SETD2 variation correlates with tumor mutational burden and MSI along with improved response to immunotherapy.

BACKGROUND: SETD2 protects against genomic instability via maintenance of homologous recombination repair (HRR) and mismatch repair (MMR) in neoplastic cells. However, it remains unclear whether SETD2 dysfunction is a complementary or independent factor to microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) for immunocheckpoint inhibitor (ICI) treatment, and little is known regarding whether this type of dysfunction acts differently in various types of cancer. METHODS: This cohort study used multidimensional genomic data of 6726 sequencing samples from our cooperative and non-public GenePlus institute from April 1 through April 10, 2020. MSIsensor score, HRD score, RNAseq, mutational data, and corresponding clinical data were obtained from the TCGA and MSKCC cohort for seven solid tumor types. RESULTS: A total of 1021 genes underwent target panel sequencing reveal that SETD2 mutations were associated with a higher TMB. SETD2 deleterious mutation dysfunction affected ICI treatment prognosis independently of TMB-H (p < 0.01) and had a lower death hazard than TMB-H in pancancer patients (0.511 vs 0.757). Significantly higher MSI and lower homologous recombination deficiency were observed in the SETD2 deleterious mutation group. Improved survival rate was found in the MSKCC-IO cohort (P < 0.0001) and was further confirmed in our Chinese cohort. CONCLUSION: We found that SETD2 dysfunction affects ICI treatment prognosis independently of TMB-H and has a lower death hazard than TMB-H in pancancer patients. Therefore, SETD2 has the potential to serve as a candidate biomarker for ICI treatment. Additionally, SETD2 should be considered when dMMR is detected by immunohistochemistry.

Pyrotinib combined with thalidomide in advanced non-small-cell lung cancer patients harboring HER2 exon 20 insertions (PRIDE): protocol of an open-label, single-arm phase II trial.

BACKGROUND: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. METHODS: This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. DISCUSSION: The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020.

Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

BACKGROUND: Thirty to 40 % of non-small cell lung cancer (NSCLC) patients developed higher hypertriglyceridemia in the process of treatment with bexarotene. And bioinformatics studies discovered that the expression of slc10a2 was increased in high-grade hypertriglyceridemia patients. So, we will explore the mechanism which may involve in this process. METHODS: We constructed slc10a2 overexpressed A549 cells and H1299 cells as cell models, normal A549 cells and H1299 cells as control. Then we explored the effects of slc10a2 on A549 cells and H1299 cells behaviors, including proliferation, invasion and apoptosis. The expression of apoptotic related genes and anti-cancer genes also been detected. RESULTS: We found that the proliferation and migration were inhibited and the apoptosis of NSCLC cells was accelerated by bexarotene. In addition, overexpressed slc10a2 in NSCLC cells can further suppress the proliferation and migration, and promote apoptosis under the treatment of bexarotene. On the contrary, the opposite results were obtained after slc10a2 gene was silenced in NSCLC cells treated with bexarotene. Moreover, the expression of caspase 3, caspase 7, PTEN, P21, P53, LKB1, TSC2 were increased and the expression of Bcl-2, cyclin D1, c-FLIP were declined in NSCLC cells and slc10a2 overexpressed NSCLC cells with the treatment of bexarotene, and the opposite situations were seen after slc10a2 gene was silenced in NSCLC cells. The further studies revealed the increased expression of slc10a2 activated the expression of peroxisome proliferator-activated receptor γ (PPARγ), then up-regulated PTEN expression and down-regulated mTOR expression. CONCLUSION: These results suggest that bexarotene inhibits the viability of lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

A systematic profile of clinical inhibitors responsive to EGFR somatic amino acid mutations in lung cancer: implication for the molecular mechanism of drug resistance and sensitivity.

Human epidermal growth factor receptor (EGFR) has become a well-established target for the treatment of patients with non-small cell lung cancer (NSCLC). However, a large number of somatic mutations in such protein have been observed to cause drug resistance or sensitivity during pathological progression, limiting the application of reversible EGFR tyrosine kinase inhibitor therapy in NSCLC. In the current work, we describe an integration of in silico analysis and in vitro assay to profile six representative EGFR inhibitors against a panel of 71 observed somatic mutations in EGFR tyrosine kinase domain. In the procedure, the changes in interaction free energy of inhibitors with EGFR upon various mutations were calculated one by one using a rigorous computational scheme, which was preoptimized based on a set of structure-solved, affinity-known samples to improve its performance in characterizing the EGFR-inhibitor system. This method was later demonstrated to be effective in inferring drug response to the classical L858R and G719S mutations that confer constitutive activation for the EGFR kinase. It is found that the Staurosporine, a natural product isolated from the bacterium Streptomyces staurosporeus, exhibits selective inhibitory activity on the T790M and T790M/L858R mutants. This finding was subsequently solidified by in vitro kinase assay experiment; the inhibitory IC50 values of Staurosporine against wild-type, T790M and T790M/L858R mutant EGFR were measured to be 937, 12 and 3 nM, respectively.

