The effects of the tumor microenvironment the therapeutic efficacy of combining chemotherapy with checkpoint inhibitors in patients with lung cancer harboring rare -driver mutations remain unclear. We utilized single-cell RNA- and T-cell receptor (TCR) -sequencing to explore the immune and stromal cell profiles of 12 tumors and five tumor-adjacent tissues in seven patients with non-small cell lung cancer (NSCLCs) with rare -driver mutations treated with anti-PD-1 agents combined with chemotherapy. A class of highly expanded T -cells, known as GZMK + CD8+ effector memory T cells (GZMK + CD8+Tem), was enriched in both responsive tumors with and without rare driver mutations, suggesting similar anti-tumor immune mechanisms in both cohorts and that high levels of GZMK + CD8+Tem might be associated with effective responses to combination therapy. Non-responsive tumors exhibited a highly immunosuppressive M2-phenotype with enriched macrophages and monocytes. In non-major pathological response tumors, tumor cells interacted with alveolar and M0 macrophages via LAMC2-(ITGA6+ITGB1), possibly leading to M2 polarization. OAS1 was specifically expressed in CHIT1+ and FABP4+ macrophages and promoted macrophage polarization. These findings suggest that combination therapy reprogramed alveolar and M0-like macrophages to a pro-tumor phenotype, creating an immunosuppressive tumor microenvironment that resisted anti-PD1 therapy. In conclusion, GZMK + CD8+Tem is crucial for effective responses, whereas myeloid cells contribute to the immunosuppressive effects in anti-PD-1 therapies for NSCLCs with rare-driver mutations.

To date, no direct comparisons have been performed to compare the effectiveness of all epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutation-positive non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of EGFR-TKIs in patients with EGFR mutation-positive NSCLC.

We conducted a network meta-analysis of randomized controlled trials comparing osimertinib, lazertinib, aumolertinib, befotertinib, furmonertinib, dacomitinib, afatinib, erlotinib, gefitinib, icotinib, and chemotherapy. Pooled estimations of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity (grade ≥ 3 adverse events) were performed within the Bayesian framework.

Twenty-three trials involving 11 treatments were included. All EGFR-TKIs improved PFS relative to chemotherapy, except for icotinib (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.26-1.44). All EGFR-TKIs demonstrated significant ORR benefits over chemotherapy. Osimertinib seemed to prolong PFS compared with icotinib (HR = 0.29, 95% CI: 0.1-0.86), gefitinib (HR = 0.39, 95% CI: 0.21-0.74), and erlotinib (HR = 0.53, 95% CI: 0.29-1.0). In addition, osimertinib showed favorable superiority in improving OS compared with chemotherapy (HR = 0.6, 95% CI: 0.43-0.82), gefitinib (HR = 0.61, 95% CI: 0.45-0.83), erlotinib (HR = 0.65, 95% CI: 0.48-0.89), and afatinib (HR = 0.65, 95% CI: 0.44-0.94). Among these regimens, afatinib showed the highest ORR (cumulative probability: 96.96%). Icotinib was associated with minimal toxicity among the EGFR-TKIs, followed by furmonertinib and osimertinib. Moreover, the toxicity spectra differed among the EGFR-TKIs. Subgroup analyses of patients with two common types of EGFR mutations indicated that furmonertinib possessed the greatest PFS benefit in patients with exon 19 deletion, and lazertinib showed the greatest PFS benefit in patients with Leu858Arg mutation. We also identified differences between EGFR-TKIs in prolonging PFS in patients with brain metastasis.

Osimertinib is the first choice of treatment with considerable efficacy and safety for EGFR mutation-positive NSCLC. The treatments associated with the best PFS in patients with exon 19 deletions and Leu858Arg mutations were furmonertinib and lazertinib, respectively.

Neoadjuvant therapy with tyrosine kinase inhibitors has been proposed as a feasible approach for downstaging potential resectable non-small cell lung cancer (NSCLC). Pralsetinib is a paradigm of precision medicine for cancers driven by mutant RET (rearranged during transfection). In this case, we reported dramatic response to Pralsetinib in a stage IV NSCLC patient with RET rearrangement. Strikingly, treatment with 10 months of Pralsetinib impended downstaging of the N2 lymph node and metastatic pleural disease. Histological examination of the surgically resected specimen indicated a pathologic complete response (pCR). The patient was recommended to continue Pralsetinib as an adjuvant therapy. This case highlighted potential application of Pralsetinib in locally advanced RET-positive NSCLC to prime surgical resection. Postoperative Pralsetinib adjuvant therapy should also be considered.

Our previous study has showed the safety and efficacy of preoperative gefitinib in patients with stage II-IIIA resectable non-small cell lung cancer (NSCLC). This study aimed to report the long-term survival analysis and recurrent patterns.

This was a single-arm, phase II clinical trial. Patients with resectable stage II-IIIA NSCLC harboring EGFR exon 19 deletion or exon 21 L858R mutations were enrolled. Patients were administrated with preoperative gefitinib (250 mg once daily for 42 days), followed by surgical resection. The primary endpoint was objective response rate (ORR); secondary endpoints included the rate of major pathologic response (MPR), disease-free survival (DFS), overall survival (OS). MPR was defined as the presence of no more than 10 % viable tumor. Chi-square test was used to assess the differences in CNS recurrence rates and recurrent patterns.

Of the 33 intention-to-treat patients, ORR was 54.5 % (95 % confidence interval (CI), 37.7-70.7), and the rate of MPR was 24.2 % (95 % CI, 11.9-40.4). Among the investigated 28 patients, the median follow-up was 108.5 months. The median OS was 89.8 months (95 % CI, 44.37-NC), and the median DFS was 36.4 months (95 % CI, 18.9-NC). In addition, MPR continued to indicate significantly improved DFS, as well as OS (DFS, p = 0.015; OS, p = 0.037). The neoadjuvant gefitinib group showed prolonged DFS and OS than platinum doublet group (hazard ratio (HR) = 1.71, 95 % CI, 1.02-2.85, p = 0.038; and HR = 2.31; 95 % CI, 1.28-4.16, p = 0.0044, respectively). There was a significant difference in the distant recurrence patterns between the two groups (p = 0.032). Moreover, the gefitinib group showed similar overall brain metastasis rate than platinum doublet group (21.4 % versus 27.5 %).

With satisfying prognosis benefits and acceptable brain metastasis rate in long-term follow-up, gefitinib exhibited clinical viability for operable stage II-IIIA EGFR-mutant NSCLC over chemotherapy in the neoadjuvant setting. MPR was significantly associated with both prolonged DFS and OS, manifesting its potential as an essential endpoint for future neoadjuvant trials.

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.

The peri-operative management of non-small cell lung cancer (NSCLC) in earlier stage disease has seen significant advances in recent years with the incorporation of immune checkpoint inhibitors and targeted therapy. However, many unanswered questions and challenges remain, including the application of clinical trial data to routine clinical practice. Recognising the unique demographic profile of Asian patients with NSCLC and heterogeneous healthcare systems, the Asian Thoracic Oncology Research Group (ATORG) convened a consensus meeting in Singapore on 26 April 2024 to discuss relevant issues spanning diagnostic testing to post-neoadjuvant treatment considerations and future directions. An interdisciplinary group of 19 experts comprising medical oncologists, thoracic surgeons, radiation oncologists, pulmonologists and pathologists from Singapore, Hong Kong, Mainland China, Korea, Japan, Taiwan, India, Malaysia, Thailand, Vietnam and Australia met to discuss emerging data, identify existing gaps in clinical care and develop a multidisciplinary, multinational expert consensus statement on the peri-operative management of NSCLC tailored to the Asia-Pacific region.

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

Treatments for invasive T4 non-small cell lung cancer (NSCLC) tumors have been traditionally individualized and often require multidisciplinary team (MDT) evaluation. Advances in precision medicine may open up new opportunities for these patients.

This retrospective cohort study, using the Surveillance, Epidemiology, and End Results (SEER) database, identified T4N0-3M0 NSCLC patients with central structure invasion from 2010 to 2020. Precision medicine has progressed in three periods: 2010-2014 (targeted therapy), 2015-2017 (initial immunotherapy), and 2018-2020 (latest immunotherapy). We utilized Propensity Score Matching (PSM) to control confounding factors and competing risk regression models to evaluate cancer-specific survival (CSS).

A total of 9,106 cases were matched after PSM. For all populations, the median overall survival (OS) significantly increased with the advancement of precision medicine: 23.0 months in Period I (95 ​% CI: 22.0-25.0), 28.0 months in Period II (95 ​% CI: 26.0-31.0), and not reached (NR) in Period III (95 ​% CI: 30.0 - NR). Multivariate analysis also revealed a sequential survival improvement from Period I to III (p ​< ​0.001). Surgery-based treatment yielded the longest median OS at 46.0 months (95 ​% CI: 43.0-49.0, p ​< ​0.001), compared with chemoradiotherapy, chemotherapy alone and radiation alone. Surgery-based treatment has also yielded the best survival in three precision medicine eras, in both N0-1 and N2-3 categories. After analyzing CSS, the results above remained consistent. The survival following chemoradiotherapy and chemotherapy alone has seen significant and progressive enhancements across the three eras of precision medicine. There were no significant survival differences between Periods I and II among surgery-based patients, but a slight improvement trend was noted in Period III.

This retrospective study indicated that as precision medicine for NSCLC evolved, personalized treatment strategies supported by effective MDT led to survival improvement. Notably, for invasive stage III patients, surgery-based strategies have consistently shown substantial benefits across all the periods, irrespective of the N stage. The integration of perioperative therapies to enhance surgical feasibility, especially the latest immunotherapy, holds particular promise for further survival benefits.

The absolute overall survival (OS) improvement with preoperative chemotherapy or chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) patients is controversial and unsatisfactory. We designed this trial to explore the efficacy and safety of perioperative sintilimab plus platinum-based chemotherapy for potentially resectable stage IIIB NSCLC to facilitate further optimization of this therapeutic strategy.

Patients diagnosed with stage IIIB NSCLC through invasive staging approaches and/or PET/CT scans and evaluated as having a high probability of radical resection of the primary lesion and metastatic lymph nodes with clear pathological margins by a multidisciplinary team were enrolled in this open-label, single-arm, phase II trial at a single centre in China. The participants received two cycles of intravenous neoadjuvant treatment with PD-1 inhibitor sintilimab (200 mg), pemetrexed (500 mg/m2) for adenocarcinoma, paclitaxel (175 mg/m2) or nab-paclitaxel (260 mg/m2) for other histological subtypes, plus carboplatin (area under the curve 5) or cisplatin (75 mg/m2) on the first day of each 3-week cycle. Surgical resection was performed 28-42 days later. After recovery from surgery, two cycles of adjuvant treatment were carried out in strict conformity with the neoadjuvant regimen, and then sintilimab maintenance monotherapy were given. The primary endpoint was major pathological response (MPR). The key secondary endpoints included the objective response rate (ORR), radical resection (R0) rate, pathological complete response (pCR) rate, event-free survival (EFS), disease-free survival (DFS), OS, treatment-related adverse events (TRAEs), surgical complications, and surgery delay rate. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2000040673).

Forty-one patients were assessed for eligibility between December 2020 and August 2022; 30 patients were enrolled and given two cycles of neoadjuvant chemoimmunotherapy (neoCIT). Nineteen patients achieved a radiographic partial response, resulting in an ORR of 63.3%. Although 26 patients (86.7%) experienced TRAEs during the neoadjuvant phase, only two patients (6.7%) had ≥ grade 3 TRAEs. Surgical resection was performed on 27 patients (90%), with two patients experienced surgical delay because of coronavirus disease 2019, and the R0 rate was 96.4%. Twelve patients (44.4%) in the per-protocol (PP) population achieved an MPR, including six patients (22.2%) with a pCR. The most common postoperative complications were atrial fibrillation (6, 22.2%), pneumonitis (5, 18.5%), and heart failure (4, 14.8%); no deaths occurred within 90 days after surgery. As of October 31, 2024, the median follow-up was 34.7 months. The estimated EFS and OS rates at 36 months in the intention-to-treat population were 42.8% and 70.1%, respectively, and the estimated DFS and OS rates at 36 months in the PP population were 52.5% and 70.4%, respectively.

Perioperative sintilimab plus platinum-based chemotherapy is an emerging treatment option for patients with potentially resectable stage IIIB NSCLC; it has a high response rate and tolerable treatment-related toxic effects, and enables radical resection in most patients.

The Cancer Research Program of National Cancer Center (NCC201919B02), Shenzhen Clinical Research Center for Cancer (No. [2021]287), Shenzhen High-level Hospital Construction Fund, Shenzhen Key Medical Discipline Construction Fund (SZXK075) and Sanming Project of Medicine in Shenzhen (SZSM201612097) funded this study.

The contemporary management and resectability of locally advanced lung cancer are undergoing significant changes as new data emerge regarding immunotherapy and targeted treatments. The objective of this document is to review the literature and present consensus among a group of multidisciplinary experts to guide the determination of resectability and management of locally advanced non-small cell lung cancer (NSCLC) in the context of contemporary evidence.

The Society of Thoracic Surgeon Workforce on Thoracic Surgery assembled a multidisciplinary expert panel composed of thoracic surgeons and medical and radiation oncologists with established expertise in the management of lung cancer. A focused literature review was performed, and expert consensus statements were developed using a modified Delphi process to address 3 major themes: (1) assessing resectability and multidisciplinary management of locally advanced lung cancer, (2) neoadjuvant (including perioperative) therapy, and (3) adjuvant therapy.

A consensus was reached on 19 recommendations. These consensus statements reflect updated insights on resectability and multidisciplinary management of locally advanced lung cancer based on the latest literature and current clinical experience, mainly focusing on the appropriateness of surgical therapy and emerging data regarding neoadjuvant and adjuvant therapies.

Despite the complex decision-making process in managing locally advanced lung cancer, this expert panel agreed on several key recommendations. This document provides guidance for thoracic surgeons and other medical professionals in the optimal management of locally advanced lung cancer based on the most updated evidence and literature.

The challenge with breast cancer is its ongoing high prevalence and difficulties in early detection and access to effective care. A solution lies in creating tailored metal-organic frameworks to encapsulate anticancer drugs, enabling precise and targeted treatment with less adverse effects and improved effectiveness. Zeolitic imidazolate framework-8 (ZIF-8) and carboplatin (CP)-loaded ZIF-8 were synthesized and characterized using various analytical techniques. High Resolution-transmission electron microscopy of ZIF-8 and CP@ZIF-8 indicates that the particles had a spherical shape and were nanosized. The drug release rate of CP is 98% under an acidic medium (pH 5.5) because of the dissolution of ZIF-8 into its coordinating ions, whereas 35% in a physiological medium (pH 7.4) with the addition of CP, the high porosity, and pore diameter of ZIF-8 decrease from 1243 to 1041 m2/g. Breast cancer MCF-7 cells were shown greater IC50 in CP@ZIF-8 (15.01 ± 3.03 µg/mL) than free CP (34.98 ± 4.25 µg/mL) in an in vitro cytotoxicity assessment. The cytotoxicity of the CP@ZIF-8 against MCF-7 cells was studied using the methylthiazolyldiphenyl-tetrazolium bromide method. The morphological changes were examined using fluorescent staining (acridine orange-ethidium bromide and Hoechst 33258) methods. The comet assay assessed the DNA fragmentation (single-cell gel electrophoresis). The results from the study revealed that CP@ZIF-8 can be used in the treatment of breast cancer.

Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare (3%-4%) driver mutation in non-small cell lung cancer (NSCLC). Tepotinib, a selective MET inhibitor, has shown promise in treating METex14 skipping-mutated NSCLC. However, its feasibility for perioperative application remains unclear. This report describes a 60-year-old man with stage IIIA (cT2N2M0) lung adenocarcinoma harboring a METex14 skipping mutation. After initial treatment with savolitinib was discontinued due to grade 4 transaminitis, the patient was switched to tepotinib, resulting in significant tumor regression. Six months later, further shrinkage was observed, and surgery revealed remarkable pathological response with no residual tumor in lymph nodes (ypT2N0M0, IB). Postoperative tepotinib continued, with no relapse at 6-month follow-up. This case highlights the potential of tepotinib as neoadjuvant therapy for resectable METex14 skipping-mutated NSCLC, warranting further clinical trials.

