Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.

This study aimed to assess the predictive and evaluative value of PD-L1 targeted 68Ga-THP-APN09 PET/CT in the neoadjuvant immunotherapy combined with chemotherapy for resectable non-small cell lung cancer (NSCLC), and to explore its potential in indicating immunotherapy-related adverse effects (irAEs).

Fifty patients with resectable NSCLC enrolled in this prospective study underwent baseline 68Ga-THP-APN09 PET/CT and 18F-FDG PET/CT, with follow-up 18F-FDG PET/CT conducted, additionally, 36 patients received follow-up 68Ga-THP-APN09 PET/CT. Surgery was performed following 2-4 cycles of toripalimab combined with chemotherapy if R0 resection was feasible. The major pathologic response (MPR) state of the post-operative specimen and the adverse effects following combined therapy were documented. The correlation between PD-L1 expression and baseline 68Ga-THP-APN09 PET/CT uptake was determined. The predictive and evaluative efficacies of baseline and follow-up 68Ga-THP-APN09 PET/CT, along with 18F-FDG PET/CT, in determining MPR, were compared.

The SUVmax values of baseline 68Ga-THP-APN09 PET/CT were significantly higher in patients exhibiting high-positive PD-L1 expression compared to those with low-positive and negative expression (P = 0.001). And the SUVmax values of baseline 68Ga-THP-APN09 PET/CT in the response group, as determined by 18F-FDG PET/CT evaluation, were significantly higher than those in the non-response group (3.4 vs. 2.4, P < 0.001). Totally, 41 patients underwent surgery, of which 27 achieved MPR, while 14 did not. The SUVmax in baseline 68Ga-THP-APN09 PET/CT demonstrated statistical significance between the MPR and non-MPR groups, with area under the ROC curve (AUC) of 0.88 (95%CI: 0.77-0.99) in identifying MPR. However, the SUVmax in baseline 18F-FDG PET/CT failed to demonstrated significant predictive power, with AUC values of 0.68 (95%CI: 0.50-0.86, P = 0.076). While the SUVmax in follow-up 68Ga-THP-APN09 and 18F-FDG PET/CT, along with their change rate (ΔSUVmax%), demonstrated good predictive efficacy in identifying MPR, with AUC values of 0.81 (0.64-0.98), 0.91 (0.82-1.00), 0.93 (0.84-1.00), and 0.96 (0.89-1.00), respectively. Furthermore, the follow-up 68Ga-THP-APN09 PET/CT could remarkedly indicate the potential for thyroiditis.

Baseline 68Ga-THP-APN09 PET/CT alone could predict efficacy and assist in patient screening for immunotherapy combined chemotherapy in resectable NSCLC, and the follow-up 68Ga-THP-APN09 PET/CT and their change rates could aid in therapy evaluation. Additionally, follow-up 68Ga-THP-APN09 PET/CT could be utilized to monitor the immunotherapy-related thyroiditis during the therapy.

NCT05156515, registered 8 December 2021, https://register.

gov/prs/app/action/SelectProtocol?sid=S000BMSI%26;selectaction=Edit%26;uid=U000503E%26;ts=2%26;cx=zeghuw .

Neoadjuvant chemoimmunotherapy has been successfully used in patients with resectable non-small-cell lung cancer (NSCLC). However, its application to potentially resectable IIIA/IIIB NSCLC remains controversial. This retrospective study aims to evaluate the efficacy and safety of neoadjuvant chemoimmunotherapy followed by conversion surgery in patients with potentially resectable stage III NSCLC, focusing on conversion rate and survival benefits. Patients with 'potentially resectable' stage IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection at initial diagnosis were retrospectively identified. After 2-4 cycles of treatment, all patients were reevaluated for surgical resectability. Data on patient characteristics, radiological and pathological responses, and survival outcomes were collected. In total, 148 patients were included in the final analysis. Upon the completion of neoadjuvant therapy, 105 patients were considered suitable for conversion surgery. Three patients refused surgery, and 102 patients ultimately underwent surgery, yielding a conversion rate of 70.9% and a resection rate of 68.9%. The rate of complete (R0) resection was 100%, with a major pathological response (MPR) of 64.7% and a pathologic complete response (pCR) of 41.2%. Postoperative complications were observed in nine patients (8.8%), and there was no surgery-related mortality within 30 days. The median progression-free survival (PFS) was 19.1 months in the non-surgery group, and the overall survival (OS) was not reached. In the 102 patients who underwent conversion surgery, both the median PFS and OS were not reached, accompanied by 2-year OS and PFS rates of 87.3% and 78.4%, respectively. Our findings showed that neoadjuvant chemoimmunotherapy expanded the opportunities for conversion surgery in potentially resectable cases. Subsequent conversion surgery is safe and has the potential for significant survival benefits.

This study aimed to evaluate the predictive value of 18F-FDG PET/CT for pathological complete response (pCR) after neoadjuvant immunochemotherapy in resectable non-small cell lung cancer (NSCLC) and develop a quantitative pCR prediction model. We compared the model's performance with RECIST 1.1 and PERCIST.

A retrospective review was conducted on patients with resectable NSCLC who received neoadjuvant immunochemotherapy from January 2020 to December 2023. Patients with both pre-treatment (18F-FDG PET/CT scan-1) and preoperative scans (18F-FDG PET/CT scan-2) were included. 18F-FDG PET/CT parameters, clinical characteristics, and follow-up data were collected. Logistic regression was used to identify independent predictors and construct the prediction model. The model's predictive performance was compared with RECIST 1.1 and PERCIST criteria. The model was validated with an external cohort from January to September 2024. Postoperative pathological results serve as the gold standard for pCR.

36 patients were included for model development, with 19 (52.8%) achieving pCR. ΔTLR% (percentage change between two scans in tumor-to-liver ratio) and SULpeak from scan-2 were significant predictors. The developed prediction model demonstrated outstanding performance with an area under the curve (AUC) of 0.975, 100% sensitivity, and 94.1% specificity. In comparison, RECIST 1.1 showed poor sensitivity (10.5%) but high specificity (100%), while PERCIST had moderate sensitivity (73.7%) and specificity (94.1%). Validation with 8 patients confirmed the model's accuracy.

