Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer.

BACKGROUND: Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy. METHOD: 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy. RESULTS: After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041). CONCLUSION: Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted. STATEMENT: The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression.

Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations.

Background: For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients. Methods: We reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS). Results: Of the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016). Conclusion: For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

EGFR and ERBB2 Exon 20 Insertion Mutations in Chinese Non-small Cell Lung Cancer Patients: Pathological and Molecular Characterization, and First-Line Systemic Treatment Evaluation.

BACKGROUND: Data from studies looking at both EGFR and ERBB2 exon 20 insertion mutations (-20ins) in the same cohort of patients with non-small cell lung cancer (NSCLC) are limited. OBJECTIVE: The purpose of this study was to analyze EGFR/ERBB2-20ins in all-stage NSCLC patients to reveal their histological and molecular features, and to retrospectively evaluate the results of first-line real-world systemic treatments in patients with advanced-stage disease. PATIENTS AND METHODS: We collected 13,920 formalin-fixed paraffin-embedded NSCLC specimens. Clinicopathological features were recorded and DNA-based next-generation sequencing was performed. First-line systemic treatment data were obtained via chart review. RESULTS: In total, 414 (2.97%) EGFR-20ins cases and 666 (4.78%) ERBB2-20ins cases were identified. Both were more common in women, non-smokers, and patients with adenocarcinoma. The incidence of EGFR/ERBB2-20ins in adenocarcinoma is inversely proportional to the degree of invasion; 77 and 26 variants were detected in EGFR-20ins and ERBB2-20ins cases, respectively. The most common concurrently mutated genes were TP53 and RB1. In invasive adenocarcinoma, lepidic components were more common in EGFR/ERBB2-20ins-alone cases than in those with other concurrent mutated genes. In EGFR-/ERBB2-20ins patients, there was no significant difference in progression-free survival (PFS) or treatment response to first-line systemic treatments in this study. There was no significant difference in PFS or treatment response among patients with different EGFR/ERBB2-20ins variants and those with or without concurrent mutated genes. CONCLUSIONS: EGFR/ERBB2-20ins is more common in early lung adenocarcinoma. EGFR-20ins had more variants. In both cohorts, the results for first-line systemic treatments showed no significant difference.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Single-cell RNA-sequencing uncovers the dynamic changes of tumour immune microenvironment in advanced lung adenocarcinoma.

BACKGROUND: The heterogeneity of lung adenocarcinoma (LUAD) plays a vital role in determining the development of cancer and therapeutic sensitivity and significantly hinders the clinical treatment of LUAD. OBJECTIVE: To elucidate the cellular composition and reveal previously uncharacterised tumour microenvironment in LUAD using single-cell RNA-sequencing (scRNA-seq). METHODS: Two scRNA-seq datasets with 106 829 high-quality cells from 34 patients including 11 normal, 9 early (stage I and II) and 14 advanced (stage III and IV) LUAD were integrated and clustered to explore diagnostic and therapeutic cell populations and their biomarkers for diverse stages of LUAD. Three independent bulk RNA-seq datasets were used to validate the results from scRNA-seq analysis. The expression of marker genes for specific cell types in early and advanced LUAD was verified by immunohistochemistry (IHC). RESULTS: Comprehensive cluster analysis identified that S100P+ epithelial and SPP1+ macrophage, positively related to poor outcomes, were preferentially enriched in advanced stage. Although the accumulation of KLRB1+CD8+ T cell and IGHA1+/IGHG1+ plasma cell both significantly associated the favourable prognosis, we also found KLRB1+CD8+ T cell decreased in advanced stage while IGHA1+/IGHG1+ plasma cells were increased. Cell-cell communication analysis showed that SPP1+ macrophage could interact with most of CD8+ subclusters through SPP1-CD44 axis. Furthermore, based on three independent bulk RNA-seq datasets, we built risk model with nine marker genes for specific cell subtypes and conducted deconvolution analysis, both supporting our results from scRNA-seq data. We finally validated the expression of four marker genes in early and advanced LUAD by IHC. CONCLUSION: Our analyses highlight the molecular dynamics of LUAD epithelial and microenvironment and provide new targets to improve LUAD therapy.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Rationale and design of a multicenter, randomized phase II trial of durvalumab with or without multitarget tyrosine kinase inhibitor as maintenance treatment in extensive-stage small-cell lung cancer patients (DURABLE study).

