A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer.

BACKGROUND: Cadonilimab is a bispecific antibody that simultaneously targets programmed cell death receptor-1 and cytotoxic T lymphocyte-associated antigen-4. This study aimed to assess the safety and efficacy of cadonilimab plus anlotinib for the first-line treatment of advanced non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK/ROS1 mutations. METHODS: Patients received cadonilimab 15 mg/kg and 10 mg/kg every three weeks (Q3W) plus anlotinib at doses of 10 or 12 mg once daily for two weeks on a one-week-off schedule. The primary endpoints included safety and objective response rate (ORR). RESULTS: Sixty-nine treatment-naïve patients received cadonilimab 15 mg/kg Q3W combination (n = 49) and 10 mg/kg Q3W combination (n = 20). Treatment-related adverse events (TRAEs) were reported in 48 (98.0%) and 19 (95.0%) patients, with grade ≥3 TRAEs occurring in 29 (59.2%) and five (25.0%) patients, respectively. TRAEs leading to cadonilimab discontinuation occurred in eight (16.3%) and one (5.0%) patients in the cadonilimab 15 mg/kg Q3W and 10 mg/kg Q3W dosing groups. The confirmed ORRs were 51.0% (25/49) and 60.0% (12/20) accordingly. CONCLUSIONS: Cadonilimab 10 mg/kg Q3W plus anlotinib showed manageable safety and promising efficacy as a first-line chemo-free treatment for advanced NSCLC. GOV IDENTIFIER: NCT04646330.

Efficacy and safety of dacomitinib in treatment-naïve patients with advanced NSCLC harboring uncommon EGFR mutation: an ambispective cohort study.

BACKGROUND: About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC. METHODS: Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. RESULT: Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs. CONCLUSIONS: Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.

Treatment outcomes and prognosis of patients with primary and acquired BRAF-mutated non-small cell lung cancer: A multicenter retrospective study.

The incidence of primary and acquired BRAF mutations is low in non-small cell lung cancer (NSCLC), with limited demographic and treatment outcome data available for this patient population. We evaluated lung cancer samples with programmed cell death ligand 1 (PD-L1) information extracted from 12 051 cases (cohort A) of lung cancer from OncoPanscan™-based sequencing of tissue (Genetron Health) and conducted retrospective multicenter data analysis using the database of Zhejiang Cancer Hospital and four other centers (cohort B, including 73 primary BRAF mutation and 14 acquired BRAF mutation cases) to compare treatment outcomes of patient groups with primary and acquired BRAF mutations. In cohort A, after propensity score analysis, 165 samples of NSCLC with BRAF mutations were screened along with 165 paired non-BRAF mutation samples. We observed no significant differences in the proportion of samples with ≥1% PD-L1 between BRAF and non-BRAF mutant groups. The median progression-free survival (mPFS) period in 13 patients with primary BRAF mutations receiving BRAF tyrosine kinase inhibitors (BRAF-TKIs) was 7.0 months. The group with primary BRAF mutations receiving immune checkpoint inhibitor (ICI) combination chemotherapy had better PFS than those administered ICI monotherapy (14.77 months vs. 5.0 months, p = 0.025) and similar results were obtained for OS (unreached vs. 20.3 months, p = 0.013). For acquired BRAF mutations, mPFS of BRAF-TKI, ICI-based, and chemotherapy-based regimens were 3.8, 1.5, and 1.9 months, respectively. Therefore, for patients with the primary BRAF V600E mutation, targeted therapy or immunochemotherapy could serve as effective treatment choices, while for those with acquired BRAF V600E, targeted drug therapy may remain the preferred solution in China.

Utility of cell-free DNA from bronchial washing fluid in diagnosis and genomic determination for radiology-suspected pulmonary nodules.

