In nasopharyngeal carcinoma, cisplatin is known to be associated with poor treatment compliance and notable side effects. More effective and safer platinum drugs are needed for the treatment of patients with nasopharyngeal carcinoma. In 2021, our multicenter, randomized, phase 3 trial reported that lobaplatin and fluorouracil induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than did cisplatin-based therapy in nasopharyngeal carcinoma. Data from the 10-year survival analysis are updated here. With a median follow-up of 10.6 years in the intention-to-treat population, 10-year progression-free survival is 70.7% in the lobaplatin-based therapy group vs. 71.9% in the cisplatin-based therapy group (HR 1.02, 95% CI 0.72-1.43; log-rank p = 0.885). The difference between the groups is 1.2% (95% CI -6.7-9.1, pnon-inferiority = 0.015), which is lower than the prespecified non-inferiority margin of 10%. The results are similar when we analyze patients in the per-protocol population. In the univariable and multivariable analyses, stage is an independent prognostic factor for progression-free survival (p = 0.001). The subgroup analyses suggest that the non-inferiority of lobaplatin-based therapy did not differ among specific populations. The incidence of late toxic effects is similar between the therapy groups, except for grades 1-2 peripheral neuropathy (p = 0.033), grades 1-2 deafness/otitis (p = 0.021), and grades 1-2/3 nephrotoxicity (p = 0.005; p = 0.021), the incidence of which is greater in the cisplatin-based therapy group than in the lobaplatin-based therapy group. Our findings suggest that lobaplatin and fluorouracil induction chemotherapy plus lobaplatin-based concurrent chemoradiotherapy is an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

PURPOSE:Patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) have limited therapeutic options after failing platinum and anti-PD-1/PD-L1 therapy. We investigated the efficacy and safety of an epidermal growth factor receptor (EGFR)-directed antibody-drug conjugate (ADC) becotatug vedotin (BV) combined with a PD-1 inhibitor pucotenlimab in this setting of patients. MATERIALS AND METHODS:Magic-C001 (ClinicalTrials.gov identifier: NCT05688605) is an ongoing, open-label, multicohort, dose escalation (phase I) and expansion (phase II) study in patients with EGFR-positive solid tumors. Eligible patients received pucotenlimab 3.0 mg/kg and BV at 1.8-2.3 mg/kg (phase I) or 2.0 mg/kg (phase II for NPC) once every 3 weeks. The primary end point for phase II was objective response rate (ORR). Secondary end points included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Among 31 patients with NPC at the recommended phase II dose (RP2D) from phase I and II who had received anti-PD-1/PD-L1 and platinum-based therapy, the confirmed ORR was 71.0% (95% CI, 52.0 to 85.8); DCR was 93.5% (95% CI, 78.6 to 99.2). The median DoR and PFS were 14.0 months (95% CI, 5.7 to not estimated) and 12.0 months (95% CI, 6.8 to 15.4), respectively. Median OS was not mature. Most common treatment-related adverse events (TRAEs) were pruritus (71.9%), hypoesthesia (65.6%), anemia (59.4%), and rash (56.3%). TRAEs of ≥grade 3 occurred in 40.6% of patients. No TRAEs led to death. CONCLUSION:To our knowledge, we report the first trial combining an ADC with immunotherapy for platinum and anti-PD-1/PD-L1-resistant NPC. BV plus pucotenlimab yielded a notable ORR with exceptionally durable responses and substantially prolonged PFS, alongside manageable toxicities. This regimen may offer a promising anti-PD-1 rechallenge strategy in this population, which is being confirmed in an ongoing, multicenter, randomized controlled, phase III study.