ETV6::NTRK3 gene fusion in a patient with metastatic lung atypical carcinoid successfully treated with repotrectinib: A case report.

INTRODUCTION: Chromosomal rearrangements involving the neurotrophin kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 with different fusion partners occur in non-small cell lung cancers (NSCLCs) and other solid tumors. Novel NTRK rearrangement-related tumors are still being discovered. METHODS: Herin, we describe a male patient with a mass in the left upper lobe that was biopsied by bronchoscopy. This case was diagnosed with stage Ⅳ lung atypical carcinoid (AC) harboring the ETV6::NTRK3 gene fusion. RESULTS: He received 1st line treatment with everolimus lasting for 4 months. After chemotherapy failure, he received 3rd treatment with VC004 in a phase 1/2 study and achieved stable disease, but he stopped taking it due to intolerance. He subsequently received repotrectinib treatment and achieved a partial response of more than ten months. CONCLUSIONS: To the best of our knowledge, we reported the first case demonstrating anti-tumor activity of repotrectinib in a patient with AC carring an ETV6-NTRK3 gene fusion, indicating that repotrectinib may be an efficient therapeutic option for tumors with NTRK gene rearrangements.

SAFE-MIL: a statistically interpretable framework for screening potential targeted therapy patients based on risk estimation.

Patients with the target gene mutation frequently derive significant clinical benefits from target therapy. However, differences in the abundance level of mutations among patients resulted in varying survival benefits, even among patients with the same target gene mutations. Currently, there is a lack of rational and interpretable models to assess the risk of treatment failure. In this study, we investigated the underlying coupled factors contributing to variations in medication sensitivity and established a statistically interpretable framework, named SAFE-MIL, for risk estimation. We first constructed an effectiveness label for each patient from the perspective of exploring the optimal grouping of patients' positive judgment values and sampled patients into 600 and 1,000 groups, respectively, based on multi-instance learning (MIL). A novel and interpretable loss function was further designed based on the Hosmer-Lemeshow test for this framework. By integrating multi-instance learning with the Hosmer-Lemeshow test, SAFE-MIL is capable of accurately estimating the risk of drug treatment failure across diverse patient cohorts and providing the optimal threshold for assessing the risk stratification simultaneously. We conducted a comprehensive case study involving 457 non-small cell lung cancer patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors. Results demonstrate that SAFE-MIL outperforms traditional regression methods with higher accuracy and can accurately assess patients' risk stratification. This underscores its ability to accurately capture inter-patient variability in risk while providing statistical interpretability. SAFE-MIL is able to effectively guide clinical decision-making regarding the use of drugs in targeted therapy and provides an interpretable computational framework for other patient stratification problems. The SAFE-MIL framework has proven its effectiveness in capturing inter-patient variability in risk and providing statistical interpretability. It outperforms traditional regression methods and can effectively guide clinical decision-making in the use of drugs for targeted therapy. SAFE-MIL offers a valuable interpretable computational framework that can be applied to other patient stratification problems, enhancing the precision of risk assessment in personalized medicine. The source code for SAFE-MIL is available for further exploration and application at https://github.com/Nevermore233/SAFE-MIL.

Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial.

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%-49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%-45.4%). The median PFS and OS were 5.9 (95% CI 2.5-9.3) and 18.4 (95% CI 9.7-27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4-5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient's blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Cisplatin-induced Pyroptosis Enhances the Efficacy of PD-L1 Inhibitor in Small-Cell Lung Cancer via GSDME/IL12/CD4Tem Axis.

The combination therapy of platinum-based chemotherapy and PD-L1 inhibitors but not the single anti-PD-L1 therapy has significantly improved the prognosis of patients with small-cell lung cancer (SCLC). However, the synergistic mechanism of combination therapy has not been fully elucidated. In this work, we identified a positive correlation between the expression of pyroptosis-related proteins Gasdermin E (GSDME) and the survival rates of patients with SCLC. Importantly, it was shown that human SCLC cell lines with high expression of GSDME showed more sensitivity to cisplatin, as well as cisplatin plus anti-PD-L1 treatment both in vitro and in vivo. Mechanically, cisplatin induced the activation of GSDME and the release of cytokines including IL-12, which enhance the expression of IFN-γ in T cells in the tumor immune microenvironment (TME) and subsequently improve anti-PD-L1 response. Altogether, our work demonstrates that cisplatin could induce GSDME-dependent cell pyroptosis to improve the response of anti-PD-L1 therapy though switching the TME from "cold" to "hot" in SCLC, indicating GSDME as a response biomarker for combination therapy of anti-PD-L1 and chemotherapy, as well as a potential target to sensitize the response to PD-L1 inhibitor therapy in future.