BACKGROUND: Bronchial washing fluid (BWF) is a less-invasive specimen. Due to the limited sensitivity of BWF cellular component diagnosis, the aim of this study was to explore the potential role of BWF supernatant as a source of liquid biopsy of lung cancer. METHODS: This prospective study enrolled 76 suspected and 5 progressed lung cancer patients. Transbronchial biopsy tissues, BWF supernatant (BWF_Sup) and BWF precipitant (BWF_Pre) were tested by a targeted panel of 1021 genes. RESULTS: BWF_Sup cell-free DNA (cfDNA) was superior to tissue biopsy and BWF_Pre in determining mutational allele frequency, tumour mutational burden, and chromosomal instability. Moreover, BWF_Sup and BWF_Pre achieved comparable efficacy to tissue samples in differentiating malignant and benign patients, but only BWF_Sup persisted differentiated performance after excluding 55 malignancies pathologically diagnosed by bronchoscopic biopsy. Among 67 malignant patients, 82.1% and 71.6% of tumour-derived mutations (TDMs) were detected in BWF_Sup and BWF_Pre, respectively, and the detectability of TDMs in BWF_Sup was independent of the cytological examination of BWF. BWF_Sup outperformed BWF_Pre in providing more subclonal information and thus might yield advantage in tracking drug-resistant markers. CONCLUSIONS: BWF_Sup cfDNA is a reliable medium for lung cancer diagnosis and genomic profiles and may provide important information for subsequent therapeutic regimens.

Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901).

BACKGROUND: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers. METHODS: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis. RESULTS: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC. CONCLUSION: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.

The prognostic impact of mild and severe immune-related adverse events in non-small cell lung cancer treated with immune checkpoint inhibitors: a multicenter retrospective study.

Patients treated with immune checkpoint inhibitors (ICIs) often experience unique immune-related adverse events (irAEs), and the previous studies demonstrated an association between irAEs and better outcomes in patients with ICI treatment for advanced non-small cell lung cancer (NSCLC). However, the correlation between the occurrence of mild and severe irAEs and prognosis remains unclear. Additionally, little is known regarding the association between the timing of mild and severe irAEs and clinical outcomes. We retrospectively conducted a multicenter study of advanced NSCLC patients treated with ICI monotherapy. Of the 222 patients, 79 patients (35.6%) experienced at least one irAE, and most were of grade 1 or 2 (mild) (26.6%). The most common irAEs were pneumonitis (n = 21, 9.5%) and skin-related adverse reactions (n = 19, 8.6%). The median progression-free survival of all patients treated with ICIs was 3.2 months. Patients experiencing irAEs had a better prognosis than those without such events (6.5 vs. 2.6 months, p = 0.004), and mild irAEs were associated with the best prognosis. The difference in overall survival between mild and severe irAEs was significant (34.3 vs. 17.3 months, p = 0.021). We further analyzed differences between patients with irAEs occurring at 3 or 6 weeks, and found that the earlier the occurrence of mild irAEs, the better the prognosis; however, the opposite was true for severe irAEs. In summary, patients with early occurring mild irAEs showed better clinical outcomes, whereas those with early severe irAEs tended to show poorer clinical outcomes.

The prognostic impact of immune checkpoint inhibitors for the treatment of pulmonary sarcomatoid carcinoma: A multicenter retrospective study.