6094 Background: Real-world evidence regarding the efficacy and safety of neoadjuvant chemoimmunotherapy (NACI) in the treatment of curable head and neck squamous cell carcinoma (HNSCC) is currently limited. This multi-center study aimed to evaluate the outcomes of NACI in China. Methods: This retrospective study examined stage II-IVB HNSCC patients who underwent NACI followed by radical surgery (Group A) or definitive concurrent chemoradiotherapy (CCRT) (Group B) at four medical centers in China from 2019 to 2025. Propensity score matching was employed to balance baseline covariates between the groups. The primary endpoint was progression-free survival (PFS), while key secondary endpoints included complete pathological response (pCR), major pathological response (MPR), overall survival (OS), and treatment-related adverse events (TRAEs), which were graded according to the CTCAE v5.0 criteria. Survival analyses were conducted using Kaplan-Meier/log-rank tests and Cox proportional hazards models. Results: After matching (n=756), baseline characteristics were well-balanced (|SMD|<0.1). Group A (NACI + surgery, n=457) showed a 67% radiological response and MPR rate, with a 38% pCR, while Group B (NACI + CCRT, n=299) achieved a higher 76% radiological response rate. Regimens were similar (taxane-platinum-immunotherapy), but Group A received fewer chemotherapy cycles (3-4 cycles: 66% vs. 90%). Post-NACI progression was lower in Group B (0.7%). Group B demonstrated significantly longer PFS (hazard ratio [HR] 0.68; p=0.036) and markedly improved OS (HR 0.20; p<0.001). Multivariate analysis confirmed NACI + CCRT (Group B) as a significant independent predictor of improved OS (HR=0.20, 95% CI 0.07–0.59; p=0.003), considering factors such as betel nut use, tumor location, and T and N staging. Common grade 3-4 TRAEs were neutropenia and transaminase elevations; among grade 3 immune-related AEs, thyroid dysfunction predominated. Conclusions: This multicenter real-world study highlights that the combination of NACI and CCRT (Group B) results in significantly better PFS and OS outcomes compared to the NACI and surgical intervention (Group A), despite a pCR rate of 38% in Group A. These findings support the potential benefit of concurrent chemoradiotherapy as a consolidative approach following NACI. However, it is important to recognize that the observational nature of this study prevents definitive conclusions about causality. Therefore, prospective randomized controlled trials are essential to confirm these findings and to ascertain the optimal consolidative strategy. Additionally, further investigation into biomarker-driven patient selection is vital for enhancing treatment precision and effectiveness.

6090 Background: Segmental mandibulectomy for locally advanced oral squamous cell carcinoma (OSCC) severely compromises quality of life. In patients without radiographic mandibular invasion but still requiring mandibulectomy to achieve negative margins, effective tumor downstaging strategies that enable mandibular preservation are of major clinical importance. Neoadjuvant chemo-immunotherapy may reduce tumor burden, potentially enabling less radical resection and mandibular preservation. This study aimed to evaluate the efficacy and safety of mandibular preservation using neoadjuvant tislelizumab plus platinum-doublet chemotherapy in resectable locally advanced OSCC. Methods: This phase II, open-label, single-arm trial enrolled previously untreated patients with locally advanced, resectable OSCC (stage III-IVB, T3-T4N0-3M0) necessitating mandibulectomy based on conventional surgical criteria despite the absence of definitive clinicoradiologic mandibular invasion. Neoadjuvant treatment consisted of tislelizumab (200 mg), docetaxel (75 mg/m 2 ) and cisplatin (60 mg/m 2 ) on day 1 of each 21-day cycle for three cycles. All patients then proceeded to surgery. The primary endpoint was mandibular preservation rate. Secondary endpoints included pathological complete response (pCR), major pathological response (MPR), margin-negative resection (R0) rate, objective response rate (ORR), progression-free survival, disease-free survival, overall survival and treatment-related adverse events (TRAEs). Results: Between October 2023 and September 2025, a total of 53 patients were enrolled, and 49 were evaluable. All 49 patients completed three cycles of neoadjuvant therapy and underwent surgery. The mandibular preservation rate was 95.9% (47/49), and all patients achieved R0 resection. The ORR was 79.6% (39/49) and the pCR rate was 51.0% (25/49). TRAEs occurred in 100% (49/49) of patients. Grade 3 TRAEs were reported in 10.2% (5/49), including leukopenia, fatigue, and hypertension. No grade 4–5 TRAEs were observed. Conclusions: Neoadjuvant tislelizumab combined with platinum-doublet chemotherapy achieved a high mandibular preservation rate and a favorable pathological response profile with manageable toxicity in patients with locally advanced, resectable OSCC. This strategy represents a promising organ-preserving approach. Longer follow-up is ongoing to determine long-term survival outcomes. Clinical trial information: NCT06130007 .