This study suggests that 18F-FDG PET/CT, specifically the ΔTLR% and SULpeak from scan-2, is a reliable predictor of pCR in resectable NSCLC undergoing neoadjuvant immunochemotherapy. The quantitative prediction model outperforms both RECIST 1.1 and PERCIST. These findings highlight the potential clinical utility of this model, although further validation with larger cohorts is required to confirm its robustness and generalizability.

Neoadjuvant immunotherapy has shown impressive outcomes in treating non-small cell lung cancer (NSCLC) recently due to advancements in immune checkpoint inhibitors (ICIs) research. Neoadjuvant immunotherapy can lower the tumor load, raise the complete surgical (R0) resection rate, and improve clinical outcomes by alleviating the immune system repression caused by tumor cells. This review provides a comprehensive evaluation of neoadjuvant immunotherapy in NSCLC, focusing on: (1) its safety and efficacy profiles, (2) the most recent clinical trial evidence, and (3) critical unresolved challenges including predictive biomarker development, management of driver mutation-positive patients, chronic obstructive pulmonary disease (COPD) comorbidity considerations, and its application in stage III-IVA (oligometastatic) disease. Furthermore, we explore future research directions to optimize neoadjuvant immunotherapy approaches for resectable NSCLC, aiming to guide clinical practice and investigation.

This study aims to compare the survival benefits of perioperative versus neoadjuvant immune checkpoint inhibitors (ICI)-based therapy in patients with resectable non-small cell lung cancer (NSCLC), focusing specifically on those who achieve major pathological response (MPR) or pathological complete response (pCR) following neoadjuvant ICI-based treatment.

s: A systematic literature review was performed using PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases. A trial-level proportional meta-analysis was conducted to compare the two treatment modalities. A patient-level-based analysis was also conducted to obtain more evidence of different perioperative treatment regimens. Cox regression and accelerated failure time models were used to analyze the survival benefits in patients who achieved MPR or pCR for the proper treatment modality.

Twenty-three studies were included in the trial-level proportional meta-analysis, wherein no statistical significance was observed in the 1-, 2-, and 3-year event-free survival (EFS) rates between patients with MPR and pCR receiving perioperative or neoadjuvant ICI-based therapy. The pooled median EFS (mEFS) was 40.1 and 32.1 months in patients with MPR receiving perioperative and neoadjuvant ICI-based therapies, respectively. Meanwhile, the pooled mEFS was 35.4 and 34.2 months in patients with pCR receiving perioperative and neoadjuvant ICI-based therapies, respectively. Multivariable Cox analysis showed that perioperative chemoimmunotherapy was a favorable prognostic factor compared with neoadjuvant chemoimmunotherapy in MPR patients (P = 0.038), but not in those with pCR (P = 0.408).

The EFS were similar among patients with NSCLC who received neoadjuvant and perioperative ICI-based treatment and achieved MPR or pCR. Multivariable Cox analysis indicated that perioperative chemoimmunotherapy was a favorable prognostic factor in patients who achieved MPR after neoadjuvant chemoimmunotherapy, but not in those who reached pCR.

The conventional neoadjuvant chemotherapy regimen for locally advanced penile squamous cell carcinoma (La-PSCC) has shown moderate response rates and survival benefits. This single-arm, phase II trial (NCT04475016) evaluated a neoadjuvant regimen of four cycles of toripalimab (anti-PD-1 antibody), nimotuzumab (anti-EGFR antibody), and taxol-based chemotherapy (TNT), followed by consolidative surgery. The primary endpoint was the pathological complete response (pCR) rate. Among 29 enrolled patients, 24 (82.8%) underwent consolidative surgery, with 14 (48.3%, 95% confidence interval [CI], 29.4-67.5%) achieving pCR. The objective response rate (ORR) was 82.8% (95% CI, 64.2-94.2). Median follow-up was 39.97 months, with two-year overall survival (OS) and progression-free survival (PFS) rates of 72.4% and 65.5%. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 12 (41.4%) patients, with no treatment-related deaths. Biomarker analysis identified PD-L1 expression, TP53 mutation status, and CD8+ T cell density as potential predictive markers. Therefore, neoadjuvant TNT shows promising anti-tumor activity and acceptable toxicity.

Immunotherapy, particularly anti-PD-1 therapy, has assumed a progressively significant position in the management of non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAD). Nevertheless, a subset of patients exhibit resistance to anti-PD-1 therapy, and the exploration of biomarkers for evaluating the responsiveness to anti-PD-1 therapy necessitates further investigation. FLT3LG is regarded as being associated with tumor diagnosis and immunotherapy in a variety of tumor types, but its function in LUAD is uncertain.

Bioinformatics analysis was conducted to evaluate the clinical value, functional enrichment, genetic correlation, and immune infiltration of FLT3LG in LUAD. We then used a mouse model to detect immune cell infiltration and relevant protein expression by flow cytometry and immunohistochemistry under anti-PD-1 treatment after overexpression of FLT3LG. The serum FLT3LG expression in LUAD patients was detected via ELISA, and PD-L1 expression in tumor samples was detected by immunohistochemistry.

In LUAD patients, a better prognosis is associated with elevated FLT3LG expression. Among the genes strongly associated with FLT3LG, the majority were involved in immune-related processes and were enriched predominantly in immune-related pathways. Moreover, high expression of FLT3LG was significantly positively correlated with increased infiltration of multiple immune cells, including T cells and natural killer (NK) cells, in lung adenocarcinomas, as well as the expression of several immune cell markers, such as CD4 and CD8a. In a mouse model, overexpression of FLT3LG in mice subjected to subcutaneous graft tumor elicited a pronounced immune response and could enhance the efficacy of anti-PD-1 therapy.

FLT3LG could be considered as a diagnostic and prognostic marker for LUAD and might play a role in enhancing the therapeutic response to immunotherapy in patients with LUAD.

The role of immunotherapy as systemic therapy for nonmetastatic non-small cell lung cancer (NSCLC) has evolved rapidly over the last decade. There are several well-conducted phase 3 clinical trials evaluating immunotherapy in the neoadjuvant, perioperative, adjuvant and nonoperative setting. In this narrative review, we summarize the data from these studies and discuss ongoing controversies in applying these data to clinical practice. These controversies relate to the value of the adjuvant component of perioperative immunotherapy, treatment of patients with PDL1 negative tumors, defining resectability, optimal use of operative versus nonoperative management, the role of stereotactic radiation therapy for very early lung cancers, and management of tumors with an oncogenic driver.

Immuno-chemotherapy has demonstrated significant anti-tumor effects in patients with resectable nonsmall cell lung cancer (NSCLC). Additionally, for patients initially diagnosed with unresectable stage III NSCLC, induction immuno-chemotherapy may achieve tumor downstaging, enabling conversion to resectable disease allowing for by R0 resection. This study aimed to assess the effectiveness and safety of induction immuno-chemotherapy followed by conversion surgery in unresectable stage III NSCLC.

A total of 113 patients with unresectable stage Ⅲ NSCLC who received induction immuno-chemotherapy at three institutions in China from March 2019 to April 2022 were retrospectively identified. After 2-4 cycles of immuno-chemotherapy, a multisiciplinary team (MDT) reassessed the tumor response and resectability in each case. Surgical resection was performed for patients who achieved tumor downstaging to resectable disease. Surgical and oncological outcomes of the patients were analyzed.

Of the 113 patients treated with immuno-chemotherapy, 79 (69.9%) achieved conversion to resectable state and underwent surgery. Surgical procedures included lobectomy in 55 (69.6%) patients, sleeve lobectomy in 14 (17.7%) patients, bilobectomy in 6 (7.6%) patients, and pneumonectomy in 4 (5.1%) patients, achieving an R0 resection rate of 98.7% (78/79). No surgical-related 30-day or 90-day mortalities were recorded, although 17 patients (21.5%) experienced postoperative complications. In terms of pathological response, 44 (55.7%) patients achieved major pathologic response and 25 (31.6%) patients achieved complete pathologic response. Median progression-free survival (PFS) and overall survival (OS) was not reached. The 12- and 24-month PFS rates were 82.3% and 72.2%, while OS rates were 94.9% and 84.5%, respectively.

Conversion surgery following immuno-chemotherapy is feasible and safe, yielding promising pathological responses and favorable survival outcomes for patients with unresectable stage III NSCLC.

This retrospective study aimed to investigate the validity of fluorodeoxyglucose PET (FDG-PET) visual assessments to predict programmed death-ligand 1 (PD-L1) expression levels in patients with non-small cell lung cancer (NSCLC).

One hundred and seven NSCLC patients who underwent FDG-PET/computed tomography (CT) scans and PD-L1 expression tests were retrospectively identified. Patients were divided into two groups according to PD-L1 expression: PD-L1 high group (PD-L1 tumor proportion score ≥50%) and PD-L1 low group (<50%). We compared clinicopathological characteristics and PET assessments [maximum standardized uptake value (SUVmax) and Deauville score] between the two groups based on PD-L1 expression.

High expression of PD-L1 was detected in 25 of 107 cases. In both univariable and multivariable analysis, there were significant differences in PET visual assessments in NSCLC (P < 0.05). Receiver operating characteristics for the PET visual assessments [area under the curve (AUC) = 0.712, 95% confidence interval (CI) 0.628-0.793] and SUVmax (AUC = 0.753, 95% CI 0.647-0.861) showed equivalent accuracy (P = 0.227). Based on histopathology, in adenocarcinoma patients, there were significant differences between PET visual assessments and PD-L1 expression (P < 0.05), while no significant differences were observed in squamous cell carcinoma patients. Based on epidermal growth factor receptor (EGFR) mutation analysis, in patients with EGFR wild type, there were significant differences between PET visual assessments and PD-L1 expression (P = 0.006), while in patients with EGFR mutations, there were no significant differences between PET visual assessments and PD-L1 expression.

Results of PET visual assessments correlated with PD-L1 expression in NSCLC.

Background. To comprehensively assess surgical safety, we conducted a meta-analysis on neoadjuvant chemo-immunotherapy for NSCLC. Methods. This systematic review and meta-analysis followed PRISMA guidelines (PROSPERO: CRD42023470682). A literature search and data extraction were performed independently by two reviewers. Primary outcomes included surgical feasibility and safety. Pooled prevalence proportions with 95% confidence intervals (CIs) were calculated. A random-effects model was applied if heterogeneity was significant (I2 ≥ 50% or p ≥ 0.10). Sensitivity analysis assessed robustness and publication bias was examined using funnel plots and Egger's test (p < 0.05 significant). Results. Fifteen studies were included, analyzing different immune checkpoint inhibitors with 2-3 cycles of neoadjuvant therapy. Surgery occurred 10-45 days post-treatment. The pooled surgical resection rate was 98.96% (95% CI: 98.93-98.98, I2 = 0%). The conversion to thoracotomy rate was 16.49% (95% CI: 12.95-20.03, I2 = 89.74%). Minimally invasive surgery was performed in 53.62% (95% CI: 49.53-57.72, I2 = 95.92%). The median surgical delay was 28.53 days (95% CI: 23.66-33.41, I2 = 0%). Surgical time averaged 165.27 min (95% CI: 112.32-218.22, I2 = 0%), with mean blood loss of 182.0 mL (95% CI: 134.0-230.0, I2 = 0%). Conclusions. Surgical intervention following neoadjuvant chemo-immunotherapy for NSCLC is feasible and safe, with a high resection rate (98.96%). Variability in minimally invasive surgery and conversion rates suggests differences in surgical approaches, while surgical time, blood loss, and delay showed consistency. These findings highlight the need for a multidisciplinary approach to optimize patient outcomes.

The progression of lung adenocarcinoma is primarily driven by cancer stem cells (CSCs), which have self-renewal capabilities and confer resistance to therapies, including neoadjuvant treatments combining chemotherapy and immune checkpoint inhibitors. In this study, we identified that OV6+ tumor cells exhibit stem-like characteristics and are notably enriched in patients with non-major pathological response, closely associated with resistance to combination therapies. Hypoxia and HIF1α were found to drive the formation of OV6+ CSCs. METTL3, a methyltransferase, was revealed as a critical regulator of OV6+ CSCs by stabilizing NFE2L3 messenger RNA via an N6-methyladenosine-dependent manner, thereby up-regulating NFE2L3 and activating the intrinsic WNT signaling pathway essential for maintaining stemness. OV6+ tumor cells promoted M2 macrophage infiltration and the formation of an immunosuppressive tumor microenvironment (TME). Targeting METTL3 effectively eliminated OV6+ CSCs and suppressed tumor progression. Moreover, the combination of STM2457 with cisplatin overcame chemoresistance, remodeled the TME, and provided promising insights for enhancing the efficacy of neoadjuvant combination therapies.

Lung cancer is currently the most prevalent malignancy and the leading cause of cancer deaths worldwide. Although the early stage non-small cell lung cancer (NSCLC) presents a relatively good prognosis, a considerable number of lung cancer cases are still detected and diagnosed at locally advanced or late stages. Surgical treatment combined with perioperative multimodality treatment is the mainstay of treatment for locally advanced NSCLC and has been shown to improve patient survival. Following the standard methods of neoadjuvant therapy, perioperative management, postoperative adjuvant therapy, and other therapeutic strategies are important for improving patients' prognosis and quality of life. However, controversies remain over the perioperative management of NSCLC and presently consensus and standardized guidelines are lacking for addressing critical clinical issues in multimodality treatment.

The working group consisted of 91 multidisciplinary experts from thoracic surgery, medical oncology, radiotherapy, epidemiology, and psychology. This guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The clinical questions were collected and selected based on preliminary open-ended questionnaires and subsequent discussions during the Guideline Working Group meetings. PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNKI) were searched for available evidence. The GRADE system was used to evaluate the quality of evidence and grade the strengths of recommendations. Finally, the recommendations were developed through a structured consensus-building process.

The Guideline Development Group initially collected a total of 62 important clinical questions. After a series of consensus-building conferences, 24 clinical questions were identified and corresponding recommendation were ultimately developed, focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assement, and follow-up protocols for NSCLC.

This guideline puts forward reasonable recommendations focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assessment, and follow-up protocol of NSCLC. It standardizes perioperative multimodality treatment and provides guidance for clinical practice among thoracic surgeons, medical oncologists, and radiotherapists, aiming to reduce postoperative recurrence, improve patient survival, accelerate recovery, and minimize postoperative complications such as atelectasis.

Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer-related mortality globally. Most patients who undergo surgical procedures may encounter distant metastasis or local recurrence, necessitating supplementary treatments such as radiation therapy, chemotherapy, or targeted therapy as adjuvant alternatives. Recent advancements in molecular biology and immunotherapy have paved the way for innovative therapeutic approaches that target specific genetic mutations and promote the immune response against tumour cells. This review explores emerging therapies, including targeted therapies such as tyrosine kinase inhibitors (TKIs) for actionable mutations (e.g., EGFR, ALK, ROS1), as well as the role of immune checkpoint inhibitors (ICIs) that employ the body's immune system to combat cancer. Additionally, we discuss the potential of exosome therapies, as well as promising nanotherapeutic options for the treatment of NSCLC. This study attempts to provide a thorough overview of the changing landscape of NSCLC treatment and its implications for enhancing patient outcomes by presenting these innovative techniques.

Neoadjuvant chemo-immunotherapy is one of the standard treatment options for resectable stage II to III NSCLC. Nevertheless, this treatment yielded insufficient local control in the CheckMate 816 trial. We hypothesized that adding radiotherapy could improve local control, thereby improving survival outcomes.

Eligible patients had clinical T1 to T3 or T4 (tumor size) N2 stage IIIA to B NSCLC (American Joint Committee on Cancer version 8), pathologically confirmed as N2 without extranodal invasion. Patients received concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with 50 Gy radiation over 25 d) and durvalumab (1500 mg) on days 1 and 29, followed by surgical resection within two to six weeks. After surgery, durvalumab adjuvant therapy was administered for up to one year. The primary endpoint was major pathologic response (MPR: ≤10% viable tumor), with secondary endpoints being pathologic complete response, progression-free survival (PFS), overall survival (OS), and safety.

From January 2020 through February 2022, 31 patients were enrolled from 10 Japanese institutions. The MPR rate was 63% (90% confidence interval: 47%-78%), which met the primary endpoint, and the pathologic complete response rate was 23%. At a median follow-up of 28 months, the two-year PFS and OS rates were 43% and 76%, respectively. Grade 3 or 4 adverse events occurred in 48% of cases, including one treatment-related death.

Compared with recently published results of peri-operative chemo-immunotherapy trials, this treatment regimen had a higher MPR rate. Nevertheless, this benefit did not necessarily translate into improved PFS or OS.

This study aimed to evaluate the predictive value of baseline PD-L1 targeted peptide 68Ga-NOTA-WL12 PET/CT in neoadjuvant immunotherapy combined with chemotherapy of resectable NSCLC.

Patients with resectable NSCLC (n = 20) enrolled in this prospective study received baseline paired 68Ga-NOTA-WL12 PET/CT and 18F-FDG PET/CT. After 2-4 cycles of toripalimab plus nab-paclitaxel and cisplatin, surgery was performed if R0 resection was available. The major pathologic response (MPR) state of the post-operative specimen was recorded. The imaging parameters of the 68Ga-NOTA-WL12 PET/CT, 18F-FDG PET/CT and CT between the MPR and non-MPR groups and their predictive efficacy of MPR were compared.

Among 20 patients, 17 patients underwent surgery, 10 achieved an MPR and 7 did not. The SUVmax and tumour-to-blood pool (TBR) of baseline 68Ga-NOTA-WL12 in the MPR group were higher than those in the non-MPR group, and the difference in TBR was statistically significant. The ΔSULpeak% of 18F-FDG exhibited differences between the MPR and non-MPR groups with no significance. Baseline 18F-FDG PET/CT parameters and ΔD% failed to differentiate the two groups. The areas under the ROC curves of SUVmax, TBR in 68Ga-NOTA-WL12 PET/CT, ΔD% and ΔSULpeak% in 18F-FDG PET/CT were 0.76, 0.79, 0.71 and 0.80, respectively, in predicting MPR.

Baseline 68Ga-NOTA-WL12 PET/CT has a potential to predict the pathological response of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable NSCLC, whose efficacy is comparable to that of therapy evaluations employing baseline and follow-up CT and 18F-FDG PET/CT examinations.

NCT04304066, registered 13 November 2020, https://register.

gov/prs/app/action/SelectProtocol?sid=S000AEI9&selectaction=Edit&uid=U000503E&ts=2&cx=-awajet .

Recent neoadjuvant clinical trials in lung cancer have demonstrated the survival benefits in carefully selected patients. Standardization of the assessment of pathologic response to neoadjuvant therapy in surgically resected specimens is required.

To review the current pathology practices in the gross processing and microscopic assessment of surgically resected non-small cell lung carcinoma specimens after neoadjuvant therapy.

PubMed publications and experience of the author.

Gross processing of the surgically resected lung carcinoma after neoadjuvant therapy needs further refinement and standardization in clinical trials and in a real-world clinical practice. Microscopic assessment of the response includes quantification of viable tumor, necrosis, and stroma. The best approach would be to use a single standardized and most reproducible scoring system. Published studies on gross processing of lung carcinoma specimens in the neoadjuvant setting and microscopic assessment of pathologic response provide a good foundation for the future standardization of pathology practice.

Immunotherapies targeting the programmed death receptor-1/programmed death ligand-1(PD-1/PD-L1) checkpoint have a major impact on the treatment of both resectable and advanced non-small cell lung cancer (NSCLC). Additional blockade of the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-receptor may synergistically foster the immune-related response. Several trials are currently investigating the combination of neoadjuvant platinum-based chemotherapy and dual checkpoint inhibition prior to curative surgery. The investigator-initiated NeoTRACK trial (EU CT number: 2022-501322-38-00; ClinicalTrials.gov identifier: NCT05825625; IKF056) aims to evaluate the feasibility and safety of perioperative anti-PD-L1 (by atezolizumab) and anti-TIGIT (by tiragolumab) treatment in combination with chemotherapy in patients with early stage NSCLC.

NeoTRACK is an open-label, single-arm, prospective, bicentric phase II trial. Patients with NSCLC in clinical stages II, IIIA and IIIB (only T3N2) will receive two cycles of standard platinum-based chemotherapy in combination with the anti-TIGIT antibody tiragolumab and the anti-PD-L1 antibody atezolizumab, followed by curative surgery. After surgery, patients without pathological complete response (pCR) will receive another two cycles of chemotherapy in combination with tiragolumab and atezolizumab, followed by tiragolumab/atezolizumab maintenance for up to 1 year (maximum 16 cycles). Patients with pCR will only receive dual immunotherapy. All patients will be followed-up for 30 months after the last study treatment. The clinical study will be aligned with a translational research programme to investigate treatment-naïve tumour tissues, surgical specimens and longitudinally collected blood samples. 35 patients are planned for enrolment. Patient recruitment started in August 2023, and treatment of the last patient is estimated to start 2.5 years thereafter.

The NeoTRACK trial aims to assess the feasibility and efficacy of combining tiragolumab and atezolizumab as both neoadjuvant and adjuvant therapies in patients with resectable NSCLC. The concept of treatment personalisation based on postoperative pCR is of great clinical interest.

The trial obtained ethical and regulatory approval in Germany through the Clinical Trials Information System (CTIS, ID: 2022-501322-38-00) and the Paul Ehrlich Institute (PEI, competent authority for approval of clinical trials using medicinal products for human use in Germany, process number: PB00148) on 30 March 2023. A data safety and monitoring board will meet regularly to review ongoing treatment in terms of safety.Study results will be published in peer-reviewed journals, presented at conferences and in the public registry of CTIS, following trial completion.

NCT05825625.

Neoadjuvant immune checkpoint inhibitors (ICIs) have emerged as a promising treatment strategy for resectable non-small cell lung cancer (NSCLC). However, optimal combination strategies, treatment cycles, and predictive indicators for long-term outcomes remain unclear. This study aimed to evaluate the efficacy of various neoadjuvant ICI-based therapies in resectable NSCLC, identify the optimal treatment cycles for neoadjuvant immunochemotherapy, and assess the prognostic value of pathological complete response (pCR) and major pathological response (MPR) for event-free survival (EFS).

A systematic literature search was conducted in PubMed, EMBASE, Cochrane CENTRAL, and Web of Science, including studies published up to October 2024. Bayesian models were used to analyze the efficacy of different ICI-based treatment combinations, assess the impact of immunochemotherapy cycles on MPR and pCR, and examine the predictive value of MPR and pCR for EFS.

Data from 34 studies were included, consisting of 32 single-arm studies (reported in 26 papers) and 8 RCTs, involving 4,593 patients. Immunochemotherapy combined with anti-angiogenesis agents was the most effective treatment strategy, significantly improving both MPR and pCR. No significant improvement in efficacy was observed when the number of neoadjuvant immunochemotherapy cycles exceeded 3 cycles. Both MPR and pCR were strong predictors of EFS. MPR showed a stronger negative correlation with event risk compared to pCR, with a log (HR) of -2.110 (95% CI: -4.150, -0.071) for MPR, and a log (HR) of -1.665 (95% CI: -2.419, -0.992) for pCR.

Neoadjuvant immunochemotherapy combined with anti-angiogenesis agents appears to be a highly effective strategy for resectable NSCLC. Three cycles of neoadjuvant immunochemotherapy demonstrated optimal efficacy in this study. Both MPR and pCR are valuable prognostic indicators for EFS, with MPR showing a stronger predictive value. These findings offer important insights for optimizing treatment strategies and informing clinical decision-making in resectable NSCLC.