Pulmonary sarcomatoid carcinoma (PSC) is an aggressive and poorly differentiated type of non-small cell lung carcinoma. Because of the rarity of PSC, the efficacy and toxicity of immunotherapy remain unclear. Hence, the aim of this study was to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) for the treatment of advanced PSC. The study cohort was limited to 33 patients with pathologically confirmed PSC treated with ICIs in four hospitals in China from March 2018 to March 2022. Expression of programmed death ligand 1 (PD-L1) was detected by immunohistochemical analysis. Categorical variables were compared with the Fisher exact test and survival analysis was conducted with the Kaplan-Meier method. Of the 33 PSC patients, 8 (24.2%) received monotherapy with ICIs and 25 (75.8%) received combination therapy with ICIs. The objective response rate (ORR) and disease control rate (DCR) were 36.4% and 78.8%, respectively. The median durations of progression-free survival (PFS) and overall survival (OS) were 6.07 and 21.33 months, respectively. PD-L1 status in 16 available samples was assessed, which included 30.3% PD-L1-positive patients. The ORRs for PD-L1-positive vs. -negative patients were 50.0% and 90.0%, the DCR was 33.3% and 83.3%, and the median PFS was 17.50 and 6.07 months, respectively (p=0.812). The median OS was not reached in PD-L1-positive and -negative patients (p=0.655). The incidence of immune-related adverse (irAEs) was 48.5% and mainly included grade 1 or 2 (39.4%), while the incidence of grade 3 or 4 was 9.1%. Pneumonia (9.1%) and skin rash (9.1%) were the most frequent irAEs. Immunotherapy with ICIs was a promising regimen to improve the prognosis of patients with advanced PSC.

Clinical features and treatment outcome of lymphoepithelioma-like carcinoma from multiple primary sites: a population-based, multicentre, real-world study.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is a rare and unique subtype of cancer that histologically resembles undifferentiated nasopharyngeal carcinoma (NPC). The population-based analysis of LELC and the optimal treatment remains unclear. MATERIALS AND METHODS: This real-world, retrospective study investigated 770 patients with LELC for primary site, treatment, and survival outcomes from 2005 to 2019 from five cancer centres in China. The overall survival (OS) of different subgroups was appraised by log-rank tests and Kaplan-Meier analysis. RESULTS: Primary sites LELC included the lung (597 cases, 77.5%), salivary gland (115 cases, 14.9%), and others. The median progression-free survival (PFS) of LELC patients was 47.4 months. The median overall survival (OS) was not reached. The 5-year survival rate for LELC patients was 77.8%. Most patients in stages I and II received surgery. The majority of patients in stage III received surgery and radiotherapy. More than half of the patients in stage IV received chemotherapy. Among relapsed or metastatic cases receiving chemotherapy, patients who received immunotherapy at any time presented with a superior OS than those without immunotherapy (P < 0.0001, HR = 0.39, 95% CI 0.25-0.63). Compared with the SEER database, patients with LELC had a better prognosis than NPC, with a 5-year overall survival of 77.3% vs. 56.8% (P < 0.001). CONCLUSION: Our data provide treatment patterns and outcomes for LELC from various primary sites. Randomized controlled studies are necessary to further define the standard of care for patients with LELC. Trial registration This clinical trial was registered at ClinicalTrials.gov (No. NCT04614818).

Variants with a low allele frequency detected in genomic DNA affect the accuracy of mutation detection in cell-free DNA by next-generation sequencing.

BACKGROUND: Next-generation sequencing of cell-free DNA (cfDNA) has been shown to be a useful noninvasive test for detecting mutations in solid tumors. METHODS: Targeted gene sequencing was performed with a panel of 263 cancer-related genes for cfDNA and genomic DNA of peripheral blood mononuclear cells (PBMCs) obtained from presurgical specimens of 6 lung cancer patients, and mutation calls in these samples were compared with those of primary tumors and corresponding patient-derived xenografts (PDXs). RESULTS: Approximately 67% of the mutations detected in the tumor samples (primary tumors and/or PDXs) were also detected in genomic DNA from PBMCs as background mutations. These background mutations consisted of germline polymorphisms and a group of mutations with low allele frequencies, mostly <10%. These variants with a low allele frequency were repeatedly detected in all types of samples from the same patients and at similarly low allele frequency levels in PBMCs from different patients; this indicated that their detection might be derived from common causes, such as homologous sequences in the human genome. Allele frequencies of mutations detected in both primary tumors and cfDNA showed 2 patterns: 1) low allele frequencies (approximately 1%-10%) in cfDNA but high allele frequencies (usually >10% or >3-fold increase) in primary tumors and further enrichment in PDXs and 2) similar allele frequencies across samples. CONCLUSIONS: Because only a small fraction of total cfDNA might be derived from tumor cells, only mutations with the first allele frequency pattern may be regarded as tumor-specific mutations in cfDNA. Effective filtering of background mutations will be required to improve the accuracy of mutation calls in cfDNA. Cancer 2018;124:1061-9. © 2017 American Cancer Society.