INTRODUCTION:Recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) remains a significant clinical challenge despite advances in chemoradiation, with approximately 30% of patients ultimately developing R/M disease. There is an ongoing unmet need for novel therapeutic approaches that improve outcomes in this population. Becotatug vedotin (MRG003) is an antibody-drug conjugate (ADC) that couples an anti‑epidermal growth factor receptor (EGFR) monoclonal antibody to the microtubule‑disrupting payload monomethyl auristatin E (MMAE). Early clinical experience has suggested antitumor activity of becotatug vedotin in R/M NPC. AREAS COVERED:This review summarizes available clinical data on becotatug vedotin, with emphasis on the pivotal studies that have informed its clinical approved. Key trials include the Phase I MRG003‑001 study and the Phase II a/b MRG003‑005 study, which collectively provide the principal evidence base for efficacy and safety in NPC. Trial designs, patient populations, efficacy endpoints, and safety profiles are summarized and compared with outcomes reported for other EGFR‑targeting ADCs to contextualize becotatug vedotin's therapeutic application and limitations. EXPERT OPINION:Becotatug vedotin demonstrates promising antitumor activity in R/M NPC and represents a potentially valuable addition to the therapeutic drug. Future investigations should define the most effective dosing regimens and explore rational combination approaches, including integration into front-line.

BACKGROUND:Recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) patients who failed platinum-based chemotherapy, with or without PD-1/L1 inhibitors, face limited treatment options. We evaluated the efficacy and safety of MRG003 (becotatug vedotin), an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (ADC), in previously treated R/M NPC. METHODS:This multicenter, single-arm, phase IIa study was part of a phase II trial (NCT05126719). Eligible patients received MRG003 (2.0 or 2.3 mg/kg) intravenously every 3 weeks. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR); disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety were secondary endpoints. FINDINGS:Sixty-one patients were enrolled with a median follow-up of 21.9 months. IRC-assessed ORR and DCR were 42% (95% confidence interval [CI], 30-56) and 81% (95% CI, 69-90), respectively. Median DoR and PFS were 8.0 months (95% CI, 4.6-not evaluable [NE]) and 5.8 months (95% CI, 3.3-7.6), respectively. Median OS reached 15.8 months (95% CI, 11.0-NE) for all patients and 25.2 months (95% CI, 11.0-NE) for 2.3 mg/kg. Among 33 patients who had failed PD-1/L1 inhibitors and ≥2 prior chemotherapy lines, ORR and DCR were 30% and 76%, respectively. Grade ≥3 treatment-related adverse events occurred in 24 patients (39%). No treatment-related deaths occurred. CONCLUSIONS:MRG003 demonstrated promising efficacy and manageable safety in pretreated R/M NPC patients. This is also the first long-term evaluation of an EGFR-targeted ADC in this population. FUNDING:Study was supported by Shanghai Miracogen Inc, one subsidiary of Lepu Biopharma Co., Ltd.

Purpose: To investigate the optimal replanning timing for adaptive radiotherapy and the role of programmed cell death protein-1 (PD-1) blockade in nasopharyngeal carcinoma (NPC). Patients and Methods: In this retrospective, longitudinal time-series, cohort study, patients with NPC underwent intensity-modulated radiotherapy with daily or weekly cone beam computed tomography (CBCT) in China between 2020 and 2023. CBCT image-based delineations were conducted to evaluate dynamic changes of the primary tumor, lymph nodes, and parotid glands. Parotid function was assessed via the European Organization for Research and Treatment of Cancer questionnaire. Between-group comparisons were performed using Two-way Repeated-Measures ANCOVA. Kaplan-Meier analysis and Cox regression were used to compare survival outcomes. Results: Analysis of 404 eligible patients (31·8% women) revealed two distinct patterns of rapid and slow regression for primary tumors (25,580 images; least‑squares mean difference, -0·929cm2; p<0·001) and lymph nodes (4,041 images; least‑squares mean difference, -0·083cm2; p<0·001). Parotid glands were more susceptible to shrinkage in the rapid regression group than in the slow regression group, with an increased risk of dry mouth (p=0·033) and sticky saliva (p=0·029). The primary tumor showed sustained significant reduction in the rapid regression group until the 21st fractions, before the mean parotid dose reached the restricted threshold of 25 Gy. Concurrent PD-1 blockade correlated with slower regression of the primary tumor (p=0·035) and lymph nodes (p=0·005). Patients with primary tumor regression by the 6th fraction had significantly improved event-free survival (HR, 0·37; 95% CI, 0·15 to 0·95; p=0·031) and overall survival (HR, 0·24; 95% CI, 0·05 to 0·98; p=0·043). Conclusions: The 21st fraction was proposed to trigger radiotherapy replanning for rapidly regressing NPC. Compared with concurrent chemoradiotherapy, additional PD-1 blockade was associated with poorer tumor regression.

Background: Plastics, extensively used in daily life, have seen exponential growth in production. However, inadequate recycling and poor biodegradability have led to the rapid accumulation of microplastics (MPs) in the environment, making them pervasive in air, water, and food. As a result, MPs pollution has become one of humanity's most urgent environmental challenges. Growing evidence indicates that MPs may harm the respiratory system, yet their functional role and the molecular mechanisms in lung adenocarcinoma progression remain to be fully elucidated. Methods: To investigate the effects of MPs on lung adenocarcinoma metastasis and growth, we established longterm chronic exposure models. In vitro, cell migration, invasion, colony formation, and CCK-8 assays were performed; in vivo, a nude mouse metastasis model was used to assess the impact of MPs on malignant behaviors. We further investigated the specific role of EREG and elucidated its underlying mechanisms and downstream signaling pathways through restoration experiment, luciferase reporter assays, co-immunoprecipitation, and western blotting in differential models. Results: Long-term exposure to polystyrene MPs (PS-MPs) significantly enhances migration, invasion, and proliferation of lung adenocarcinoma cells in vitro and promotes tumor metastasis in vivo. Multi-omics analysis identified epiregulin (EREG) as a key mediator of PS-MP-induced malignant progression. Functional assays confirmed that EREG is essential for PS-MP-driven malignant cell migration, invasion, and proliferation. Enrichment analyses and a pNF-kappa B-luc reporter assay implicated and validated NF-kappa B signaling as a critical downstream pathway, with EREG markedly enhancing NF-kappa B activity. Mechanistically, EREG physically interacts with the NF-kappa B subunits p65 and p50 as well as I kappa B alpha. This interaction promotes the phosphorylation of p65 at Ser536 and I kappa B alpha at Ser32/36, leading to I kappa B alpha degradation and the consequent activation of NF-kappa B. Consistently, pharmacological inhibition of NF-kappa B signaling with BMS-345541, a specific inhibitor, abolished PS-MP-induced oncogenic phenotypes, confirming NF-kappa B dependence. Clinically, elevated EREG expression correlates with tumor metastasis and poor prognosis in lung adenocarcinoma (LUAD) patients. Conclusion: Chronic PS-MPs exposure promotes lung adenocarcinoma metastasis and progression through the EREG-NF-kappa B signaling axis, in which EREG interacts with the NF-kappa B/I kappa B alpha complex to provoke its phosphorylation-dependent activation.

Nanoplastics (NPs) are emerging as environmental pollutants, yet their long-term impact on lung cancer progression remains largely unexplored. This study explored the influence of extended exposure to polystyrene nanoplastics (PS-NPs) on the growth and movement of A549 lung cancer cells, with particular emphasis on the molecular mechanisms involved in metabolic reprogramming. We demonstrated that prolonged exposure to PS-NPs markedly increased the ability of lung cancer cells to proliferate and migrate. Using an integrated approach combining transcriptomic profiling and C13-labeled glucose flux analysis, we observed that chronic PS-NPs exposure induced metabolic reprogramming characterized by the activation of gluconeogenesis and suppression of glycolysis. Mechanistically, PS-NPs upregulated the gluconeogenic enzyme mitochondrial phosphoenolpyruvate carboxykinase (PCK2) and downregulated enolase-1 (ENO1), a glycolytic enzyme. Notably, knockdown of PCK2 attenuated PS-NPs-induced cell proliferation and migration, underscoring its functional role. We further identified that stress-responsive activating transcription factor-3 (ATF3) serves as a crucial mediator of PCK2 and ENO1 expression. Chromatin immunoprecipitation followed by PCR (ChIP-PCR) confirmed enhanced binding of ATF3 to the promoter regions of PCK2 and ENO1 upon PS-NPs exposure. Silencing ATF3 abolished PS-NPs-induced changes in PCK2 and ENO1 expression and blocked the associated increase in cell proliferation and migration. Clinically, elevated ATF3 and PCK2 expression levels are associated with poor prognosis in patients with lung cancer. In conclusion, chronic exposure to PS-NPs promotes lung cancer progression by inducing metabolic reprogramming via ATF3-mediated regulation of PCK2 and ENO1. These findings shed light on the cancer-promoting capabilities of PS-NPs and identify the ATF3-PCK2 axis as a promising target for lung cancer therapy.