PROSPERO, identifier CRD42024592346.

Predicting the response to neoadjuvant chemoimmunotherapy in patients with resectable non-small cell lung cancer (NSCLC) facilitates clinical treatment decisions. Our study aimed to establish a machine learning model that accurately predicts the pathological complete response (pCR) using 18F-FDG PET radiomics features.

We retrospectively included 210 patients with NSCLC who completed neoadjuvant chemoimmunotherapy and subsequently underwent surgery with pathological results, categorising them into a training set of 147 patients and a test set of 63 patients. Radiomic features were extracted from the primary tumour and lymph nodes. Using 10-fold cross-validation with the least absolute shrinkage and selection operator method, we identified the most impactful radiomic features. The clinical features were screened using univariate and multivariate analyses. Machine learning models were developed using the random forest method, leading to the establishment of one clinical feature model, one primary tumour radiomics model, and two fusion radiomics models. The performance of these models was evaluated based on the area under the curve (AUC).

In the training set, the three radiomic models showed comparable AUC values, ranging from 0.901 to 0.925. The clinical model underperformed, with an AUC of 0.677. In the test set, the Fusion_LN1LN2 model achieved the highest AUC (0.823), closely followed by the Fusion_Lnall model with an AUC of 0.729. The primary tumour model achieved a moderate AUC of 0.666, whereas the clinical model had the lowest AUC at 0.631. Additionally, the Fusion_LN1LN2 model demonstrated positive net reclassification improvement and integrated discrimination improvement values compared with the other models, and we employed the SHapley Additive exPlanations methodology to interpret the results of our optimal model.

Our fusion radiomics model, based on 18F-FDG-PET, will assist clinicians in predicting pCR before neoadjuvant chemoimmunotherapy for patients with resectable NSCLC.

Background: The objective of this study is to indirectly compare the efficacy and safety of all currently available neoadjuvant chemoimmunotherapy and perioperative chemoimmunotherapy in randomized controlled trials (RCTs) involving patients with resectable non-small cell lung cancer (NSCLC) to identify optimal treatment regimens. Methods: Eligible studies evaluating neoadjuvant chemoimmunotherapy and perioperative chemoimmunotherapy-based regimens in resectable NSCLC patients were included. Clinical outcomes were extracted for event-free survival (EFS) and overall survival (OS), as well as the incidence of pathological complete response (pCR), major pathological response (MPR), any-grade adverse events (AEs), and treatment-related adverse events (TRAEs) in the Bayesian framework. A subgroup analysis of EFS was conducted according to PD-L1 expression, histological type and reaching pCR or not. Results: We selected eight RCTs involving 3113 patients. Our analysis found no significant differences between perioperative immunotherapy and neoadjuvant immunotherapy in terms of MPR (RR 0.72, 95% CI 0.39 -1.3), pCR (RR 0.73, 95% CI 0.24-2.3), EFS (HR 0.95, 95% CI 0.56-1.7), and OS (HR 95% CI 3.9-4.2). Subgroup analyses revealed that neoadjuvant immunotherapy demonstrated superiority in the programmed death-ligand 1 (PD-L1) high-expression cohort, the non-squamous cell carcinoma cohort, and the non-smoking cohort. Conversely, perioperative immunotherapy ranked first in the PD-L1 low-expression cohort, squamous cell carcinoma cohort, and non-pCR cohort. Conclusions: Our findings indicate that neoadjuvant immunotherapy and perioperative immunotherapy exhibit comparable efficacy in patients with NSCLC. These results provide valuable evidence for guiding the treatment of patients with resectable NSCLC.

Conventional neoadjuvant chemotherapy provides limited benefit for patients with resectable non-small cell lung cancer (NSCLC). Recently, neoadjuvant chemoimmunotherapy (NCIT) has transformed the perioperative management of NSCLC by priming systemic anti-tumor immunity before surgery, yet it remains ineffective for at least 50% of patients. Through single-cell sequencing analysis of our NCIT cohort, we identify that antigen-presenting cancer-associated fibroblasts (apCAFs) can impede the efficacy of NCIT. Using a custom cancer-associated fibroblast biobank, we uncover that interferon (IFN)-γ stimulates apCAF expansion via the JAK1/2-STAT1-IFI6/27 pathway. Mechanistically, apCAFs significantly contribute to PD-L2 expression in the tumor microenvironment (TME), triggering the accumulation of FOXP1+regulatory T cells (Tregs) through the PD-L2-RGMB axis. Reprogramming apCAFs by inhibiting the IFN-γ pathway or blocking the PD-L2-RGMB axis substantially mitigates apCAFs-mediated FOXP1+Tregs' expansion. In summary, we reveal the role of apCAFs in compromising NCIT efficacy and propose applications for anti-PD-L2/RGMB regimens to synergize with anti-PD1 therapies by targeting apCAFs.

The phase I induction trial (NCT04287894) assessed the feasibility and safety of induction immunotherapy (IIT) prior to concurrent chemoradiotherapy (cCRT) in patients with locally advanced non-small cell lung cancer (NSCLC).

Patients with unresectable stage II/III NSCLC were eligible for inclusion. Patients received either one cycle of tremelimumab (75 mg) with two cycles of durvalumab (1,500 mg) in cohort I, one cycle of tremelimumab (300 mg) with two cycles of durvalumab in cohort II, or one cycle of tremelimumab (300 mg) with one cycle of durvalumab in cohort III. After IIT, a comprehensive radiological and pathological restaging was performed followed by cCRT. The combined primary endpoint was the feasibility and safety of IIT-cCRT.

Fifteen of 17 included patients were treated per protocol. IIT-cCRT was completed in 13 of the 15 patients within the predefined feasibility criteria. Grade ≥3 immune-related adverse events occurred in seven of the 15 patients, of which six were treated in the high-dose tremelimumab cohorts, thereby violating the safety criteria in cohorts II and III. The low-dose tremelimumab cohort (I) complied with safety criteria. Eleven patients had multilevel N2 or N3 disease at baseline; eight of these patients were downstaged to either N0/N1 or single-level N2 after IIT. Multiparametric MRI accurately identified nodal downstaging in all seven patients.