Patient-derived tumor immune microenvironments in patient-derived xenografts of lung cancer.

BACKGROUND: Because patient-derived xenografts (PDXs) are grown in immunodeficient mouse strains, PDXs are regarded as lacking an immune microenvironment. However, whether patients' immune cells co-exist in PDXs remains uncharacterized. METHODS: We cultured small pieces of lung PDX tissue in media containing human interleukin-2 and characterized the proliferated lymphocytes by flow cytometric assays with antibodies specific for human immune cell surface markers. Presence of immune cells in PDXs was also determined by immunohistochemical staining. RESULTS: Human tumor-infiltrating lymphocytes (TILs) were cultured from nine of 25 PDX samples (36%). The mean time of PDX growth in immunodeficient mice before obtaining TILs in culture was 113 days (range 63-292 days). The TILs detected in PDXs were predominantly human CD8+ T cells, CD4+ T cells, or CD19+ B cells, depending on cases. DNA fingerprint analysis showed that the TILs originated from the same patients as the PDXs. Further analysis of two PDX-derived CD8+ T cells showed that they were PD-1-, CD45RO+, and either CD62L+ or CD62L-, suggesting they were likely memory T cells. Immunohistochemical staining showed that human T cells (CD8+ or CD4+), B cells (CD19+), and macrophages (CD68+) were present in stroma or intraepithelial cancer structures and that human PD-L1 was expressed in stromal cells. Moreover, the patient-derived immune cells in PDX can be passaged to the F2 generation and may migrate to spleens of PDX-bearing mice. CONCLUSIONS: Patient-derived immune cells co-exist in early passages of PDXs in some lung cancer PDX models. The CD8+ cells from PDXs were likely memory T cells. These results suggest that PDXs can be used for evaluating the functionality of immune components in tumor microenvironments.

Immunotherapy for non-small cell lung cancers: biomarkers for predicting responses and strategies to overcome resistance.

Recent breakthroughs in targeted therapy and immunotherapy have revolutionized the treatment of lung cancer, the leading cause of cancer-related deaths in the United States and worldwide. Here we provide an overview of recent progress in immune checkpoint blockade therapy for treatment of non-small cell lung cancer (NSCLC), and discuss biomarkers associated with the treatment responses, mechanisms underlying resistance and strategies to overcome resistance. The success of immune checkpoint blockade therapies is driven by immunogenicity of tumor cells, which is associated with mutation burden and neoantigen burden in cancers. Lymphocyte infiltration in cancer tissues and interferon-γ-induced PD-L1 expression in tumor microenvironments may serve as surrogate biomarkers for adaptive immune resistance and likelihood of responses to immune checkpoint blockade therapy. In contrast, weak immunogenicity of, and/or impaired antigen presentation in, tumor cells are primary causes of resistance to these therapies. Thus, approaches that increase immunogenicity of cancer cells and/or enhance immune cell recruitment to cancer sites will likely overcome resistance to immunotherapy.

Association of miR-146a gene polymorphism with risk of nasopharyngeal carcinoma in the central-southern Chinese population.