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.

Long-term survival in thymic epithelial tumors: a single-center experience from China.

BACKGROUND: To evaluate long-term survival in thymic epithelial tumors (TETs), we present our experiences at a single institution in China. METHODS: We performed a retrospective analysis including 115 patients with TETs from 2001 to 2006. Histological diagnosis was completed based on the new WHO classification system. A univariate and multivariate survival analysis was performed, which included myasthenia gravis (MG), WHO histological type, Masaoka stage, completeness of resection, and adjuvant radiotherapy (RT). RESULTS: WHO histological subtype was closely correlated with that of Masaoka stage. The overall median survival time was 84.4 months and the 7-year survival rate was 78%. In the univariate analysis, three prognostic factors, including WHO histology type, Masaoka stage and complete resection, were statistically significant. In the analysis of the cases with complete resection, adjuvant RT did not show obvious survival benefit. In the multivariate analysis, Masaoka stage was the only independent factor that predicted long-time survival. CONCLUSIONS: Thymic carcinoma should be regarded as a different category of the disease due to its aggressive and poorer prognosis. Complete resection of the tumor and Masaoka stage I and II were found to contribute to a better survival. Adjuvant RT is not recommended for patients with complete resection in thymomas.

Identification of RAC1 in promoting brain metastasis of lung adenocarcinoma using single-cell transcriptome sequencing.

This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

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.

Clinical analysis of postoperative venous thromboembolism risk factors in lung cancer patients.

BACKGROUND AND OBJECTIVES: The objective of this study is to explore clinical risk factors for venous thromboembolism (VTE) in postoperative lung cancer patients in order to provide a basis for the prevention and treatment of postoperative VTE. METHODS: A total of 1,001 lung cancer patients were retrospectively analyzed. Each patient was confirmed with surgical pathology diagnosis and had a complete clinical and follow-up record. VTE was identified in a combination of spiral computed tomography (CT), pulmonary angiography, and color Doppler ultrasound. We used life table method to create an occurrence frequency curve of thrombosis. We also searched for high risk factors for postoperative VTE with Cox multivariate regression model and created frequency curves of thrombosis against different risk factors using Kaplan-Meier method. RESULTS: As of July 31, 2011, the median follow-up time is 25.73 ± 0.11 months (19.23-31.37). The cumulative frequency of VTE among 1,001 lung cancer patients is 2%, 3%, 4%, 5%, and 5.3% over 1, 3, 6, 12, and 30 months after the surgery. COX regression analysis showed that the hazard ratio of VTE occurrence in patients with incomplete resection relative to ones with complete resection is 9.867 (95% CI: 5.275-18.459, P = 0.000). And the hazard ratio of VTE occurrence is 3.472 (95% CI: 1.761-6.845, P = 0.000) in patients with anti-angiogenesis treatment compared to patients without such treatment. The hazard ratio of VTE occurrence is 2.808 (95% CI: 1.439-5.479, P = 0.002) in patients with EGFR-TKI treatment relative to patients without the treatment, and 7.520 (95% CI: 3.968-14.250, P = 0.000) in patients with an increase in D-dimer level relative to normal ones CONCLUSIONS: The highest incidence of VTE is within 1 month after lung cancer surgery. High risk factors for VTE include incomplete surgical resection, postoperative use of anti-angiogenesis drugs, EGFR-TKI application and an increase in preoperative D-dimer level.

Tagrisso incremental therapy in a case of meningeal metastasis of lung cancer with EGFR mutation: a case report.

The advent of precision treatment for non-small cell lung cancer (NSCLC) has witnessed the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR tyrosine kinase inhibitors (TKIs) have proven efficacy in treating patients with advanced lung cancer and can significantly prolong overall survival (OS). The incidence of advanced lung cancer with central nervous system (CNS) metastasis has increased significantly. Patients with EGFR mutations are more likely than wild-type patients to develop meningeal metastasis. Many questions still surround treatment-related decision-making for patients with TKI-sensitive mutations, as well as the optimal treatment strategy after progress with TKI treatment. Moreover, the accurate and timely diagnosis of meningeal metastasis and the treatment for patients with TKI-sensitive mutated meningeal metastases also need to be addressed. Here, we report the case of a patient who was diagnosed as stage IV NSCLC with EGFR 21 exon L858R mutation combined with EGFR 20 exon T790M mutation based on an elevated carcinoembryonic antigen (CEA) level (193 ng/mL) as the first symptom. After being diagnosed as meningeal metastasis by cerebrospinal fluid (CSF) cytology, the patient received a regular double dose of Tagrisso. The patient's progression-free survival (PFS) was extended by 7 months, and the OS reached more than 5 years, which is rare in clinical practice. This case suggests that: (I) meningeal metastases should be diagnosed based on clinical presentation, CSF examination, and magnetic resonance imaging (MRI); and (II) in patients with EGFR-mutant meningeal metastases, incremental targeted drug treatment should be considered a therapeutic strategy.

Comprehensive analysis of MET mutations in NSCLC patients in a real-world setting.

Background: Aberrant mesenchymal-epithelial transition/hepatocyte growth factor (MET/HGF) regulation presented in a wide variety of human cancers. MET exon 14 skipping, copy number gain (CNG), and kinase domain mutations/arrangements were associated with increased MET activity, and considered to be oncogenic drivers of non-small cell lung cancers (NSCLCs). Methods: We retrospectively analyzed 564 patients with MET alterations. MET alterations were classified into structural mutations or small mutations. MET CNG, exon 14 skipping, gain of function (GOF) mutations, and kinase domain rearrangement were defined as actionable mutations. Results: Six hundred thirty-two MET mutations were identified including 199 CNG, 117 exon 14 skipping, 12 GOF mutations, and 2 actionable fusions. Higher percentage of MET structural alterations (CNG + fusion) were detected in advanced NSCLC patients. Moreover, MET CNG was enriched while exon 14 skipping was rare in epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI)-treated advanced NSCLC patients. Ten of the 12 MET GOF mutations were also in EGFR-TKI-treated patients. Fifteen (68.1%) of the 22 patients treated with crizotinib or savolitinib had a partial response. Interestingly, one patient had a great response to savolitinib with a novel MET exon 14 skipping mutation identified after failure of immune-checkpoint inhibitor. Conclusions: Half of the MET alterations were actionable mutations. MET CNG, exon 14 skipping and GOF mutations had different distribution in different clinical scenario but all defined a molecular subgroup of NSCLCs for which MET inhibition was active.

Durable Response to the Combination of Atezolizumab With Platinum-Based Chemotherapy in an Untreated Non-Smoking Lung Adenocarcinoma Patient With BRAF V600E Mutation: A Case Report.

BACKGROUND: Immune checkpoint inhibitor (ICPi) has become a major treatment in advanced non-small cell lung cancer (NSCLC) and demonstrated a clinical benefit for NSCLC patients with high programmed death ligand-1 (PD-L1) expression without EGFR/ALK/ROS1 drivers; however, the benefit in BRAF V600E NSCLC is so far unknown. Here, we report a case of prolonged tumor response to the combination of immunotherapy with chemotherapy in a non-smoking BRAF V600E NSCLC patient. MATERIALS AND METHODS: We verify a co-expression of BRAF V600E mutation and PD-L1 high expression more than 50% on formalin-fixed paraffin-embedded tumor sample of a newly diagnosed lung adenocarcinoma patient by immunohistochemistry and BRAF V600E/EGFR/ALK/ROS1 Mutations Detection Kit. The tissue and liquid biopsies were further subjected to next-generation sequencing (NGS) for identification of mutations with progression on immunotherapy and BRAF inhibitor (BRAFi). The patient had provided written informed consent and authorized the publication of clinical case. RESULTS: We demonstrate the case of 62-year-old female non-smoker with high PD-L1 expression and BRAF V600E mutated NSCLC. The progression-free survival (PFS) of first-line combination of atezolizumab with platinum-based chemotherapy and sequential second-line treatment with BRAFi Vemurafenib are 20 and 5.5 months, respectively. CONCLUSION: This case shows a durable response to ICPi in BRAF V600E non-smoking lung adenocarcinoma with PFS of 20 months under first-line atezolizumab plus chemotherapy treatment. The case supports the idea that the combination immunotherapy may be an attractive option for BRAF V600E mutated non-smoking NSCLC with high PD-L1 expression.

Sintilimab, stereotactic body radiotherapy and granulocyte-macrophage colony stimulating factor as second-line therapy for advanced non-small cell lung cancer: safety run-in results of a multicenter, single-arm, phase II trial.