INTRODUCTION: Durvalumab is a check-point inhibitor against programmed death ligand-1 (PD-L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES-SCLC patients. METHODS: This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum-based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. DISCUSSION: We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES-SCLC patients.

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

Tislelizumab plus chemotherapy for patients with EGFR-mutated non-squamous non-small cell lung cancer who progressed on EGFR tyrosine kinase inhibitor therapy.

BACKGROUND: Treatment options are limited for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after treatment failure with EGFR tyrosine kinase inhibitors (TKIs). This multicenter open-label, phase II study aims to evaluate the efficacy and safety of tislelizumab plus chemotherapy (cohort 1, TIS+chemo) or tislelizumab plus chemotherapy and bevacizumab (cohort 2, TIS+chemo+ beva) in EGFR-mutated non-squamous NSCLC patients who progressed on EGFR TKI therapies. Here, the primary analysis of the TIS+chemo cohort is reported. METHODS: In the TIS+chemo cohort, patients with EGFR-sensitizing mutations with prior EGFR TKI failure received tislelizumab plus carboplatin and nab-paclitaxel as induction treatment, followed by maintenance with tislelizumab plus pemetrexed. The primary endpoint was 1-year progression-free survival (PFS) rate. The planned sample size was 66 with a historical control of 7%, an expected value of 20%, a one-sided α of 0.05, and a power of 85%. RESULTS: Between July 11, 2020 and December 13, 2021, 69 patients were enrolled. As of June 30, 2022, the median follow-up was 8.2 months. Among the 62 patients in the efficacy analysis set, estimated 1-year PFS rate was 23.8% (90% CI 13.1% to 36.2%), and its lower bound of 90% CI was higher than the historical control of chemotherapy (7%), which met the primary endpoint. The median PFS was 7.6 (95% CI 6.4 to 9.8) months. Median overall survival (OS) was not reached (95% CI 14.0 to not estimable), with a 1-year OS rate of 74.5% (95% CI 56.5% to 86.0%). The objective response rate and disease control rate were 56.5% (95% CI 43.3% to 69.0%) and 87.1% (95% CI 76.1% to 94.3%), respectively. Patients who had progressed on first-generation/second-generation and third-generation EGFR-TKIs at baseline had shorter PFS than those who progressed on first-generation/second-generation EGFR-TKIs (median 7.5 vs 9.8 months, p=0.031). Patients with positive ctDNA had shorter PFS (median 7.4 vs 12.3 months, p=0.031) than those with negative ctDNA. No grade 5 treatment-emergent adverse events (TEAEs) were observed. Grades 3-4 TEAEs occurred in 40.6% (28/69) of patients. Grades 3-4 immune-related AEs occurred in 5 (7.2%) patients. CONCLUSION: The study met the primary endpoint for the TIS+chemo cohort. Tislelizumab plus chemotherapy is effective with an acceptable safety profile for EGFR-mutated non-squamous NSCLC after EGFR TKI failure.

A randomized double-blind trial of TQB2450 with or without anlotinib in pretreated driver-negative non-small cell lung cancer.

OBJECTIVE: Immune monotherapy as second-line treatment confers only modest survival benefit on non-small cell lung cancer (NSCLC) patients with no mutated driver genes, necessitating combination treatment strategies. This phase Ib trial investigated the efficacy and safety of anti-PD-L1 antibody TQB2450 plus antiangiogenic drug anlotinib for NSCLC. MATERIALS AND METHODS: Pretreated stage IIIB or IV NSCLC patients with wild-type EGFR/ALK and minimally one measurable lesion were randomized 1:1:1 to receive TQB2450 1200 mg plus placebo, or TQB2450 1200 mg plus anlotinib 10 or 12 mg. The primary outcome was progression-free survival (PFS) and the secondary outcomes included objective response rate (ORR). RESULTS: Thirty-three patients received TQB2450 plus placebo and 34 patients each received TQB2450 plus anlotinib 10 mg and 12 mg. At the data cutoff, the median PFS was 8.7 months (95% CI 6.1-17.1) in the TQB2450 plus anlotinib group and 2.8 months (95% CI 1.4-4.7) in the TQB2450 only group. The ORR reached 30.9% (95% CI 20.2%-43.3%) in the TQB2450 plus anlotinib group and was 3.0% (95% CI 0.1%-15.8%) in the TQB2450 only group. In patients with PD-L1 ≥ 1%, the ORR was 50.0% (95% CI 33.4%-66.6%) for TQB2450 plus anlotinib and 5.3% (95% CI 0.1%-26.0%) for TQB2450 plus placebo. No new safety signals were observed. CONCLUSION: Anlotinib plus TQB2450 demonstrated promising antitumor activities in advanced NSCLC patients without EGFR and ALK alterations and the toxicities were overall manageable. The study findings support the continued development of TQB2450 plus anlotinib for advanced NSCLC patients without driver gene alterations.

