Background::Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods::We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort ( n = 125), a validation cohort ( n = 82), and a control cohort ( n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. Results::A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment.Conclusion::These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

For advanced non-small cell lung cancer(NSCLC)patients with negative driver gene mutations,chemo-therapy has always been the standard treatment option,and immune checkpoint inhibitors(ICIs)provide other treatment op-tion for these patients.At present,the first-line treatment can choose chemotherapy,anti-angiogenic drugs or immunotherapy.Although the initial treatment can achieve a certain clinical curative effect,disease progression or treatment failure is eventually unavoidable.The second-line and subsequent treatments have poor efficacy and more effective drugs are needed clinically.An expert panel of respiratory medicine,pathology and medical oncology organized by Expert Committee on Non-small Cell Lung Cancer of the Chinese Society of Clinical Oncology conducted an in-depth discussion on evidences of clinical studies for second-line treatment of NSCLC patients with negative driver gene mutations,aiming to provide guidances for Chinese clini-cians in choosing second-line treatment for NSCLC patients with negative driver gene mutations.

The standard clinical practice of managing the non-small cell lung cancer(NSCLC)with epider-mal growth factor receptor(EGFR)exon 20 insertion(ex20ins)mutations was elaborated in Chinese expert consensus on non-small cell lung cancer with EGFR exon 20 insertion mutations(2023 edition),and this rare subset has gradually attracted attention recently.With the deepening of treatment area exploration and the approval of new targeted drugs,there are more options for the diagnosis and treatment of EGFR ex20ins positive NSCLC patients.Therefore,based on the previous version of consensus,the expert panel has updated this consensus on the standardized clinical diagnosis and treatment of EGFR ex20ins mutation NSCLC through reference to literature and clinical data,and combined with the experts'own clinical experience.The updated recommendations includes disease congnition,testing methods,therapy and recent relevant clinical trials for NSCLC patients with EGFR ex20ins mutation,in order to provide better medication reference for clinical physicians.

In recent years,perioperative immunotherapy for non-small cell lung cancer(NSCLC)has made significant progress.Several inter-national phase Ⅲ clinical trials(such as CheckMate-816,IMpower010 and KEYNOTE-091)have demonstrated that neoadjuvant and ad-juvant immunotherapy can significantly improve pathological response rates,event-free survival(EFS),and disease-free survival(DFS)in stage Ⅱ-Ⅲ NSCLC patients,leading to regulatory approvals worldwide.Further studies,including KEYNOTE-671,AEGEAN,and CheckMate-77T,have validated the potential advantages of the"neoadjuvant+adjuvant"immunotherapy approach,significantly reducing the risk of postoperative recurrence in certain populations.Additionally,biomarkers such as PD-L1 expression,minimal residual disease(MRD)status,and ctDNA monitoring are being investigated as predictive indicators to optimize individualized treatment strategies.However,there are still controversies regarding the choice of perioperative immunotherapy modes,the optimal treatment cycle,and the application in patients with driver gene mutations.Future research will continue to explore the efficacy of immunotherapy in different patient subgroups to maximize clinical benefits while minimizing the toxicity risks associated with treatment.

Humans ; Aminoquinolines/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation/genetics* ; Standard of Care

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
.

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, most NSCLC patients are at advanced stage at the time of diagnosis. For patients without sensitive driven-oncogene mutations, chemotherapy is still the main treatment at present, the overall prognosis is poor. Improving outcomes and obtaining long-term survival are the most urgent needs of patients with advanced NSCLC. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs), especially targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), have made a breakthrough in the treatment of NSCLC, beneficial to patients' survival and changed the treatment pattern for NSCLC. It shows more and more important role in the treatment of NSCLC. Led by NSCLC expert committee of Chinese society of clinical oncology (CSCO), relevant experts in this field were organized. On the basis of referring to domestic and foreign literature, systematically evaluating the results of Chinese and foreign clinical trials, and combining the experiences of the experts, the experts group reached an agreement to develop this consensus. It will guide domestic counterparts for better application of ICIs to treat NSCLC.

With the advances in molecular detection technology and the emergence of various targeted agents, we have entered the era of precision medicine across the whole process of cancer diagnosis and treatment. Tyrosine kinase inhibitors targeting epidermal growth factor receptor gene mutation, the most common driver, have been developed from the first generation to the third generation, improving the survival and life quality of patients with advanced non-small cell lung cancer. It is critically important how to rank these targeted agents and arrange combination therapies, and this review will focus on the strategies of the third-generation EGFR-TKI in the context of precision medicine.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR-TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients.