Treatment Of Nasopharyngeal Carcinoma Research Articles

Shift in Tissue-Specific Immune Niches and CD137 Expression in Tuberculoma of Pembrolizumab-Treated Nasopharyngeal Carcinoma Patients.

The use of immune checkpoint inhibitors (ICIs) in cancer treatment has shown promise but can also have unintended consequences, such as reactivating latent tuberculosis (TB). To develop treatments that address ICIs-related adverse events, it is essential to understand cellular heterogeneity across healthy and pathological tissues. We performed cross-tissue multiplexed staining analysis on samples from two patients with TB reactivation during pembrolizumab treatment for metastatic nasopharyngeal carcinoma. CD8+ T cells, rather than CD4+ T cells, accumulated preferentially in the tuberculoma and were associated with increased production of IFNγ and expression of CD137. Additionally, CD137 enrichment played a role in the spatial organization of the tuberculoma, with specific interaction limited to spatial proximal cells between IFNγ+ CD137+ CD8+ T cells and IL12+ CD137+ type-1 macrophages. This unique feature was not observed in non-tumoral or tumoral tissues. Our analysis of public transcriptomic datasets supported the notion that this cellular interaction was more prominent in patients with durable ICI responses compared to those with non-ICI-related TB. We suggest that shifts towards CD137-rich immune niches are correlated with both off-target immune-related adverse events and anti-tumor efficacy. Targeting the tumor microenvironment through conditional activation of anti-CD137 signaling in combination with ICIs can modulate the reactivity of T cells and macrophages for localized tumor killing without the potential off-target immune-related risks associated with ICIs alone.

Prognostic Significance of Excision Repair Cross-Complementation Group 1 on Circulating Tumor Cells for Nasopharyngeal Carcinoma.

Liquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC. We retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed. The positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001). Our findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

Complicação iatrogênica do pneumoencéfalo hipertensivo da osteorradionecrose no tratamento do carcinoma nasofaríngeo. Um relato de caso e revisão crítica da literatura

Complicação iatrogênica do pneumoencéfalo hipertensivo da osteorradionecrose no tratamento do carcinoma nasofaríngeo. Um relato de caso e revisão crítica da literatura

Deep Learning-Based Prediction of Radiation Therapy Dose Distributions in Nasopharyngeal Carcinomas: A Preliminary Study Incorporating Multiple Features Including Images, Structures, and Dosimetry.

Purpose: Intensity-modulated radiotherapy (IMRT) is currently the most important treatment method for nasopharyngeal carcinoma (NPC). This study aimed to enhance prediction accuracy by incorporating dose information into a deep convolutional neural network (CNN) using a multichannel input method. Methods: A target conformal plan (TCP) was created based on the maximum planning target volume (PTV). Input data included TCP dose distribution, images, target structures, and organ-at-risk (OAR) information. The role of target conformal plan dose (TCPD) was assessed by comparing the TCPD-CNN (with dose information) and NonTCPD-CNN models (without dose information) using statistical analyses with the ranked Wilcoxon test (P < .05 considered significant). Results: The TCPD-CNN model showed no statistical differences in predicted target indices, except for PTV60, where differences in the D98% indicator were < 0.5%. For OARs, there were no significant differences in predicted results, except for some small-volume or closely located OARs. On comparing TCPD-CNN and NonTCPD-CNN models, TCPD-CNN's dose-volume histograms closely resembled clinical plans with higher similarity index. Mean dose differences for target structures (predicted TCPD-CNN and NonTCPD-CNN results) were within 3% of the maximum prescription dose for both models. TCPD-CNN and NonTCPD-CNN outcomes were 67.9% and 54.2%, respectively. 3D gamma pass rates of the target structures and the entire body were higher in TCPD-CNN than in the NonTCPD-CNN models (P < .05). Additional evaluation on previously unseen volumetric modulated arc therapy plans revealed that average 3D gamma pass rates of the target structures were larger than 90%. Conclusions: This study presents a novel framework for dose distribution prediction using deep learning and multichannel input, specifically incorporating TCPD information, enhancing prediction accuracy for IMRT in NPC treatment.

Metabolic reprogramming in the pathogenesis and progression of nasopharyngeal carcinoma: molecular mechanisms and therapeutic implications.

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with a complex etiology involving genetic predispositions, environmental factors, and Epstein-Barr virus (EBV) infection. Despite progress in radiotherapy and chemotherapy, the prognosis for advanced NPC is still unfavorable, prompting the need for innovative therapeutic approaches. Metabolic reprogramming plays a crucial role in the development and progression of NPC, marked by substantial changes in glycolysis, lipid, and amino acid metabolism. These alterations aid tumor cell proliferation, survival under stress, and immune evasion, with features such as enhanced aerobic glycolysis (Warburg effect) and shifts in lipid and amino acid pathways. Oncogenic drivers like MYC, RAS, EGFR, and the loss of tumor suppressors such as TP53 and PTEN, along with key signaling pathways including mTOR, AMPK, and HIF-1α, orchestrate these metabolic changes. This review discusses the molecular mechanisms of metabolic reprogramming in NPC and outlines potential therapeutic targets within these pathways. Advances in metabolic imaging and biomarker discovery are also enhancing the precision of diagnostics and treatment monitoring, fostering personalized medicine in NPC treatment. This manuscript aims to provide a detailed overview of the current research and its implications for improving NPC management and patient outcomes through targeted metabolic therapies.

Targeting GABARAPL1/HIF-2a axis to induce tumor cell apoptosis in nasopharyngeal carcinoma.

The primary gene mutations associated with nasopharyngeal carcinoma (NPC) are located within the phosphoinositide 3-kinase-mammalian target of rapamycin signaling pathways, which have inhibitory effects on autophagy. Compounds that target autophagy could potentially be used to treat NPC. However, autophagy-related molecular targets in NPC remain to be elucidated. We aimed to examine levels of autophagy-related genes, including autophagy-related 4B cysteine peptidase (ATG4B) and gamma-aminobutyric acid (GABA) type A receptor-associated protein-like 1 (GABARAPL1), in NPC cells and explored their potential role as novel targets for the treatment of NPC. The mRNA and protein expression of autophagy-related genes were detected in several NPC cells. Levels of GABARAPL1 were modified by either overexpression or knockdown, followed by examining downstream targets using RT-qPCR and western blotting. The role of GABARAPL1 in NPC proliferation and apoptosis was examined by flow cytometry. Furthermore, the role of GABARAPL1 was assessed in vivo using a nude mouse xenograft tumor model. The underlying mechanism by which GABARAPL1 regulated nasopharyngeal tumor growth was investigated. Autophagy-related 4B cysteine peptidase (ATG4B), GABARAPL1, and Unc-51-like kinase 1 (ULK1) were significantly down-regulated in multiple NPC cell lines. Overexpression of GABARAPL1 up-regulated the expression of autophagy-related proteins, decreased the level of hypoxia-inducible factor (HIF)-2α, and induced apoptosis in NPC cells. Importantly, overexpression of GABARAPL1 slowed tumor growth. Western blotting showed that autophagy was activated, and HIF-2α was down-regulated in tumor tissues. HIF-2α, as a substrate for autophagic degradation, may play an interesting role during NPC progression.

Allicin inhibits the growth of HONE-1 and HNE1 human nasopharyngeal carcinoma cells by inducing ferroptosis.

Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.

TRAF4 regulates ubiquitination-modulated survivin turnover and confers radioresistance.

Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or persistence of cancer after radiotherapy is still inevitable, highlighting the need to identify therapeutic resistance factors and develop effective methods for NPC treatment. Herein, we found that TRAF4 is overexpressed in NPC cells and tissues. Knockdown TRAF4 significantly increased the radiosensitivity of NPC cells, possibly by inhibiting the Akt/Wee1/CDK1 axis, thereby suppressing survivin phosphorylation and promoting its degradation by FBXL7. TRAF4 is positively correlated with p-Akt and survivin in NPC tissues. High protein levels of TRAF4 were observed in acquired radioresistant NPC cells, and knockdown of TRAF4 overcomes radioresistant in vitro and the xenograft mouse model. Altogether, our study highlights the TRAF4-survivin axis as a potential therapeutic target for radiosensitization in NPC.

Multi-Sequence Fusion Network via Single- Sequence CycleGANs for Improved Synthetic CT in Nasopharyngeal Carcinoma Treatment Planning

Multi-Sequence Fusion Network via Single- Sequence CycleGANs for Improved Synthetic CT in Nasopharyngeal Carcinoma Treatment Planning

The current state and future prospect of surgical treatment for nasopharyngeal carcinoma

The current state and future prospect of surgical treatment for nasopharyngeal carcinoma

Hypothalamic pituitary dysfunction after nasopharyngeal carcinoma irradiation

PurposeRadiotherapy (RT) is the corner stone of nasopharyngeal carcinoma (NPC) treatment but it exposes to late effects especially hypothalamic pituitary deficiency (HPD). In this article,we aimed to assess the impact of RT on pituitary function in NPC survivors. MethodsWe included 55 patients treated in the radiation oncology department, of Farhat Hached Hospital in Sousse, Tunisia. ResultsAll patients received facio-cervical RT with a mean dose of 73.3 Gy to the nasopharynx. After a mean follow up of 9.56 years, 34 patients (61.8%) presented HPD. Associated peripheral involvement was seen in 18.2%. The most prevalent deficiency was of the GH axis in 50.9% followed by secondary adrenal insufficiency in 20%. Panhypopituitarism was noted in 8.8%. The development of HPD wasn’t related to RT dose (OR: 0.41(0.05–2.92), p = 0.36) but was significantly associated with male gender (OR: 1.67 (1.21–2.37), p = 0.01). ConclusionHPD post RT is a common phenomenon. Therefore, we recommend regular assessment of pituitary function amongst patients treated with RT for NPC because identification of deficits is crucial to allow early and appropriate hormone replacement therapy in order to improve patients quality of life.

Preliminary evidence for endoscopic surgery combined with postoperative anti-PD-1 immunotherapy in advanced recurrent nasopharyngeal carcinoma

BackgroudEndoscopic surgery can be used as the main treatment for advanced recurrent nasopharyngeal carcinoma (rNPC). However, there is a huge clinical controversy about the need for consolidated immunotherapy after surgery.MethodsWe performed a retrospective propensity score-matched analysis (1:2) of patients with locally advanced rNPC who underwent endoscopic nasopharyngectomy (ENPG) combined with anti-programmed cell death protein-1 (PD-1) monotherapy or ENPG alone. The survival rate was analyzed by Kaplan–Meier method. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Potential surgical-related complications and immune-related adverse events (AEs) were also assessed.ResultsWe recruited 10 patients receiving ENPG plus anti-PD-1 monotherapy and 20 receiving ENPG alone. During the mean follow-up of 23.8 months, a significant improvement in the 2-year PFS was detected in the consolidation immunotherapy group compared to the ENPG alone group (80.0% vs. 40.0%; HR = 0.258; 95% CI: 0.09–0.72; p = 0.04), while the 2-year OS in the consolidation immunotherapy group was not significantly longer than that in the ENPG alone group (90.0% vs. 75.0%; HR = 0.482; 95% CI: 0.08–3.00; p = 0.50). The incidence of surgical-related complications in the consolidation immunotherapy group and ENPG alone group was 70.0 and 60.0%, respectively. Immune-related AEs were similar between the toripalimab arm (75.0%) and the camrelizumab arm (66.7%). Surgical-related complications depend on symptomatic treatments. Immune-related AEs were mild and tolerable.ConclusionsConsolidation immunotherapy regimen for patients with advanced rNPC after ENPG compared to ENPG alone provides a superior PFS rate with a manageable safety profile.

Recent Advances in Assessing the Clinical Implications of Epstein-Barr Virus Infection and Their Application to the Diagnosis and Treatment of Nasopharyngeal Carcinoma.

Reports about the oncogenic mechanisms underlying nasopharyngeal carcinoma (NPC) have been accumulating since the discovery of Epstein-Barr virus (EBV) in NPC cells. EBV is the primary causative agent of NPC. EBV-host and tumor-immune system interactions underlie the unique representative pathology of NPC, which is an undifferentiated cancer cell with extensive lymphocyte infiltration. Recent advances in the understanding of immune evasion and checkpoints have changed the treatment of NPC in clinical settings. The main EBV genes involved in NPC are LMP1, which is the primary EBV oncogene, and BZLF1, which induces the lytic phase of EBV. These two multifunctional genes affect host cell behavior, including the tumor-immune microenvironment and EBV behavior. Latent infections, elevated concentrations of the anti-EBV antibody and plasma EBV DNA have been used as biomarkers of EBV-associated NPC. The massive infiltration of lymphocytes in the stroma suggests the immunogenic characteristics of NPC as a virus-infected tumor and, at the same time, also indicates the presence of a sophisticated immunosuppressive system within NPC tumors. In fact, immune checkpoint inhibitors have shown promise in improving the prognosis of NPC patients with recurrent and metastatic disease. However, patients with advanced NPC still require invasive treatments. Therefore, there is a pressing need to develop an effective screening system for early-stage detection of NPC in patients. Various modalities, such as nasopharyngeal cytology, cell-free DNA methylation, and deep learning-assisted nasopharyngeal endoscopy for screening and diagnosis, have been introduced. Each modality has its advantages and disadvantages. A reciprocal combination of these modalities will improve screening and early diagnosis of NPC.

LncRNAs are potential prognostic markers in patients with nasopharyngeal carcinoma in China: A systematic review and meta‑analysis

lncRNAs are potential prognostic markers in patients with nasopharyngeal carcinoma in China: A systematic review and meta‑analysis

The efficacy of natural products for the treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the nasopharyngeal epithelium with a high incidence in southern China and parts of Southeast Asia. The current treatment methods are mainly radiotherapy and chemotherapy. However, they often have side effects and are not suitable for long-term exposure. Natural products have received more and more attention in cancer prevention and treatment because of their its high efficiency, low toxic side effects, and low toxicity. Natural products can serve as a viable alternative, and this study aimed to review the efficacy and mechanisms of natural products in the treatment of NPC by examining previous literature. Most natural products act by inhibiting cell proliferation, metastasis, inducing cell cycle arrest, and apoptosis. Although further research is needed to verify their effectiveness and safety, natural products can significantly improve the treatment of NPC.

Cost-effectiveness of camrelizumab combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma in China

ObjectiveThis study aimed to investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody camrelizumab to first-line platinum-doublet chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (L/M NPC) from the perspective...

Strategies for patients with recurrent nasopharyngeal carcinoma involved internal carotid artery who are intolerant to embolization