This case-control study focused on estimating the association between miR-146a polymorphism and risk of nasopharyngeal carcinoma (NPC) in central-south China. In total, 160 patients with NPC and 200 healthy controls in central-south China were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Chi-square test was used to assess the different distribution of miR-146a polymorphism between NPC patients and controls; and logistic regression analysis was applied to analyze the associations between miR-146a polymorphism with cancer risk in different contrast models. Significant differences between NPC patients and controls were found in genotype (P=0.033 for GG versus CG versus CC; and odds ratio (OR)=0.568, 95% confidence interval (CI)=0.354-0.912, P=0.019 for CG versus CC; and OR=0.503, 95% CI=0.261-0.971, P=0.041 for CG versus CC; and OR=0.564, 95% CI=0.360-0.884, P=0.012 for GG+CG versus CC, respectively) and allelic analysis (P=0.025 for G versus C). Our findings suggested that polymorphism of mir-146a was associated with NPC in the central-southern Chinese population.

The microRNA-34 Family and Its Functional Role in Lung Cancer.

Lung cancer is one of the most common malignant tumors in humans and the leading cause of cancer-related deaths worldwide. The microRNA-34 (miR-34) family is dysregulated in various human cancers and is an important family of tumor suppressor genes among microRNAs. The miR-34 family is downregulated in lung cancer. It inhibits cell proliferation, metastasis, and invasion, arrests the cell cycle, and induces apoptosis or senescence by negatively regulating many oncogenes. It is commonly used to detect and treat lung cancer. This study describes the regulatory role of the miR-34 family in lung cancer and the associated research advances in treatment.

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study.

Background: Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. Methods: In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200 mg intravenously, day one), apatinib (250 mg, q.d., five continuous days per week), and nab-paclitaxel (135 mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Findings: Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle 14. Interpretation: Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Funding: Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

Anlotinib plus docetaxel vs. docetaxel alone for advanced non-small-cell lung cancer patients who failed first-line treatment: A multicenter, randomized phase II trial.

OBJECTIVES: Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC. MATERIALS AND METHODS: In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints. RESULTS: A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups. CONCLUSION: Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Association between PIN1 promoter polymorphisms and risk of nasopharyngeal carcinoma.

Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1) plays an important role in cell transformation and oncogenesis. Association between PIN1 promoter polymorphisms and cancer risk was reported in several cancers. This study aimed to evaluate the association between two single nucleotide polymorphisms (SNPs, -667T>C, rs2233679 and -842G>C, rs2233678) on PIN1 promoter and risk of nasopharyngeal carcinoma (NPC). The two SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism in a total of 334 native Chinese subjects consisting of 178 cases and 156 controls. The results indicated that the -667CT heterozygote and -667CC homozygote exhibited a significantly decreased risk of nasopharyngeal carcinoma when compared with -667TT homozygote (OR = 0.639, 95% CI = 0.452-0.903, p = 0.011 for -667CT; and OR = 0.441, 95% CI = 0.213-0.915, p = 0.038 for -667CC, respectively). In the -842G>C polymorphism, compared with -842GG homozygote, only -842CG heterozygote but not -842CC homozygote had a significantly decreased risk of nasopharyngeal carcinoma (OR = 0.465, 95% CI = 0.249-0.871, p = 0.010). Genotype in the two SNPs in patients showed no significant associations with the clinicopathologic features examined. Our study showed that the minor genotypes of PIN1 promoter (-667CT, -667CC and -842CG) were associated with decreased risk of NPC in a Chinese population, suggested that PIN1 promoter polymorphisms might play an important role in NPC carcinogenesis.

A real-world comparison between neoadjuvant chemoimmunotherapy and chemotherapy alone for resectable non-small cell lung cancer.