PEG2000-PLA-based nanoscale polymeric micelles reduce paclitaxel-related toxicity in beagle dogs.

Nanoplatform-based drug delivery plays an important role in clinical practice. Polymeric micellar (Pm) nanocarriers have been demonstrated to reduce the toxicity of paclitaxel in rats and non-small cell lung cancer (NSCLC) patients. However, the underlying toxicological profile needs to be further illustrated. Here, we used beagles as study subjects and sought to further observe the toxicological profile of polymeric micellar paclitaxel (Pm-Pac) via acute toxicity tests and short-term and long-term toxicity tests. The results from the acute toxicity test indicated that the lethal dose of Pm-Pac in beagles was 20-30 mg/kg, and the acute toxicity-targeted organs were the digestive system and immuno-haematopoietic system. The short-term toxicity test suggested that paclitaxel-induced toxicity (peripheral neuropathy toxicity, haemopoietic toxicity, heart system toxicity, and so on) in beagles can be reduced when paclitaxel is delivered via the Pm delivery system. The long-term toxicity test suggested that Pm-Pac can reduce haemopoietic toxicity in beagles. Collectively, this study provides novel insight into the toxicological profile of Pm-Pac in healthy beagles and provides a potential basis for promising clinical combination strategies in the future.

Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance.

Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.

On-treatment lung immune prognostic index is predictive for first-line PD-1 inhibitor combined with chemotherapy in patients with non-small cell lung cancer.

Background: Inflammation is a factor that promotes tumor progression and immunosuppression. Lung immune prognostic index (LIPI) is a non-invasive and easily calculated indicator of inflammation. This study aimed to investigate whether continuous assessment of LIPI has predictive value for chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients receiving first-line programmed cell death 1 (PD-1) inhibitor plus chemotherapy. In addition, the predictive value of LIPI in patients with the negative or low programmed death-ligand (PD-L1) expression level was also explored. Methods: Totally, 146 stage IIIB to IV or recurrent NSCLC patients who received first-line PD-1 inhibitor combined with chemotherapy were enrolled in this study. The LIPI scores were calculated at baseline (PRE-LIPI) and after two cycles of the combined administration (POST-LIPI). This study analyzed the relationship between good/intermediate/poor PRE (POST)-LIPI and objective response rate (ORR), as well as progression-free survival (PFS) using logistic and Cox regression models. In addition, the predictive value of LIPI in patients with the negative or low PD-L1 expression level was explored. To further assess the potential predictive value of continuous assessment of LIPI, the association of sum (LIPI) [sum(LIPI) = PRE-LIPI + POST-LIPI] and PFS was analyzed in the 146 patients. Results: Compared with good POST-LIPI group, significantly lower ORRs were found in intermediate POST-LIPI (P = 0.005) and poor POST-LIPI (P = 0.018) groups. Moreover, intermediate POST-LIPI (P =0.003) and poor POST-LIPI (P < 0.001) were significantly associated with a shorter PFS than good POST-LIPI. Additionally, a higher POST-LIPI score was still significantly associated with poorer treatment efficacy in patients with the negative or low PD-L1 expression level. Moreover, a higher sum (LIPI) score was significantly correlated with a shorter PFS (P = 0.001). Conclusion: Continuous assessment of LIPI might be an effective method for predicting the efficacy of PD-1 inhibitor plus chemotherapy in NSCLC patients. In addition, in patients with the negative or low PD-L1 expression level, it might also have a potential predictive value for therapeutic efficacy to continuously assess LIPI during the treatment.