Given that immunotherapy has resulted in a significant overall survival (OS) benefit in advanced-stage disease, it is of notable interest to determine the effectiveness of these agents in early-stage non-small cell lung cancer (NSCLC). The potential exists for the immunotherapeutic approach in early-stage NSCLC to mirror the paradigm seen in advanced NSCLC, wherein survival enhancements have notably benefited the majority of patients. However, their performance in early-stage epidermal growth factor receptor (EGFR) mutant NSCLC is controversial. In the limited studies that included patients with EGFR mutation status, we found unexpected, good survival benefits of perioperative immune checkpoint inhibitors (ICIs) in resectable EGFR-positive NSCLC, which is controversial with those in advanced EGFR-mutant NSCLC. It is possible because of the shift toward immunosuppression that the immune environment undergoes during tumor progression. In the early disease stages, the anti-tumor immune response can be activated with fewer hindrances. In the context of EGFR mutant tumors, intratumor genetic heterogeneity can generate treatment-sensitive and -resistant subclones. The subclonality of the resistant subclone is pivotal in therapy response, with tyrosine kinase inhibitors (TKIs) selectively controlling EGFR-mutant cell proliferation and "competitive release" potentially explaining lower pathological responses in adjuvant TKIs trials. This review delves into emerging data on perioperative treatment modalities for early-stage EGFR mutant NSCLC, exploring unique mechanisms and predictive biomarkers to guide perioperative management strategies.

Lung cancer remains the leading cause of cancer death in the United States, underscoring the critical need to optimize treatment strategies. Compared to conventional treatments such as surgical resection, radiotherapy, chemotherapy, and immunotherapy, targeted therapy stands out for its higher selectivity and minimal adverse effects. Among these, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most widely used in targeted therapy for non-small-cell lung cancer (NSCLC). In our paper, we will conduct a comprehensive review of current literature on EGFR TKIs to contribute to advancements in molecular genomics and the treatment of lung cancer.

There is limited literature on the prevalence of EGFR mutations in early stage NSCLC. EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early stage NSCLC.

This noninterventional, real-world study enrolled consecutive patients with resected stages IA to IIIB (American Joint Committee on Cancer eighth edition) NSCLC from 14 countries across Asia, Latin America, and the Middle East and Africa. The primary end point was prevalence of EGFR mutations and secondary end points included prevalence of EGFR mutation subtypes and treatment patterns.

Of 601 patients (median [range] age: 62.0 [30.0-86.0] y) enrolled, 52.7% were females and 64.2% were nonsmokers. Most had stages IA to IB NSCLC (64.1%) and adenocarcinoma (98.7%). Overall prevalence of EGFR mutations was 51.0%; most reported exon 19 deletions (48.5%) followed by exon 21 L858R mutations (34.0%). Women had a higher EGFR mutation rate than men (64.0% versus 36.4%). Compared with no EGFR mutations, patients with EGFR mutations were more likely to be nonsmokers (35.1% versus 60.9%) and have stage I NSCLC than stages II and III NSCLC (54.8% versus 47.3% and 35.6%). Systemic adjuvant therapy was planned in 33.8% of the patients with stages IB to IIIB disease and adjuvant chemoradiotherapy in 6.8%. Age above or equal to 60 years, females, and Asians were found to have a significantly (p < 0.05) higher odds of EGFR mutations, whereas smoking history and stage III disease had lower odds of EGFR mutations.

The EARLY-EGFR study provides an overview of EGFR mutations and subtype prevalence in patients with early stage NSCLC. The study highlights the limited adherence to treatment guidelines suggesting an unmet need for improved adjuvant therapy.

Advances in primary lung cancer drug therapy have extended patients' survival, including patients with stage IV disease. This study assessed the safety and effectiveness of salvage surgery following tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) therapy in primary lung cancer.

A retrospective chart review was conducted of 2050 primary lung cancer surgeries performed at our institution between 2012 and 2022. The study included patients who underwent salvage surgery for unresectable lesions that became resectable or localized residual lesions after treatment. We investigated patients' clinicopathological characteristics, therapeutic responses, and survival outcomes.

We identified eight cases of salvage surgery after TKI treatment and eight cases after ICI treatment. Five patients experienced early recurrence after surgery; however, the long-term outcome in the post-TKI group was favorable, with a median overall survival (OS) of 66 (range: 28-80) months. Postoperative recurrence was confined to local lymph node recurrence in one patient in the post-ICI group. Despite the relatively short observation period, the long-term prognosis remained promising, with a median OS of 18.7 (range: 9.7-55.8) months.

Salvage surgery after TKI or ICI treatment can be safely performed, and the OS may be favorable.

This case report details the successful treatment of a 68-year-old male patient with locally advanced RET-rearranged lung adenocarcinoma using neoadjuvant pralsetinib. The patient initially presented with a suspicious right upper lobe nodule, which was later diagnosed as lung adenocarcinoma following genetic testing that revealed a RET exon 12 fusion. After 2 months of neoadjuvant treatment with pralsetinib, a significant radiological response was observed, with a reduction in tumor size and metabolic activity. Subsequently, the patient underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection. Postoperative pathological analysis revealed a major pathological response, with only 5% residual tumor cells in the primary lesion and no viable tumor cells in the lymph nodes. Postoperative pathological staging of TNM was ypT1aN0M0, stage IA1(AJCC, 8th edition). The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC).

This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling.

A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%).

Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

We evaluated the clinicopathological and oncological characteristics of epidermal growth factor receptor-mutated clinical stage IA radiological pure-solid lung adenocarcinoma and compared them with those of a ground-glass opacity component.

Between 2008 and 2020, data from 1014 surgically resected clinical stage 0-IA epidermal growth factor receptor-mutated lung adenocarcinomas were evaluated. Oncological outcomes were assessed using multivariable analysis. Overall survival was estimated using Kaplan-Meier analysis and the log-rank test. The cumulative incidence of recurrence was estimated using the Gray's test.

Of these, 233 (23%) were radiologically pure-solid tumors, which demonstrated a higher proportion of nodal metastasis, micropapillary component, spread through alveolar space, and Ex19 subtype compared with those of tumors with ground-glass opacity (P < .001). Multivariable analysis revealed that the presence of ground-glass opacity was an independently significant factor for overall survival (P = .037) and cumulative incidence of recurrence (P < .001). In cases where the oncological outcomes were stratified by the presence of ground-glass opacity component, the 5-year overall survival was excellent at more than 90% in tumors with ground-glass opacity despite clinical-T categories (P = .2044); however, tumor size significantly affected survival only in pure-solid tumors (T1a, 100%; T1b, 77.7%; T1c, 68.5%; P = .0056). Furthermore, the cumulative incidence of recurrence was low in tumors with ground-glass opacity despite the clinical-T categories, whereas tumor size significantly affected the cumulative incidence of recurrence only in pure-solid tumors (5-year cumulative incidence of recurrence: T1a-b, 18.9%; T1c, 41.3%; P < .001).

Oncologic behavior and prognosis of radiologically pure-solid tumors were significantly poorer than those of tumors with ground-glass opacity among patients with epidermal growth factor receptor-mutated early-stage lung adenocarcinoma. These findings imply distinct tumorigenesis based on the presence of ground-glass opacity, even in tumors with epidermal growth factor receptor mutations.

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

Neoadjuvant therapy improves survival benefits in patients with locally advanced non-small cell lung cancer but increases tissue density, presenting challenges for surgeons.

To compare the differences in surgical complexity and short-term prognostic outcomes between neoadjuvant targeted therapy (NTT) and neoadjuvant chemoimmunotherapy (NCI).

This study enrolled 106 patients underwent curative surgery after neoadjuvant therapy between January 2020 and December 2023 at the National Cancer Center of China. Differences in surgical complexity and short-term prognostic outcomes between the two neoadjuvant therapy cohorts were evaluated. The pathological indicators such as pathological response rate and lymph node upstaging/downstaging were then analyzed.

In total, 33 patients underwent NTT and 73 underwent NCI preoperatively. Patients who received NTT showed a higher minimally invasive surgery rate (84.8% versus 53.4%, p < 0.01), shorter operative time (144 versus 184 min, p < 0.01), lower conversion rate (3.3% versus 17.8%, p = 0.03), less postoperative drainage (day 3: 140 versus 200 mL, p = 0.03), and lower incidence of postoperative complications including arrhythmias (6.1% versus 26%, p = 0.02). The pathological response rate in the NTT and NCI groups was 70% and 75%, respectively, with the latter group showing a higher complete pathological response rate. The two groups had no significant differences in major pathological response and lymph node pathological response rate.

Patients who received NTT presented fewer surgical challenges for surgeons and had better surgical outcomes than those who received NCI therapy, with comparable pathological response rates between the two cohorts. Accordingly, NTT is the preferred induction regimen for patients harboring mutation status.

Non-small cell lung cancer (NSCLC) that is operable still carries a high risk of recurrence, approaching 50% of all operable cases despite adding adjuvant chemotherapy. However, the utilization of immunotherapy and targeted therapy moving beyond the metastatic NSCLC setting and into early-stage perioperative management has generated tremendous enthusiasm and has been practice-changing. Adjuvant atezolizumab in NSCLC first demonstrated a clinical benefit with an immune checkpoint inhibitor. Then, with studies studying a significant benefit in major pathologic response in surgical patients treated preoperatively with immunotherapy compared to only chemotherapy, neoadjuvant nivolumab and chemotherapy were evaluated and showed significant event-free survival benefit leading to subsequent studies evaluating perioperative immunotherapy and chemotherapy. Meanwhile, with regards to targeted therapies, adjuvant osimertinib in EGFR-mutated NSCLC and adjuvant alectinib in ALK-rearranged NSCLC have both received regulatory approvals following demonstrated clinical benefit in clinical trials. With rapidly evolving changes in the field, new combinations such as multiple immunotherapy agents and antibody-drug conjugates in development, perioperative NSCLC management has quickly become complicated with different pathways to perioperative treatment. Furthermore, circulating tumor DNA and studies looking at better tools to prognosticate immunotherapy response will help with decision-making regarding which patients should receive immunotherapy and if so, either only pre-operatively or both pre- and post-operatively. In this review, we look at the evolution of systemic therapy in the perioperative setting from adjuvant chemotherapy to adjuvant immunotherapy to perioperative immunotherapy and look at perioperative targeted therapy while looking ahead to future considerations.

This study aimed to assess the role and effect of neoadjuvant targeted therapy (TT) versus targeted combined with chemotherapy (TC) for resectable EGFR-mutant non-small cell lung cancer (NSCLC).

Between March 2021 and June 2023, 20 patients with stage IA3-IIIB NSCLC were enrolled in the study. Eleven patients received EGFR-TKIs in the TT group, while nine patients received EGFR-TKIs and two cycles of cisplatin-based doublet chemotherapy (TC group). We compare the differences between the two groups through the following variables, including age, sex, surgical approach, postoperative complications, neoadjuvant therapy adverse events, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), major pathologic response (MPR), and pathologic complete response (pCR).

Patients were predominantly female (75%) and never-smokers (95%). The average age was 59.2 years (range 46-79 years). Fifty-five percent harbored an exon 19 EGFR mutation and 45% an exon 21 mutation. The average targeted drug dosing time was 2.91 ± 1.7 (range 1-6) months in the TT group and 3.56 ± 3.54 (range 1-12) months in the TC group (P=0.598). The most common side effects were rash and diarrhea. No grade 5 events with neoadjuvant therapy were observed. The rate of R0 resection was 100% in all patients. Among the 11 patients in the TT group, 6 achieved a PR and 5 had SD, resulting in an ORR of 54.5%. Among the 9 patients in the TC group, 6 had PR and the remaining 3 had SD, resulting in an ORR of 66.6%. one patient (11.1%) in the TC group achieved pCR, while no patients in the TT group achieved pCR (P = 0.142). Two patients (18.2%) in the TT group reached MPR, and 2 patients (22.2%) in the TC group reached MPR (P = 0.257). The overall clinical downstage rate is 60%. Only 9 (45%) cases of yield clinical TNM (ycTNM) were consistent with yield pathologic TNM (ypTNM).

Results from this retrospective controlled research indicate that the neoadjuvant TT group is likely to be more effective outcomes and has safer profile in patients with EGFR-positive NSCLC than the neoadjuvant TC group. However, our results need to be validated in a multicenter, large sample prospective study.

Osimertinib is a third-generation tyrosine kinase inhibitor that targets mutant epidermal growth factor receptor (EGFR). The success of FLAURA and ADAURA trials prompted the license of Osimertinib for the treatment of EGFR mutant non-small cell lung cancer (NSCLC) at advanced stage and for patients with stages IB to IIIA disease in post-operative setting. In the present study, we described neoadjuvant use of Osimertinib in an EGFR mutant NSCLC patient with locally metastatic disease (T2aN2M0). Intriguingly, the cavitated NSCLC resembled an impressive"Halloween pumpkin" appearance that dramatically responded to Osimertinib treatment. Downstaging of N2 metastatic disease was reached and surgical resection was scheduled. The post-operative clinical stage was IA3. The patient was recommended to continue Osimertinib adjuvant treatment and our follow-ups showed no signs of disease recurrence. Our case study underscored the feasibility of Osimertinib as a neoadjuvant and adjuvant therapy for patients with locally advanced EGFR mutant NSCLC.

Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC.

Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained.

A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group.

Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

Non-small cell lung cancer (NSCLC) stages I-III are predominantly treated with surgery and combination immunotherapy and chemotherapy. A majority of these studies excluded patients with EGFR and ALK alterations. There are several completed and ongoing trials evaluating neoadjuvant treatment with EGFR-TKI monotherapy, combination therapy with chemotherapy, and combination therapy with immunotherapy. Here, we review completed clinical trials and discuss current ongoing trials' potential benefits, challenges, and future directions in the field.

To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.

To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.

MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients.

Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded.

Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis.

Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%).

This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

Radiofrequency ablation (RFA) is an effective alternative to surgery for managing some malignant solid tumors. However, for medium-to-large tumors (>3 cm), tumors adjacent to large blood vessels, and certain irregular tumors, sublethal radiofrequency hyperthermia (RFH) often produces a margin of ablated tumor owing to the "heat-sink" effect. This effect typically leaves behind viable residual tumors at the margin. Several studies have reported that a sublethal RFH can significantly enhance the efficacy of chemotherapy, radiotherapy, immunotherapy, and gene therapy for malignant solid tumors. The possible mechanisms by which RFH enhances these therapies include heat-induced tissue fracturing, increased permeability of the cytoplasmic membrane, exaggerated cellular metabolism, blockade of the repair pathways of radiation-damaged tumor cells, and activation of the heat shock protein pathways. Therefore, RFA in combination with chemotherapy, radiotherapy, immunotherapy, or gene therapy may help reduce the rates of residual and recurrent tumors after RFA of malignant solid tumors.

The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC) is unclear. Previous studies have shown that EGFR-TKIs have excellent anti-tumor activity. However, almost all studies on neoadjuvant EGFR-TKI treatment for EGFR-mutated NSCLC have been non-randomized controlled trials with small sample sizes and different methods of statistical analysis, which may lead to a lack of valid metrics to assess the feasibility and safety of neoadjuvant EGFR-TKI treatment. This meta-analysis aimed to assess the efficacy and safety of neoadjuvant EGFR-TKI treatment for NSCLC patients with EGFR mutations.

Relevant studies were systematically searched in PubMed, Embase, and Web of Science databases. Results including objective response rate (ORR), complete resection rate (R0), downstaging rate, pathological complete response (PCR), major pathological response (MPR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were used for further analysis.

This meta-analysis ultimately included 11 studies involving 344 patients with EGFR-positive mutations in NSCLC. In terms of tumor response, the pooled ORR was 57% (95% CI: 42%-73%), and in the Osimertinib subgroup, the pooled ORR was 80% (95% CI: 63%-98%). Analysis of studies that reported a downstaging rate showed the pooled downstaging rate of 41% (95% CI: 9%-74%) and the pooled downstaging rate of 74% (95% CI: 22%-100%) in the Osimertinib subgroup. In terms of surgical outcomes, the pooled pCR rate was 3% (95% CI: 0%-7%), the pooled MPR rate was 11% (95% CI: 6%-17%), and the pooled R0 resection rate was 91% (95% CI: 85%-95%). The most common adverse events associated with neoadjuvant therapy were rash and diarrhea. The pooled incidence of any grade of rash was 47.1% (95% CI: 25.4%-69.3%), and the pooled incidence of grade ≥ 3 rash was 0.6% (95% CI: 0.0%-2.5%). The pooled incidence of diarrhea of any grade was 28.8% (95% CI: 14.4%-45.4%), with the pooled incidence of grade ≥ 3 diarrhea of 0.2% (95% CI: 0.0%-1.6%). The pooled incidence of ≥ grade 3 adverse events was significantly lower.

Our meta-analysis confirmed the efficacy and safety of neoadjuvant EGFR-TKIs for the treatment of NSCLC patients with EGFR-positive mutations and that third-generation EGFR-TKIs were superior to first- and second-generation EGFR-TKIs in terms of shrinking tumor volume and lowering tumor stage; however, future large-scale and multicenter randomized controlled trials are needed to confirm this conclusion.

PROSPERO CRD42023466731.

Stage IIIA-N2 non-small cell lung cancer (NSCLC) is a heterogeneous group with different potential therapeutic approaches. Treatment is typically multimodal with either surgical resection after neoadjuvant chemotherapy and/or radiation or concurrent chemotherapy and radiation if unresectable. Despite the multimodal treatment and early stage, cure rates have traditionally been low. The introduction of immunotherapy changed the treatment landscape for NSCLC in all stages, and the introduction of immunotherapy in early-stage lung cancer has improved event free survival and overall survival. Tyrosine Kinase inhibitors (TKIs) have also improved outcomes in early-stage mutation-driven NSCLC. Optimal treatment choice and sequence is increasingly becoming based upon personalized factors including clinical characteristics, comorbidities, programmed death-ligand 1 (PD-L1) score, and the presence of targetable mutations. Despite encouraging data from multiple trials, the optimal multimodal sequence of stage IIIA-N2 NSCLC treatment remains unresolved and warrants further investigation. This review article summarizes recent major clinical trials of neoadjuvant and adjuvant treatment including stage IIIA-N2 NSCLC with a focus on immunotherapy and TKIs.

Studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resectable non-small-cell lung cancer (NSCLC) have been conducted. The purpose of our study was to evaluate the benefits of osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC.

This retrospective study evaluated patients with EGFR mutations in exon 19 or 21 who received targeted therapy with osimertinib (80 mg per day) before surgery between January 2019 and October 2023 in Henan Cancer Hospital.

Twenty patients were evaluated, all of whom underwent surgery. The rate of R0 resection was 100% (20/20). The objective response rate was 80% (16/20), and the disease control rate was 95% (19/20). Postoperative pathological analysis showed a 25% (5/20) major pathological response rate and 15% (3/20) pathological complete response rate. In total, 25% (5/20) developed adverse events (AEs), and the rate of grades 3-4 AEs was 10% (2/20). One patient experienced a grade 3 skin rash, and 1 patient experienced grade 3 diarrhea.

Osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC is safe and well tolerated. Osimertinib has the potential to improve the radical resection rate and prognosis.

Treatment with 3 years of adjuvant osimertinib is considered a new standard in patients with completely resected stage I to IIIA NSCLC harboring a common sensitizing EGFR mutation. This therapeutic approach significantly prolonged the disease-free survival and the overall survival versus placebo and revealed a significant role in preventing the occurrence of brain metastases. However, many unanswered questions remain, including the optimal duration of this therapy, whether all patients benefit from adjuvant osimertinib, and the role of adjuvant chemotherapy in this population. Indeed, there is a renewed interest in neoadjuvant strategies with targeted therapies in resectable NSCLC harboring oncogenic drivers. In light of these considerations, we discuss the past and current treatment options, and the clinical challenges that should be addressed to optimize the treatment outcomes in this patient population.

Pancreatitis is a crucial risk factor for pancreatic ductal adenocarcinoma (PDAC), and our previous study had proved high-temperature requirement protein A1 (HTRA1) exacerbates pancreatitis insult; however, the function and mechanism of HTRA1 in pancreatitis-initiated PDAC is still unclear. In the present paper, we clarified the expression of HTRA1 in PDAC using bioinformatics and immunohistochemistry of tissue chip, and found that HTRA1 is significantly upregulated in PDAC. Moreover, the proliferation, migration, invasion and adhesion of PANC-1 and SW1990 cells were promoted by overexpression of HTRA1, but inhibited by knockdown of HTRA1. Meanwhile, we found that HTRA1 arrested PANC-1 and SW1990 cells at G2/M phase. Mechanistically, HTRA1 interacted with CDK1 protein, and CDK1 inhibitor reversed the malignant phenotype of PANC-1 and pancreatitis-initiated PDAC activated by HTRA1 overexpression. Finally, we discovered a small molecule drug that can inhibit HTRA1, carfilzomib, which has been proven to inhibit the biological functions of tumor cells in vitro and intercept the progression of pancreatitis-initiated PDAC in vivo. In conclusion, the activation of HTRA1-CDK1 pathway promotes the malignant phenotype of tumor cells by blocking the cell cycle at the G2/M phase, thereby accelerating pancreatitis-initiated PDAC. Carfilzomib is an innovative candidate drug that can inhibit pancreatitis-initiated PDAC through targeted inhibition of HTRA1.

