligand 1 (PD-L1) expression levels, and prior immunotherapy on PFS and OS. Of these, prior immunotherapy negatively influenced OS [hazard ratio (HR): 2.95, 95% CI: 1.21-7.24]. Overall, the combination was safe and tolerable. The combination of imprime and pembrolizumab is tolerable but did not improve the outcome of advanced stage NSCLC patients who previously progressed on anti-programmed death 1 (PD-1)/PD-L1 immunotherapies. Further investigation is needed to understand the effects of therapeutic PAMPs to mount a strong innate immune response against cancer.

Treatment of metastatic ALK-positive non-small cell lung cancer: real-world outcomes in a single center study.

Rearrangement in anaplastic lymphoma kinase (ALK) occurs in 4-7% of non-small cell lung cancer (NSCLC) cases. Despite improved survival with tyrosine kinase inhibitors (TKIs), treatment resistance remains challenging. This retrospective study analyzed advanced ALK-positive NSCLC patients, focusing on clinical aspects, treatments, resistance, and outcomes. Patients diagnosed between January 2009 and December 2021 who received at least one ALK-TKI line at the Karolinska University Hospital, were included. We evaluated crizotinib or 2nd generation ALK-TKI effectiveness in first-line treatment and lorlatinib in subsequent lines. Overall survival (OS) was defined as from the date of advanced lung cancer diagnosis until the date of last follow-up (April 22, 2022) or the date of death from any cause. Progression-free survival (PFS), from the date of starting ALK-TKI until the date of progression, death, or last follow-up. Resistance mechanisms were assessed through re-biopsies utilizing next-generation sequencing (NGS). Out of 160 eligible patients, 10 were excluded. Median follow-up was 54.0 months from diagnosis and 45.0 months from initial ALK-TKI treatment. Crizotinib showed a median PFS of 8.0 months and a median OS of 35.0 months. Second generation ALK-TKIs demonstrated a median PFS of 52.0 months [OS was not reached (NR)]. Overall, the median OS was 65.0 months. Poor prognostic factors included male sex, thromboembolism, crizotinib treatment, and chronic obstructive pulmonary disease (COPD)/asthma. Rebiopsies in 18 cases revealed secondary ALK mutations in 8 patients, correlating with a shorter median PFS in subsequent ALK-TKI treatment (1.0 vs. 7.0 months). This comprehensive study, spanning over a decade, provides crucial insights into the clinical characteristics, treatment patterns, and resistance mechanisms of advanced ALK-positive NSCLC, where median OS exceeds 5 years. Re-biopsies during treatment are essential for advancing our understanding of resistance mechanisms and the tumor dynamics evolving during ALK-TKI therapy.

Savolitinib Induced Pathological Complete Response in Non-small Cell Lung Cancer with MET Amplification: A Case Report

Mesenchymal-epithelial transition factor (MET) gene mutation is a large class of mutations commonly seen in non-small cell lung cancer (NSCLC). MET mutation includes subtypes such as MET exon 14 skipping mutation (METex14m) and MET amplification (METamp). For advanced NSCLC with METex14m, Savolitinib has a high sensitivity as a member of tyrosine kinase inhibitors (TKIs). METamp is a relatively rare genetic mutation type which can serve as a driver gene to mediate primary and later acquired drug resistance of epidermal growth factor receptor (EGFR)-TKIs. For advanced NSCLC with secondary METamp, EGFR-TKIs combined with MET-TKIs are usually used in clinical treatment, while the optimal treatment strategy for advanced NSCLC with primary METamp has not yet been determined. For locally advanced NSCLC patients with positive driver gene mutations such as EGFR, anaplastic lymphoma kinase (ALK) fusion and METex14m, there have been relevant cases reported that neoadjuvant targeted therapy could achieve a good prognosis, but there have been no cases of neoadjuvant targeted therapy for locally advanced NSCLC patients with METamp. This report describes a case of a locally advanced NSCLC patient with dual driver gene mutations (EGFR L858R combined with primary METamp), the tumor did not shrink after 1 month of Gefitinib monotherapy, but significantly subsided after 4 months of Savolitinib monotherapy. After radical surgery, the pathological results proved pathological complete response (pCR) of the tumor, and the patient had a good response to postoperative continual Savolitinib treatment, with no recurrence nor metastasis observed to date. This case reports the feasibility and effectiveness of neoadjuvant targeted therapy for locally advanced NSCLC with primary METamp, aiming to provide effective reference for perioperative treatment of locally advanced NSCLC with primary METamp. .

Changes in soluble PD-L1 levels in patients with advanced non-small cell lung cancer

Abstract Soluble programmed death-1 ligand (sPD-L1) in the serum of non-small cell lung cancer (NSCLC) patients is a crucial factor in disease prognosis and an indicator for immunotherapy response. This study aimed to evaluate changes in sPD-L1 levels in advanced NSCLC patients. Between May 2018 and October 2022, 80 patients with advanced-stage NSCLC and 30 healthy volunteers participated in a prospective study. The findings revealed a significant rise in sPD-L1 concentration in the lung cancer group compared to the normal control group (1.08 vs. 0.42, p &lt; 0.001). No apparent correlation was found between sPD-L1 concentration and membrane-bound programmed death-1 ligand (mPD-L1) expression. The optimal diagnostic threshold for sPD-L1 was set at 0.92 ng/mL, showing a sensitivity of 56.25% and specificity of 77.33%, with an area under the curve (AUC) of 0.743 (p = 0.001). Although increased sPD-L1 levels were prevalent in individuals with advanced age, prolonged disease duration, large tumor size, and finger clubbing, these associations did not reach statistical significance (p &gt; 0.05). In conclusion, sPD-L1 levels significantly increased in advanced NSCLC patients compared to controls (p &lt; 0.05), with no association observed with mPD-L1 (p = 0.304). The study suggests that sPD-L1 concentration can be a specific biomarker for guiding the diagnosis of advanced NSCLC, with a recommended cutoff value of 0.92 ng/mL, demonstrating a sensitivity of 56.25% and specificity of 77.33% (p = 0.001). Importantly, no apparent relationship was established between sPD-L1 levels and clinical or paraclinical characteristics in advanced NSCLC patients.