BACKGROUND: The impact of neoadjuvant chemoimmunotherapy on pulmonary resection and related outcomes had been poorly reported in previous studies. The present study aims to clarify the efficacy and safety of neoadjuvant chemoimmunotherapy, and intraoperative difficulty in the following surgery, in comparison with chemotherapy alone in non-small cell lung cancer (NSCLC). METHODS: Patients with newly diagnosed clinical stages IB-IIIB(T3-4N2) NSCLC, received neoadjuvant chemotherapy + PD-1 inhibitors (PD-1 + Chemo group) or chemotherapy alone (Chemo group) followed by surgery between December 2018 and December 2020 were included. The clinicopathological characteristics were retrospectively reviewed and analyzed. RESULTS: There were 69 NSCLC patients in the PD-1 + Chemo group and 121 in the Chemo group. The major pathological response (MPR) rate in the PD-1 + Chemo group was 49.3%, higher than that of 19.0% in the Chemo group (p < 0.001). The 2-year disease-free survival (DFS) rate was 79.3% and 60.2%, respectively, in the two groups (p = 0.048). Multivariate analysis identified surgical radicality (hazard ratio (HR), 2.954, 95% confidence interval (CI), 1.527-5.714, p = 0.001), and pathological response (MPR(CR) vs. SD(PD), HR, 0.248, 95% CI, 0.107-0.572, p = 0.001) to be independent prognostic factors for DFS. Lobectomy was performed in 73.9% and 66.1% of patients, respectively, and bronchial sleeve resection/bronchoplasty rate was also comparable (43.4% vs. 40.5%, p = 0.688). More patients in the PD-1 + Chemo group received vascular sleeve resection/angioplasty (15.9% vs. 6.6%, p = 0.039) and pericardial resection (10.1% vs. 2.5%, p = 0.038). After propensity score matching analysis, pericardial resection rate was still slightly higher in the PD-1 + Chemo group (9.4% vs. 1.6%, p = 0.05). Perioperative morbidities within 30 days and mortality in 90 days were comparable between groups (p > 0.05). CONCLUSIONS: Neoadjuvant chemoimmunotherapy for NSCLC is safe and feasible, with higher MPR rates, as well as favorable DFS than chemotherapy alone. Surgical complexity might be increased in certain patients, with comparable perioperative morbidity and mortality.

Neoadjuvant Immunotherapy and Non-Small Cell Lung Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVES: To systematically evaluate the effectiveness and safety of neoadjuvant immunotherapy for patients with non-small cell lung cancer (NSCLC). METHODS: Randomized controlled trials of neoadjuvant immunotherapy in treating patients with NSCLC were comprehensively retrieved from electronic databases, eligible studies, previous systematic reviews and meta-analyses, guidelines, and conference abstracts. The meta-analysis was performed by the Stata/SE 12.0 software. RESULTS: Eleven randomized controlled trials were eventually included. The results of the meta-analysis showed that neoadjuvant immunochemotherapy significantly improved the objective response rate compared with neoadjuvant chemotherapy (CT; 62.46% vs 41.88%, P = 0.003), but the objective response rate of neoadjuvant double-immunotherapy was roughly comparable to that of neoadjuvant single-immunotherapy (15.74% vs 10.45%, P = 0.387). Major pathologic response (MPR) rate and pathologic complete response (pCR) rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT alone and neoadjuvant single-immunotherapy, respectively. Compared with neoadjuvant CT alone, neoadjuvant immunochemotherapy increased the down-staging rate (40.16% vs 26.70%, P = 0.060), the surgical resection rate (83.69% vs 73.07%, P = 0.231), and R0 resection rate (86.19% vs 77.98%, P = 0.502), but there were no statistically significant differences. Neoadjuvant immunochemotherapy did not increase the postoperative complications rate than neoadjuvant CT alone (40.20% vs 41.30%, P = 0.920). In terms of safety, neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy did not increase the incidence of treatment-related adverse events (TRAEs) and the grade 3 or higher TRAEs. CONCLUSIONS: In summary, neoadjuvant immunochemotherapy had better clinical efficacy than neoadjuvant CT for patients with NSCLC. MPR rate and pCR rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT and neoadjuvant single-immunotherapy, respectively, for patients with NSCLC, showing that MPR rate and pCR rate were probably considered as alternative endpoints for survival benefit. TRAEs were comparable between the corresponding groups. The long-term survival outcome of neoadjuvant immunotherapy for patients with NSCLC needs to be further confirmed to better guide clinical practice.