The discovery and identification of novel diagnostic markers and effective therapeutic targets for ovarian cancer are urgently required. Recent studies have demonstrated that SOX30 suppresses tumor metastasis and serves as a prognostic and chemotherapeutic marker in advanced-stage ovarian cancer. In this study, we aim to investigate the expression patterns, regulatory mechanisms, and diagnostic potential of SOX30, as well as its SOX30 in tumor growth and the underlying mechanisms in ovarian cancer. Using data from The Cancer Genome Atlas (TCGA) database, we comprehensively analyzed the association between SOX30 expression levels and copy number variations (CNVs) as well as DNA methylation in ovarian cancer. The functional role of SOX30 in tumor growth was evaluated through MTS assays, colony formation assays, rescue experiments, and xenograft models. Flow cytometry, western blotting, and confocal microscopy were employed to explore the effects of SOX30 on apoptosis and autophagy. Additionally, co-expression analysis of SOX30-related genes and functional enrichment analysis were performed to uncover potential biological pathways. SOX30 was frequently overexpressed in ovarian cancer, closely associated with copy number amplification, and effectively distinguished tumor tissues from normal tissues. Functionally, SOX30 significantly inhibited cancer cell proliferation in vitro and suppressed tumor growth in vivo, inducting slight cell apoptosis but marked autophagy in ovarian cancer cells. Mechanistically, the inhibitory effect of SOX30 on cancer cell proliferation was dependent on the regulation of autophagy. At the molecular level, SOX30 modulated biological processes and signaling pathways related to autophagy rather than apoptosis in ovarian cancer. Furthermore, SOX30 showed a strong positive correlation with key autophagy-related genes in ovarian cancer. Our findings identify SOX30 as a promising diagnostic marker and therapeutic target in ovarian cancer, and highlight the previously underappreciated role of SOX30 in suppressing cancer cell proliferation and tumor growth primarily through an autophagy-mediated mechanism, offering new insights into the pathogenesis and treatment of ovarian cancer.

The prognostic relevance of HLA class I (HLA-I)-mediated immunity in cancer immunotherapy remains unclear. We introduce deltaHED, a novel metric that quantifies evolutionary divergence between germline and tumour-acquired HLA-I alleles, integrating both inherited and somatic immunogenetic variation. Using whole-exome sequencing, we analysed deltaHED across three independent cohorts: 164 patients with recurrent/metastatic nasopharyngeal carcinoma (RM/NPC) from the POLARIS-02 trial (PD-1 monotherapy), 88 melanoma patients receiving PD-1 monotherapy, and 477 esophageal squamous cell carcinoma (ESCC) patients from the JUPITER-06 trial (PD-1 plus chemotherapy vs. chemotherapy alone). High deltaHED was significantly associated with increased tumour mutational burden and neoantigen load (p < .001), but predicted worse progression-free survival (PFS) and overall survival (OS) in patients receiving PD-1 blockade across all three cancers. In ESCC, this association was observed only in the immunotherapy arm, not in patients treated with chemotherapy alone. High deltaHED also correlated with increased mutations in antigen-processing and T-cell receptor pathways. These findings establish deltaHED as a clinically relevant biomarker of immune divergence with potential to improve patient stratification and guide personalised immunotherapy strategies.

Type I interferons (IFN-Is) are central coordinators of tumor-immune system interactions. Accumulating evidence suggests that persistent IFN-Is and a subset of IFN-stimulated genes (ISGs) might promote tumor development, but the regulation of mRNA translation and lipid metabolism during this process remains unknown. Here, we report that oligoadenylate synthetase-like (OASL) is a key ISG in mediating the pro-tumor effects of IFN-Is. OASL is highly expressed in human cancers and is associated with poor prognosis. We identify physical and functional interactions between OASL and ribosome. OASL enhances global translation initiation with the preference for a subset of mRNAs involved in fatty acid (FA) synthesis by interaction with ribosomes. Using both loss- and gain-of-function studies, we find that OASL reprograms FA metabolism to enhance oncogenesis, which can be inhibited by an FA synthesis inhibitor. Our results define OASL as an important factor in regulating mRNA translation, mediating tumor-promoting functions of IFN-Is, and providing potential therapeutic interventions.

LBA6005 Background: Becotatug vedotin (MRG003) is a novel EGFR-targeted antibody-drug conjugate. Previous Phase I/II studies have demonstrated optimistic efficacy in R/M NPC pts who had failed platinum chemotherapy and PD-(L)1 inhibitor. This study aimed to assess clinical efficacy and safety of MRG003 in pts compared with chemotherapy. Method: Eligible pts with R/M NPC had failed ≥2 lines of systemic chemotherapy and PD-(L)1 inhibitor, and were randomized to receive MRG003 (2.3 mg/kg, d1, iv, Q3W) or chemotherapy (capecitabine 1000 mg/m 2 , po, twice daily, d1-14, Q3W; or docetaxel 75 mg/m 2 , iv, d1, Q3W). Randomization was stratified according to liver metastasis (yes or no) and ECOG PS (0 or 1). The primary endpoints were ORR and PFS assessed by BICR, and OS. Pts in the chemotherapy arm were allowed to cross over to receive MRG003 after disease progression. Result: A total of 173 R/M NPC pts were randomly assigned to MRG003 (n=86) or capecitabine(n=36)/docetaxel (n=51). The median prior treatment lines (range) were 3 (2-10) vs. 3 (2-11), and the ECOG score 0 was 17.4% vs. 17.2% for two arms. 40 pts (46.5%) vs. 41 pts (47.1%) of two arms had liver metastasis. By 30 June 2024, the study reached the significantly improved BICR-assessed ORR with MRG003 compared to chemotherapy (30.2% vs. 11.5%, difference: 18.7%, 95%CI: 7.0%, 30.5%, P=0.0025). Also, PFS was significantly improved in the MRG003 arm (HR=0.63, 95%CI: 0.43, 0.91, P=0.0146). Median PFS (95%CI) by BICR were 5.8m (4.2, 6.2) vs. 2.8m (2.0, 5.5). As of 30 December 2024, the updated mOS (95%CI) were 17.1m (11.4, NE) vs. 12.0m (9.7, 15.4) of two arms (HR=0.73, 95%CI: 0.48, 1.12). By supplementary analysis excluding the impact of crossover treatment, the HR of OS was 0.59 (95%CI: 0.37, 0.93). MRG003 has shown a trend of survival benefits. The OS will be continually followed up. The incidence of adverse events in the two arms was similar. 39 pts (45.3%) vs.44 pts (50.6%) in two arms experienced grade ≥3 TRAEs. White blood cell count decreased was the most common grade ≥3 TRAE of two arms (9.3% vs. 35.6%). Conclusions: As the first ADC clinical study targeting heavily pretreated R/M NPC, becotatug vedotin demonstrated statistically and clinically meaningful benefits while maintaining a manageable safety profile in this population. This study will lead to a paradigm shift in the treatment of R/M NPC. Sponsor: Lepu Biopharma Co., Ltd. Clinical trial information: NCT05126719 . MRG003(N=86) Chemotherapy(N=87) HR (95% CI) ITT analysis Information fraction (n, %) 87, 71.3 - Median follow-up (m) 13.5 13.6 - mOS (m, 95% CI) 17.1 (11.4, NE) 12.0 (9.7, 15.4) 0.73 (0.48, 1.12) 12-m rate (%, 95% CI) 55.9 (44.2, 66.0) 48.9 (37.7, 59.2) - Supplementary analysis* mOS (m, 95% CI) 17.1 (11.4, NA) 11.1 (8.5, NA) 0.59 (0.37, 0.93) *Using hypothetical strategy to exclude the impact of crossover treatment.