Induction with high-dose tremelimumab plus durvalumab prior to cCRT in unresectable locally advanced NSCLC was associated with unacceptable toxicity, although IIT resulted in clinically relevant nodal downstaging in eight of the 11 patients with baseline multilevel N2 or N3 disease. Multiparametric MRI showed potential for evaluating treatment response.

Lung cancer is the most prevalent malignancy worldwide. Only a fraction of early-stage patients undergo radical surgery; however, many still experience recurrence and metastasis within 5 years postoperatively (approximately 30-75%). Neoadjuvant therapy has revolutionized the treatment approach for lung cancer, with a growing number of clinical trials investigating this modality. This study provides a comprehensive analysis of neoadjuvant therapy in lung cancer, intending to guide future research.

To extract literature on neoadjuvant therapy for lung cancer published in the Web of Science Core Collection, spanning January 1, 2004, to December 31, 2023. Utilizing software tools including VOSviewer, CiteSpace, and GraphPad Prism to conduct bibliometric analysis and visualization studies on countries, institutions, journals, authors, co-cited references, and keywords in this field.

A sum of 6,085 research publications from 84 countries were analyzed, with the United States leading in publications on neoadjuvant therapy for lung cancer. The institution that publishes the most articles is the University of Texas System. The most published journal is Annals of Thoracic Surgery, while the most frequently co-cited journal is Journal of Clinical Oncology. Eight of the top ten co-cited references concern immune checkpoint inhibitors(ICIs). Keyword burst analysis indicates that the current research focuses and trends mainly center around four areas: ICIs, clinical trials, efficacy, and non-small cell lung cancer (NSCLC).

This is the first bibliometric study of neoadjuvant therapy in lung cancer. Over the past two decades, interest in this field has steadily increased, particularly since 2017. The United States is the largest contributor and has the highest number of publications in this field. Immune checkpoint inhibitors, clinical trials, efficacy, and NSCLC are hotspots in neoadjuvant therapy for lung cancer, both now and in the foreseeable future.

To investigate the safety and feasibility of sleeve resection under Uni-VATS following neoadjuvant chemotherapy combined with immunotherapy for locally advanced central-type non-small cell lung cancer(NSCLC).

We analyzed 10 cIIB-IIIB NSCLC patients who underwent sleeve lung resection under single-port thoracoscopy from December 2022 to August 2023 after receiving platinum-based chemotherapy combined with albumin paclitaxel and programmed cell death protein-1 (PD-1) inhibitor drugs. Perioperative clinical data, side effects during neoadjuvant therapy, operation time, intraoperative blood loss, conversion rate to open thoracotomy, postoperative duration of chest tube placement, postoperative drainage volume, postoperative complications, and tumor outcomes were recorded.

This study included 10 patients. The preoperative clinical staging distribution was as follows: Stage IIB, 1 case; Stage IIIA, 5 cases; and Stage IIIB, 4 cases. Imaging evaluation after neoadjuvant therapy revealed that none of the patients achieved complete remission, whereas partial remission and stable disease were observed in 7 cases and 3 cases, respectively. All patients successfully underwent surgery, of which 2 patients required conversion to open thoracotomy (conversion rate, 20%) and 8 patients underwent single-port thoracoscopic minimally invasive surgery. Notably, 2 patients underwent sleeve resection of the right upper lobe, 2 patients underwent sleeve resection of the right middle and lower lobes, 2 patients underwent sleeve resection of the left upper lobe, and 4 patients underwent sleeve resection of the left lower lobe. The average operation time was 236 ± 87.7 min, the average intraoperative blood loss was 168 ± 62.5 mL, the average duration of chest tube placement was 5 days, the average total drainage volume was 1012 ± 464 mL, and the average hospitalization duration was 7 days. One patient developed encapsulated pleural effusion after surgery and underwent computed tomography (CT)-guided puncture drainage. At the 3-month and 6-month follow-up visits, no patient reported any particular discomfort, and chest radiography and CT revealed no abnormalities or signs of tumor recurrence.

Sleeve resection after neoadjuvant chemotherapy combined with immunotherapy for locally advanced central-type NSCLC under single-port thoracoscopy is safe and feasible and provides short-term postoperative benefits for patients.

Endometrial cancer is now the most lethal gynecologic malignancy, with incidence rates rising globally. Treatment strategies have historically been focused on a combination of surgery, radiation, and/or chemotherapy based primarily on histology and extent of tumor. Advances in the evaluation and treatment of endometrial cancers are occurring at a rapid pace, with a new focus on genomic profiling and targeted therapies. Surgical removal of the tumor remains the mainstay of therapy, but adjuvant treatments are a shifting paradigm. In the realm of gynecologic malignancies, endometrial cancer leads in the evolution of precision medicine. The ability to analyze patients, tumors, and therapy has increased over the past 10 years. Gaps in knowledge about racial and ethnic disparities, as well as pre-invasive disease prevention, are closing. This review describes the advances in endometrial cancer with a focus on people at risk, molecular classification, and modern therapeutic strategies.

Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window. Several signal-finding studies explored a limited number of cycles prior to surgery and reproducibly reported complete or major histopathologic responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab, or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathologic responses experienced particularly favorable long-term outcomes. It is yet unclear whether there is true synergism between immunotherapy and chemotherapy and whether outcomes are further improved by adding postoperative checkpoint inhibition. Although these pivotal trials qualify neoadjuvant chemoimmunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. In this work, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small cell lung cancer are reviewed.

In advanced non-small cell lung cancer (NSCLC), immune-checkpoint inhibitors (ICIs) can achieve significant clinical responses. This raises the question of whether to consider salvage surgery as a curative treatment option. Few case series reported encouraging results in terms of pathological response. However, intraoperative risk and postoperative morbidity have been highlighted. This study aims to assess the safety and feasibility of surgery after ICIs administration and to evaluate its effectiveness on the final pathological examination.