Patients with stage IIIA/IIIB squamous non-small cell lung cancer (SqCLC) are particularly challenging to treat with a poor 5-year survival rate and new treatment strategies are needed. In the present study, a retrospective, single-center study was conducted to explore the efficacy and safety of Endostar combined with chemotherapy as the neoadjuvant treatment in patients with stage IIIA/IIIB SqCLC. A total of 27 patients with locally advanced SqCLC treated with Endostar combined with chemotherapy as neoadjuvant therapy from January 1, 2017 to December 31, 2019 at the Zhejiang Cancer Hospital (Hangzhou, China) were included. Short-term efficacy, rate of surgical resection, long-term outcome and adverse events were analyzed. After treatment with Endostar combined with chemotherapy, 37% of the patients underwent surgery and the radical resection rate was 90%. The objective response rate was 63% for the total population and 80% for patients who received surgery. Of note, 100% of the patients achieved disease control after treatment with Endostar combined with chemotherapy. In patients who underwent surgical resection, postoperative pathology showed that 100% of the patients achieved pathological downstaging. Furthermore, 1 (10%) patient showed a pathological complete response after surgery. The median progression-free survival was 13.5 months and overall survival was 27.9 months for the total cohort. The most common adverse events (AEs) were anemia (69.4% of patients), followed by hypertension (29.6% of patients). Most of the AEs were grade 1-2 and only 4 patients (14.8%) developed grade 3-4 AEs. Endostar combined with chemotherapy was well-tolerated and showed promising efficacy in patients with stage IIIA/IIIB SqCLC. Further prospective studies are warranted to explore its value as a neoadjuvant therapy.

Purpose: This study aimed to analyze the efficacy and safety of neoadjuvant and adjuvant immunotherapies for non-small cell lung cancer (NSCLC). Methods: Electronic literature searches were conducted in PubMed, OVID, Web of SCI, Embase, Cochrane Library, and the Chinese National Knowledge Infrastructure databases. The deadline for literature update and retrieval is February 16, 2024. Studies presented at meetings were also screened. Randomized controlled trials (RCTs) and single-arm trials were included, and the data were extracted according to the inclusion and exclusion criteria. Data analysis was performed using Stata (16.0) software. Results: A total of 5850 patients in 11 RCTs and 6 single-arm trial studies involving neoadjuvant and/or adjuvant immune checkpoint inhibitor (ICI)-based therapies were included. Regarding neoadjuvant therapy, the overall complication rate after surgery reached 35% (95% CI, 0.21-0.49). Higher rates of pathological complete response (OR = 7.83; 95% CI, 5.95-10.31; P < .001) and major pathological response (OR = 5.13; 95% CI, 3.56-7.40; P < .001) were found in the resectable NSCLC patients who received neoadjuvant therapy with ICIs combined with chemotherapy compared with patients treated with chemotherapy alone. Of note, compared with chemotherapy, neoadjuvant ICIs combined with chemotherapy significantly improved the overall survival (OS) (HR = 0.65; 95% CI, 0.52-0.82; P < .001) and event-free survival (EFS) (HR = 0.59; 95% CI, 0.52-0.67; P < .001) in patients with resectable NSCLC. Regarding adjuvant therapy, a lower risk of disease progression or death (HR = 0.78; 95% CI, 0.69-0.90; P < .001) was found in the adjuvant ICI group compared with the adjuvant chemotherapy-alone group. In terms of safety, perioperative immunotherapy combined with chemotherapy did not increase toxicity compared with chemotherapy alone. Conclusion: In patients with resectable NSCLC, perioperative immunotherapy was safe and efficacious. Perioperative immunotherapy combined with chemotherapy improved the pathologic response and EFS/DFS/OS over chemotherapy alone without increasing toxicity.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC.

This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling.

A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS.

NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one-third of affected patients have locally advanced NSCLC (LA-NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA-NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA-NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA-NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA-NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA-NSCLC.

Objective.Epidermal growth factor receptor (EGFR) mutation genotyping plays a pivotal role in targeted therapy for non-small cell lung cancer (NSCLC). We aimed to develop a computed tomography (CT) image-based hybrid deep radiomics model to predict EGFR mutation status in NSCLC and investigate the correlations between deep image and quantitative radiomics features.Approach.First, we retrospectively enrolled 818 patients from our centre and 131 patients from The Cancer Imaging Archive database to establish a training cohort (N= 654), an independent internal validation cohort (N= 164) and an external validation cohort (N= 131). Second, to predict EGFR mutation status, we developed three CT image-based models, namely, a multi-task deep neural network (DNN), a radiomics model and a feature fusion model. Third, we proposed a hybrid loss function to train the DNN model. Finally, to evaluate the model performance, we computed the areas under the receiver operating characteristic curves (AUCs) and decision curve analysis curves of the models.Main results.For the two validation cohorts, the feature fusion model achieved AUC values of 0.86 ± 0.03 and 0.80 ± 0.05, which were significantly higher than those of the single-task DNN and radiomics models (allP< 0.05). There was no significant difference between the feature fusion and the multi-task DNN models (P> 0.8). The binary prediction scores showed excellent prognostic value in predicting disease-free survival (P= 0.02) and overall survival (P< 0.005) for validation cohort 2.Significance.The results demonstrate that (1) the feature fusion and multi-task DNN models achieve significantly higher performance than that of the conventional radiomics and single-task DNN models, (2) the feature fusion model can decode the imaging phenotypes representing NSCLC heterogeneity related to both EGFR mutation and patient NSCLC prognosis, and (3) high correlations exist between some deep image and radiomics features.