PURPOSE:Preclinical and clinical findings suggest that PD-1/cytotoxic T lymphocyte-associated protein 4 bispecific antibodies may offer synergistic antitumor activity. This study aimed to explore the efficacy and safety of cadonilimab combined with neoadjuvant chemotherapy in locally advanced, resectable head and neck squamous cell carcinoma. PATIENTS AND METHODS:Eligible patients were consecutively enrolled and received cadonilimab (10 mg/kg) and chemotherapy (docetaxel, 75 mg/m2 plus cisplatin, 60 mg/m2) every 3 weeks for three cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate, pathologic complete response, major pathologic response (MPR), safety, progression-free survival, and overall survival. Analyses of biomarkers and tumor-infiltrating immune cell subsets were conducted. This study is registered with ClinicalTrials.gov (NCT06023875). RESULTS:Thirty patients were included from July 2023 to December 2023. The median age was 55 years (range: 26-69), and 27 (90.0%) patients were male. The ORR was 83.3%, disease control rate was 100.0%, MPR rate was 76.7%, and pathologic complete response rate was 50.0%. All patients experienced treatment-related adverse events. Grade 3 treatment-related adverse events were reported in 7 (23.3%) patients. Progression-free survival and overall survival data were not yet mature as of the cutoff date (February 1, 2025). Subgroup analysis revealed no significant differences in biomarker expression. A higher baseline infiltration of M1-like macrophages in the tumor stroma was associated with better treatment efficacy. CONCLUSIONS:Cadonilimab plus neoadjuvant chemotherapy demonstrated favorable ORR and MPR with manageable toxicities in patients with head and neck squamous cell carcinoma.

e18095 Background: Locally advanced hypopharyngeal/laryngeal squamous cell carcinoma (LA-HLSCC) patients necessitate novel therapeutic approaches to improve their laryngeal preservation rate and quality of life. Cetuximab has been proven to be an alternative to 5-FU when combined with docetaxel and cisplatin but provides no superior objective response rate. Based on the synergistic effect of PD-1 on anti-tumor activity, this phase II trial aimed to investigate the efficacy and safety of neoadjuvant zimberelimab (a PD-1 antibody) and cetuximab plus nab-paclitaxel and cisplatin (NeoZCPC) for resectable LA-HLSCC. Methods: In this open-label, single-arm clinical trial, patients with untreated, resectable LA-HLSCC (T2N2-3M0, T3-4N0-3M0; stage III-IVB, AJCC 8th Ed) were enrolled to receive NeoZCPC, in which zimberelimab (240 mg), cisplatin (60 mg/m 2 ), and nab-paclitaxel (260 mg/m 2 ) were administered on day 1 of each 21-day cycle for three cycles, and cetuximab was given 400 mg/m 2 on day 1 and 250 mg/m 2 per week for 8 additional weeks, followed by surgery or definitive radiotherapy. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included pathological complete response (pCR), major pathological response (MPR), laryngeal preservation rate (LPR), progression-free survival (PFS), and overall survival (OS). Results: Between September 2023 and December 2024, 26 patients were enrolled (median [range] age was 60 [41-76] years; 26 male). The primary lesions were located at the hypopharynx (10/26, 38.5%) and larynx (16/26, 61.5%). After the completion of NeoZCPC, the ORR was 96.2% [25/26], including 50% [13/26] CR and 46.2% [12/26] PR. There were 11 (42.3%) patients receiving subsequent definitive radiotherapy and 15 (57.7%) patients receiving surgery, among which the pCR rate was 33.3% [5/15] and the MPR rate was 40% [6/15]. Grade 1-2 treatment-related adverse events (TRAEs) occurred in 5 (19.2%) patients. Grade 4 TRAEs were reported in only 3 (11.5%) patients, including allergic reaction (7.7%), pneumonitis (3.8%), heart failure (3.8%), and myocardial infarction (3.8%). LPR, PFS, and OS data were still not yet mature as of the cutoff date (January 1, 2025). Conclusions: NeoZCPC achieved promising ORR, pCR, and MPR rate with acceptable toxicities in LA-HLSCC patients. Follow-up is still underway to obtain long-term survival data. Clinical trial information: NCT06107114 .