BACKGROUND: The surgical treatment of recurrent nasopharyngeal carcinoma (rNPC) involving the internal carotid artery (ICA) is challenging, as the massive bleeding caused by intraoperative rupture of the ICA is life-threatening. We reported that ICA embolization is an effective pretreatment to avoid fatal bleeding, but some patients cannot tolerate the procedure. We used endovascular vascular protection (ICA stents), vascular sacrifice (bypass grafting) and extravascular vascular protection (transcervical external stent placement) of the ICA to provide alternative options for these patients. METHODOLOGYy: This study enrolled patients with rNPC adjacent to or invading the ICA who were unsuitable for ICA embolization from January 2015 to June 2020. ICA pretreatment combined with endoscopic nasopharyngectomy (ENPG) was performed for the 30 patients. We report the survival outcome and incidence of complications after ICA pretreatment. RESULTS: ICA pretreatment was performed for the 30 enrolled patients, among whom 8 underwent endoscopic-assisted transcervical protection of the parapharyngeal ICA combined with ENPG, 6 underwent bypass grafting, and 16 underwent ICA stent implantation followed by ENPG. After pretreatment, at a median follow-up of 43 months (range, 2-80 months), the 3-year locoregional overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 62.9%, 61.3%, 70.2%, and 71.4%, respectively. CONCLUSIONS: ICA pretreatment combined with salvage ENPG enables the feasible and effective resection of rNPC lesions involving the ICA in patients who cannot tolerate ICA embolization. Therefore, this treatment may be an effective method for improving outcomes. Multidisciplinary therapy is needed to reduce operation-related complications.

Prognosis Forecast of Re-Irradiation for Recurrent Nasopharyngeal Carcinoma Based on Deep Learning Multi-Modal Information Fusion.

Radiation therapy is the primary treatment for recurrent nasopharyngeal carcinoma. However, it may induce necrosis of the nasopharynx, leading to severe complications such as bleeding and headache. Therefore, forecasting necrosis of the nasopharynx and initiating timely clinical intervention has important implications for reducing complications caused by re-irradiation. This research informs clinical decision-making by making predictions on re-irradiation of recurrent nasopharyngeal carcinoma using deep learning multi-modal information fusion between multi-sequence nuclear magnetic resonance imaging and plan dose. Specifically, we assume that the hidden variables of model data can be divided into two categories: task-consistency and task-inconsistency. The task-consistency variables are characteristic variables contributing to target tasks, while the task-inconsistency variables are not apparently helpful. These modal characteristics are adaptively fused when the relevant tasks are expressed through the construction of supervised classification loss and self-supervised reconstruction loss. The cooperation of supervised classification loss and self-supervised reconstruction loss simultaneously reserves the information of characteristic space and controls potential interference simultaneously. Finally, multi-modal fusion effectively fuses information through an adaptive linking module. We evaluated this method on a multi-center dataset. and found the prediction based on multi-modal features fusion outperformed predictions based on single-modal, partial modal fusion or traditional machine learning methods.

Abstract C125: Development of attenuated orf virus as a new generation oncolytic viral vector

Abstract The orf virus (ORFV) possesses remarkable qualities that make it a potential viral vector for cancer therapy. Recently, the cancer-killing properties of ORFV have been demonstrated in a variety of human cancers, including nasopharyngeal carcinoma (NPC). Initially, we found that the ORFV-bearing wild-type genome was successful in eliminating two NPC cell lines derived from patients in Hong Kong and Taiwan, HK-1 and TW02, respectively. To make viral vectors safer for medical use, the oncolytic effects of two live attenuated ORFVs, which were created by removing one of the virulent factors, VEGF or CBP, were further evaluated in these two cell lines. Despite this attenuation, the two recombinant ORFVs were still able to effectively infect and kill NPC cells, particularly HK-1 cells. ORFV infection caused pyroptosis in NPC cells through GSDME cleavage, resulting in significant cell detachment and reduction in FAK and AKT activation during the early stages of infection. The innate immune response is also affected by ORFV infection, as shown by the increased chemotaxis of NK cells and synergistic effect of NK on the cytotoxicity of NPC cells caused by ORFV infection. Infection with both wild-type and CBP-deleted ORFVs significantly reduced HK-1 tumor growth in a xenograft mouse model, suggesting its potential as a therapeutic agent for NPC treatment. To maximize its therapeutic use, it is essential to comprehensively understand the mechanisms that drive the oncolytic activity of ORFV. Citation Format: Yumiko Yamada, Wei-Li Hsu, Yu-Chih Wang, Hao-Ping Liu. Development of attenuated orf virus as a new generation oncolytic viral vector [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C125.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma

There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. ClinicalTrials.gov Identifier: NCT03581786.