[Progress in Detection of EGFR Exon 20 Insertion Mutation and Targeted Therapies 
in Non-small Cell Lung Cancer].

Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) is one of the earliest driver gene activation mutations in non-small cell lung cancer (NSCLC). However, due to the unique structure of protein variation caused by this mutation, most patients with EGFR ex20ins mutation (except A763_Y764insFQEA) have poor response to the launched first/second/third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With the successive approval of new specific targeted drugs for EGFR ex20ins in Food and Drug Administration (FDA) and other national regulatory agencies, the development and clinical research of targeted drugs for EGFR ex20ins in China have also developed rapidly and Mobocertinib has been approved recently in China. It is worth noting that EGFR ex20ins is a variant type with strong molecular heterogeneity. How to detect it comprehensively and accurately in clinical practice, so as to enable more patients to benefit from targeted therapy, is a very important and urgent problem to be solved. This review introduces the molecular typing of EGFR ex20ins, then discusses the importance of EGFR ex20ins detection and the differences of various detection methods, and summarizes the research and development of new drugs progress of EGFR ex20ins, in order to optimize the diagnosis and treatment path of EGFR ex20ins patients by selecting accurate, rapid and appropriate detection methods, so as to improve the clinical benefits of the patients.
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Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage IIIB-IV non-small cell lung cancer.

Objectives: Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. Methods: The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. Results: A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. Conclusion: Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

Paclitaxel Has a Reduced Toxicity Profile in Healthy Rats After Polymeric Micellar Nanoparticle Delivery.

Background: Nanocarrier platforms have been indicated to have great potential in clinical practice to treat non-small cell lung cancer (NSCLC). Our previous Phase III clinical study revealed that polymeric micellar paclitaxel (Pm-Pac) is safe and efficacious in advanced NSCLC patients. However, the histopathological-toxicological profile of Pm-Pac in mammals remains unclear. Methods: We examined the Pm-Pac-induced antitumour effect in both A549/H226 cells and A549/H226-derived xenograft tumour models.. And then, we evaluated the short-term and long-term toxicity induced by Pm-Pac in healthy Sprague‒Dawley (SD) rats. The changes in body weight, survival, peripheral neuropathy, haematology, and histopathology were studied in SD rats administered Pm-Pac at different dosages. Results: In the A549-derived xenograft tumour model, better therapeutic efficacy was observed in the Pm-Pac group than in the solvent-based paclitaxel (Sb-Pac) group when an equal dosage of paclitaxel was administered. Toxicity assessments in healthy SD rats indicated that Pm-Pac caused toxicity at an approximately 2- to 3-fold greater dose than Sb-Pac when examining animal body weight, survival, peripheral neuropathy, haematology, and histopathology. Interestingly, based on histopathological examinations, we found that Pm-Pac could significantly decrease the incidences of paclitaxel-induced brain and liver injury but could potentially increase the prevalence of paclitaxel-induced male genital system toxicity. Conclusion: This study introduces the toxicological profile of the engineered nanoparticle Pm-Pac and provides a novel perspective on the Pm-Pac-induced histopathological-toxicological profile in a rat model.

Effect and outcomes analysis of anlotinib in non-small cell lung cancer patients with liver metastasis: results from the ALTER 0303 phase 3 randomized clinical trial.

PURPOSE: Liver metastasis (LM) is common in non-small cell lung cancer (NSCLC), and always predicted worse outcomes with no effective therapy. We aimed to evaluate the effects and prognosis in LM patients treated with anlotinib. METHODS: The present study is a post hoc analysis based on a multicenter, double-blind, phase 3 randomized clinical trial which designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. A total of 437 patients were enrolled in present study, and 78 patients with LM. RESULTS: Patients with LM showed a worse outcome compared to those without LM (PFS median, 2.6 vs 4.2 months), and OS (median, 5.6 vs 9.4 months, both P < 0.0001). The anlotinib was associated with longer PFS (median, 3.0 months) compared with placebo (median, 0.9 months), with a hazard ratio (HR) of 0.23 (95%CI, 0.12-0.42; P < 0.0001). Furthermore, OS was marginally significantly better in anlotinib group (median 6.6 months), compared with placebo (median 4.0 months), HR 0.61 (95%CI, 0.36-1.02; P = 0.055). Multivariate analysis confirmed normal peripheral blood LDH/TBiL level predicted better PFS and OS, lower ECOG score acted as independently prognostic factor for superior OS. Anlotinib was more associated with hand-foot syndrome (7.7% vs 0) and serum TSH level rise (7.7% vs 3.8%) and well tolerated, all AEs were no more than grade 3. CONCLUSION: Patients with LM had a dismal prognosis, anlotinib could lead to a better PFS in pretreated NSCLC patients, which suggested anlotinib is a potential third-line or further therapy in these patients.