Head and neck squamous cell carcinoma (HNSCC) is the most prevalent type of head and neck cancer; however, treatment outcomes and patient prognosis remain suboptimal. Although the survival of patients with HNSCC has improved with the widespread use of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) and immune checkpoint inhibitors (ICIs), there remains considerable potential for further improvement. Recent studies suggest that the combination of anti-EGFR monoclonal antibodies and ICIs demonstrates promising efficacy and safety, which has been recommended by international guidelines for patients with recurrent or metastatic disease. Nevertheless, the application of this combination therapy remains in the early stages of exploration, and numerous questions concerning its standardized clinical use remain unanswered, including the mechanisms underlying the synergistic effects of individual agents, therapeutic value across different patient populations, and safety considerations. The Expert Committee of Head and Neck Cancer of the Chinese Society of Clinical Oncology (CSCO) organized an expert panel to develop this expert consensus on the combination of anti-EGFR mAbs and ICIs in the treatment of HNSCC through multiple rounds of discussion based on evidence-based medicine and clinical practice experience. This consensus provides guidance on the mechanisms of treatment with anti-EGFR mAbs plus ICIs, stratified treatment approaches, applications in special populations, and safety management. It is hoped that this consensus will provide clearer and more practical guidance for clinicians, promote the rational application of this combination therapy in clinical practice, and offer more treatment options for patients with HNSCC.

Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear. To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC. Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024. Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224). The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis–free survival, locoregional relapse–free survival, overall survival, safety, and health-related quality of life. Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment. Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC. ClinicalTrials.gov Identifier: NCT03427827

Importance With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. Objective To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Design, Setting, and Participants Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Interventions Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m(2) triweekly for 2 cycles), or the concurrent cisplatin-sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Main Outcomes and Measures Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis-free survival, safety, tumor response, quality of life, and tolerability. Results In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin-sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, -3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin-sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-infinity]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin-sparing group, primarily in gastrointestinal, functional, and global health status. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT04907370

BACKGROUND:Current 8th AJCC stage is less effective in differentiating survival for nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy era. This study aims to evaluate the performance of CNG (Collaborative Nasopharyngeal Carcinoma Group) stage, a clinical downstaging of NPC based on the 7th AJCC stage, in predicting prognosis compared with the AJCC stage. METHODS:In this prospective observational study (ClinicalTrials.gov Identifier: NCT03529279), 1930 patients were restaged based on the 7th stage: CNG Stage I: Stage I, II, and III-nonT3N2; CNG Stage II: III-T3N2, IVA, and IVB; CNG Stage III: IVC. Kaplan-Meier method and the log-rank test were performed. RESULTS:The 5-year overall survival (OS) of patients with CNG Stage I, II, and III was 97.0 %, 91.4 %, and 72.1 %, and survival curves of different stage groups were well-separated (all p < 0.001). The OS curves for 7th and 8th Stage I, II, and III almost overlapped. In patients with pre-treatment plasma EBV DNA > 0 and ≥ 1000 copies/ml, overall and inter-group OS differences were observed in CNG stage, while not shown in 7th and 8th stages. Among CNG Stage I, II, and III, the proportion of patients with EBV DNA = 0 was gradually decreasing (30.9 % vs 10.8 % vs 3.4 %), while the proportion of EBV DNA ≥ 1000 was gradually increasing (33.3 % vs 60.0 % vs 84.8 %, p < 0.001). CONCLUSIONS:The CNG staging system presents a more accurate segregation of survival rates than the 7th and 8th editions, and it is well aligned with EBV DNA. Further studies of the staging system are warranted.

Environmental factors are critical for lung cancer progression, and nanoplastics (NPs) pose evolving health risks. Due to small size, NPs are readily inhaled and accumulate in lung tissues, but their long-term impact on lung cancer remains unclear. This study used long-term cell culture and orthotopic lung cancer models exposed to environmentally relevant NPs doses to investigate oncogenic potentials. Our results show that prolonged NPs exposure enhances lung adenocarcinoma A549 cell proliferation, migration, and invasion in vitro and accelerates lung tumor progression in vivo. Transcriptomic analysis identified activating transcription factor-3 (ATF3), induced by the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) and endoplasmic reticulum stress (ERs), as a key driver. Mechanistically, ATF3 activation upon NPs exposure promotes cancer progression by upregulating mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a rate-limiting enzyme in truncated gluconeogenesis and serine/glycine biosynthesis. The ATF3-PCK2 axis facilitates metabolic reprogramming through enhanced anabolic gluconeogenesis, promoting lung cancer malignant progression under NPs exposure. These findings establish NPs as environmental tumor promoters in lung cancer and elucidate a novel metabolic activation pathway underlying their oncogenic effects, providing mechanistic insights with implications for risk assessment, prevention, and therapeutic intervention.