OBJECTIVES: The SWORD trial is the first multicenter, single arm, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony stimulating factor (GM-CSF) in advanced non-small cell lung cancer (NSCLC) without sensitizing driver mutations. A safety run-in phase was conducted to determine the tolerability of the experimental treatment. MATERIALS AND METHODS: Twenty metastatic NSCLC patients who failed first-line chemotherapy were enrolled, and they received SBRT (8 Gy × 3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks, until disease progression, unacceptable toxicity, or up to 35 cycles) and GM-CSF (125 µg/m2 d1-d14, cycle 1) within 2 weeks after SBRT. In addition, blood and tissue samples were serially collected for translational research. RESULTS: Median age of the patients was 61 and all of them had more than 5 lesions at baseline. The sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). No patients had dose-limiting toxicities (DLTs) and 18 patients experienced treatment-related adverse event (TRAE). The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and they all were grade 1. Only 2 grade 3 TRAEs were observed, including elevation of liver enzymes in one and transient acute heart failure in another. No grade 4 or 5 AE was observed. CONCLUSION: Sintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants. Trial registration ClinicalTrials.gov, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular View-ClinicalTrials.gov.

Lactate anions participate in T cell cytokine production and function.

After antigen stimulation, T cells preferentially increase aerobic glycolysis to meet the bioenergetic and biosynthetic demands of T cell activation, proliferation, and effector functions. Lactate, a by-product of glycolysis, has been reported to function as an important energy source and signaling molecule. Here, we found that lactate anions are involved in cytokine production in T cells after TCR activation. During ex vivo T cell activation, the addition of excess sodium lactate (NaL) increased the production of cytokines (such as IFNγ/IL-2/TNFα) more than the addition of sodium chloride (NaCl). This enhanced cytokine production was dependent on TCR/CD3 activation but not CD28 activation. In vivo, NaL treatment inhibited tumour growth in subcutaneously transplanted tumour models in a T cell-dependent manner, which was consistent with increased T cell cytokine production in the NaL treatment group compared to the NaCl treatment group. Furthermore, a mechanistic experiment showed that this enhanced cytokine production was regulated by GAPDH-mediated post-transcriptional regulation. Taken together, our findings indicate a new regulatory mechanism involved in glycolysis that promotes T cell function.

Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial.

INTRODUCTION: Tislelizumab, an anti-programmed cell death protein-1 antibody, was specifically engineered to minimize FcÉ£R macrophage binding to abrogate antibody-dependent phagocytosis. Compared with chemotherapy alone, tislelizumab plus chemotherapy may improve clinical outcomes in patients with advanced nonsquamous NSCLC (nsq-NSCLC). METHODS: In this open-label phase 3 trial (RATIONALE 304; NCT03663205), patients with histologically confirmed stage IIIB or IV nsq-NSCLC were randomized (2:1) to receive either arm A: tislelizumab plus platinum (carboplatin or cisplatin) and pemetrexed every 3 weeks (Q3Ws) or arm B: platinum and pemetrexed alone Q3W during induction treatment, followed by intravenous maintenance pemetrexed Q3W. The primary end point was progression-free survival (PFS) assessed by an independent review committee; clinical response and safety and tolerability were secondary end points. RESULTS: Overall, 332 patients (n = 222 [A]; n = 110 [B]) received treatment. With a median study follow-up of 9.8 months, PFS was significantly longer with tislelizumab plus chemotherapy compared with chemotherapy alone (median PFS: 9.7 versus 7.6 mo; hazard ratio = 0.645 [95% confidence interval: 0.462-0.902], p = 0.0044). In addition, response rates were higher and response duration was longer with combination therapy versus chemotherapy alone. Hematologic adverse events (AEs) were common in both treatment arms; the most reported AEs were grades 1 to 2 in severity. The most common grade greater than or equal to 3 AEs were associated with chemotherapy and included neutropenia (44.6% [A]; 35.5% [B]) and leukopenia (21.6% [A]; 14.5% [B]). CONCLUSIONS: Addition of tislelizumab to chemotherapy resulted in significantly prolonged PFS, higher response rates, and longer response duration compared with chemotherapy alone, identifying a new potential option for first-line treatment of advanced nsq-NSCLC irrespective of disease stage.

Clonal Architecture of EGFR Mutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study (NCT03059641).

PURPOSE: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non-small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). PATIENTS AND METHODS: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. RESULTS: Overall, 300 treatment-naïve patients with stage IIIB-IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24-0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04-0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). CONCLUSIONS: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.