Special issue "The advance of solid tumor research in China": Real-world clinical outcomes of alectinib for advanced nonsmall-cell lung cancer patients with ALK fusion in China.

Global phase 3 trials have demonstrated the priority of several next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). However, clinical studies are conducted with specific populations that differ from the real world. The study aimed to evaluate the clinical outcomes of alectinib in real-world settings. Patients with advanced nonsmall-cell lung cancer (NSCLC) and EML4-ALK fusion were enrolled from two medical centers between June 2018 and June 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) to alectinib. The secondary endpoint was response of brain metastases. The risk factors for disease progression were also investigated. In total, 127 patients with advanced NSCLC were enrolled into this study. Of them, 54.3% received first-line alectinib. The 1- and 2-year PFS rates were 77.4% and 68.3%, respectively. ORR and disease control rate (DCR) were 53.5% and 91.3%, respectively. Among patients with brain metastases, intracranial ORR and DCR were 63.6% and 88.6%, respectively. In addition, we found that "crizotinib pretreatment", "liver metastasis" and "TP53 co-mutation" were individually associated with shorter PFS in alectinib treatment. In conclusion, this study confirms the salient clinical outcomes of alectinib for ALK-fusion-driven NSCLC patients with or without brain metastases, adding real-world evidence to the priority of alectinib in clinical practice.

Efficacy of alectinib in lung adenocarcinoma patients with different anaplastic lymphoma kinase (ALK) rearrangements and co-existing alterations-a retrospective cohort study.

Background: Alectinib significantly improves survival of non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-rearrangement. In this study, we analyzed the effects of different ALK rearrangements and co-mutations on the efficacy of alectinib. Methods: Using the electronic medical record system, we reviewed in terms of clinical and pathological features patients with advanced (IIIB/IV stage) ALK-rearranged NSCLC at Shanghai Chest Hospital between January 2018 and December 2021 who were treated with alectinib in first or second line and were assessed for objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 66 patients were enrolled in the study, and 17 types of ALK rearrangements were detected, of which five types of ALK rearrangements responded well to alectinib. We classified ALK-rearrangements into four main types, namely echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others. There was no significant difference in ORR and DCR of these types (ORR: 31.3% vs. 13.0% vs. 18.2% vs. 17.6%, P=0.575; DCR: 93.8% vs. 95.6% vs. 100.0% vs. 88.2%, P=0.627). The 3-year PFS rates were 25.0% (4/16) vs. 13.0% (3/23) vs. 27.3% (3/11) vs. 18.8% (3/16) for EML4-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others, respectively (P=0.725). The results of co-mutation analysis showed that the median PFS (mPFS) for patients with tumors harboring TP53 mutations was 30.4 months, significantly shorter than that of patients with tumors without co-mutations and whose mPFS was not mature (P=0.026). TSC1 co-mutation was also identified as a detrimental factor in outcome, with a DCR of 60% vs. 100% (P=0.031), mPFS of 30.4 months vs. not applicable (P=0.160) in patients with vs. those without this co-mutation, respectively. The efficacy of alectinib in patients with brain metastases is comparable to that in patients without distant organ metastases. There were two cases with specific fusion types that also responded to alectinib; namely, double ALK-rearrangements: EML4-ALK (E13:A20) and MSH2-ALK (M7:A20), and with a rare fusion partner, SPECC1L-ALK (S8:A20). Their PFS were 8.7 and 38.0 months, respectively. Conclusions: In this study, the efficacy of alectinib in different types of ALK-rearrangements varied slightly. TP53 and TSC1 co-mutations were identified as detrimental factors affecting efficacy. This study provides references for the response to alectinib in patients with different types of ALK rearrangements and co-mutation.