We retrospectively identified stages III-IVA NSCLC consecutive patients who underwent surgery with radical intent after ICIs at three National Centers (2016-2022). Before treatment, all patients were considered unresectable by a multidisciplinary discussion. After surgery, pathological response was evaluated according to the International Association for the Study of Lung Cancer (IASLC) recommendation.

Thirty-one patients were included; pretreatment clinical stage was: IIIA in 4 patients (10%), IIIB in 13 (42%), IIIC in 3 (13%), and IVA in 11 (35%). Median treatment duration was four cycles. Only anatomical resections were performed, with lobectomy that represent the main type of resection (22 patients, 74%). A minimally invasive approach was performed in 10 patients (32%), with a conversion rate of 0%. Postoperative complications were observed in eight patients (25%). Complete pathologic response (CPR) and major pathologic response (MPR) were 48% and 16%, respectively. Two and 3-years survival were 88%.

Based on our experience, salvage surgery of advanced NSCLC treated with ICIs confirm his feasibility and safety in responder patients. Moreover, it is associated with low morbidity, high CPR rate, and satisfying medium-term survival.

Patients with locally advanced oral squamous cell carcinoma (OSCC) have poor outcomes with standard care. Neoadjuvant therapy is shown to be effective for these patients. In the randomized, two-arm, phase 2, non-comparative trial, we investigate the efficacy and safety of the neoadjuvant programmed cell death 1 (PD-1) inhibitor camrelizumab with or without docetaxel-cisplatin-5-fluorouracil (TPF) chemotherapy in patients with resectable locally advanced OSCC. Patients with stage III-IVA OSCC receive neoadjuvant therapy with three cycles of camrelizumab (arm Cam) with or without two cycles of TPF chemotherapy (arm Cam+TPF), followed by surgery and adjuvant therapy. Major pathological response (MPR) is achieved in both arm Cam (5/34, 14.7%) and arm Cam+TPF (26/34, 76.4%). With a median follow-up of 32 months, the 2-year event-free survival (EFS) rate of arm Cam and Cam+TPF is 52.9% and 91.2%, respectively. This work demonstrates feasibility and safety for immunochemotherapy in the neoadjuvant setting for OSCC. This study was registered at ClinicalTrials.gov (NCT04649476).

Introduction: Immunotherapy has revolutionized the treatment for locally advanced resectable non-small-cell lung cancer (NSCLC). In clinical trials, the combination of neoadjuvant immunotherapy and chemotherapy has resulted in a higher rate of pathologic complete response in comparison with neoadjuvant chemotherapy alone. Our study aims to describe surgical and oncological outcomes after neoadjuvant chemoimmunotherapy and lung resection at our academic center outside clinical trials. Methods: We retrospectively analyzed 54 patients who received neoadjuvant chemoimmunotherapy and underwent surgical resection from 2018 to 2024. Demographics, pre-operative systemic treatment, surgical approach and postoperative outcomes were evaluated. Results: The median age was 65 years, 46% were female, and 67% of patients had a non-squamous histology, chiefly adenocarcinoma. The most common clinical stage was IIIA (54%). Major findings include a 41% pathologic complete response (pCR) and 52% major pathologic response (MPR) rate. Neoadjuvant chemoimmunotherapy resulted in downstaging in 78% (n = 42) of patients. Most patients (83%) had their operation completed robotically. R0 resection was achieved in 96%. Median length of stay was significantly shorter after robotic operations, with no significant difference in complications compared to the open group. At a median follow up of 16 months, 24 months of recurrence-free survival was estimated at 76% (95% CI: 61-94) and overall survival, 93% (CI: 84-100). Conclusion: At our medical center, induction chemoimmunotherapy followed by anatomic lung resection has resulted in a high rate of complete pathologic response, overall survival and recurrence-free survival. The robotic approach after induction chemoimmunotherapy is safe and associated with shorter length of stay and faster recovery time.

Adjuvant osimertinib administered over a 3-year period in patients diagnosed with stage IB-IIIA non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations has not only shown improvement in event-free survival but also demonstrated a prolonged overall survival (OS), leading to its approval as a standard treatment in this context. Meanwhile, no targeted studies have been conducted on the efficacy of adjuvant immune checkpoint inhibitors in these patients. Although studies such as IMPOWER-010 and KEYNOTE-091 have included a small number of patients with positive driver genes, no definitive conclusions regarding the OS benefit have been established. Neoadjuvant targeted therapy is not currently recommended because of insufficient evidence, characterized by a low depth of pathological response and no reported improvement in survival outcomes. The same is true for neoadjuvant immunotherapy in patients with EGFR mutations. Although numerous issues such as refining patient population selection, determining appropriate combination therapy regimens, establishing primary endpoints, assessing the influence of perioperative complications, and accurately evaluating the clinical application of circulating tumor DNA in various scenarios exist, several promising ongoing trials, including ADAURA2 and NEOADURA, are expected to provide valuable insights that will help address these questions. Here, we summarize the available evidence and clinical issues that need to be considered to optimize clinical decision-making for patients with EGFR-mutant NSCLC.

Surgical resection is the most effective therapeutic option for the cure in early stage resectable non-small-cell lung cancer (NSCLC). However, despite complete resection, up to 70% of patients die within 5 years mainly due to tumor recurrence in extra-thoracic organs. Adjuvant or neoadjuvant platinum-based chemotherapy may improve postoperative survival, but the absolute survival benefit is modest with an around 5% improvement at 5 years. Recent advance in systemic therapy has changed treatment strategy for advanced unresectable NSCLC, and also has provided a paradigm shift in treatment strategy for resectable NSCLC. For NSCLC without oncogenic driver alterations, immunotherapy using immune-checkpoint inhibitors may improve clinical outcomes in preoperative neoadjuvant setting as well as in postoperative adjuvant setting. Here, we overview recent evidence of adjuvant and neoadjuvant therapy and discuss emerging clinical questions in decision-making of treatment for potentially resectable patients with NSCLC harboring no oncogenic alterations.