Background:Patients with advanced malignancies often have limited treatment options after failure of systemic therapy, and the prognosis remains poor. Low-dose radiotherapy (LDRT) has been proposed to enhance antitumor immunity and may improve the efficacy of immune checkpoint inhibitors (ICIs). We aimed to evaluate the clinical activity and safety of LDRT combined with ICIs in patients with advanced malignancies in a real-world clinical setting. Methods:This single-center retrospective real-world study included patients with advanced malignancies treated at Taikang Xianlin Drum Tower Hospital who received LDRT (2 Gy × 3 fractions, total dose 6 Gy) directed to progressive lesions in combination with programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Clinical characteristics, treatment details, tumor response, follow-up data, and treatment-related adverse events were retrospectively collected and analyzed. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoint was disease control rate (DCR). Safety was assessed according to the incidence of treatment-related adverse events. Results:Thirteen patients with various advanced malignancies were included in the analysis. The ORR was 38.5% and the DCR was 76.9%. The median PFS was 6.7 months. Notably, all documented disease progression occurred outside the irradiated fields, whereas the irradiated lesions remained locally controlled during follow-up. Treatment-related adverse events were mainly chemotherapy-related hematologic toxicities. No clinically significant immune-related adverse events, radiotherapy-related toxicities, or treatment-related deaths were observed. Conclusions:LDRT combined with ICIs showed preliminary clinical activity with acceptable tolerability in this small real-world cohort of patients with advanced malignancies. Although limited by the small sample size, this approach may represent a feasible treatment option for selected patients and should be further evaluated in prospective studies.

The phase 3 COMPASSION-16 trial demonstrates significant progression-free survival (PFS) and overall survival (OS) benefits with cadonilimab plus standard therapy in patients with persistent, recurrent, or metastatic cervical cancer. This analysis aims to assess efficacy outcomes in patient subgroups of COMPASSION-16. The dual primary endpoints of COMPASSION-16 are PFS, assessed by the blinded independent central review (BICR) according to RECIST version 1.1, and OS. The secondary endpoint is objective response rate. In this subgroup analysis, the PFS, OS and objective response rate are evaluated in subgroups including bevacizumab use, prior concurrent chemoradiotherapy, PD-L1 combined positive score (CPS), metastatic disease at baseline, platinum use, and age. With median follow-up of 25.6 months, hazard ratios (HRs) for PFS favour cadonilimab group in all subgroups. Moreover, the addition of cadonilimab is also associated with prolonged overall survival. This subgroup analysis confirms that improvements in progression-free and overall survival are consistent with the primary results of the COMPASSION-16 study across diverse patient profiles.

Probiotics are natural systems bridging synthetic biology, physical biotechnology, and immunology, initiating innate and adaptive anti-tumor immune activity. We previously constructed an all-in-one engineered food-grade probiotic Lactococcus lactis (FOLactis) which could boost the crosstalk among different immune cells such as dendritic cells (DCs), natural killer cells, and T cells. Herein, considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines, we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides. Intranodal injection of FOLactis coated with neoantigen peptides (Ag-FOLactis) induces robust DCs presentation and neoantigen-specific cellular immunity. Notably, Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models, leading to potent inhibition of tumor growth. These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens, facilitating the development of a bio-activated platform for personalized therapy.

Although personalized neoantigen cancer vaccines have emerged as a promising strategy for cancer treatment, challenges remain to develop immune-stimulatory carriers which allow simultaneous transport of adjuvants and vaccines to lymph nodes (LNs). With inherent immunogenicity, genetic plasticity, and efficiency for large-scale production, M13 phages represent an attractive platform for vaccine delivery as natural bionanomaterials. Here, we report the discovery of an anti-CD40 designed ankyrin repeat protein (DARPin) and propose a bifunctional M13 ph age for neoantigen delivery based on this anti-CD40 DARPin protein (M13CD40). M13CD40-based neoantigen vaccines show improved accumulation and prolonged antigen retention in LNs compared with nontargeting phage vaccines due to the abundance of CD40-positive cells in LNs. Besides the intrinsic immunogenicity of phages, M13CD40-based neoantigen vaccines also benefit from additional CD40 stimulation due to multiple copies of anti-CD40 DARPins displayed on M13CD40 phages. Subcutaneous immunization with M13CD40-based neoantigen vaccines results in more robust antigen-specific immune responses and superior antitumor efficacy in poorly immunogenic tumor models compared with nontargeting phage vaccines. Combination therapy with PD-1 blockade further enhances T cell cytotoxicity and improves tumor control. To summarize, our findings highlight M13CD40 as a CD40 nanoagonist as well as an efficient vehicle for LN-targeted delivery of personalized neoantigen vaccines.

BACKGROUND:It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC). METHODS:In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. FINDINGS:205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%). CONCLUSIONS:Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC. FUNDING:This work was funded by Innovent Biologics (Suzhou).

5565 Background: IBI354 is an antibody-drug conjugate consisting of trastuzumab (anti-HER2 antibody) conjugated to a topoisomerase I inhibitor. It has showed manageable safety and encouraging efficacy in patients (pts) with advanced gynecologic cancers (including ovarian cancers [OC], Shu et al, abstract No. 720MO at 2024 ESMO annual meeting). Here, we present the updated safety and efficacy in OC. Methods: Eligible OC pts with HER2 alteration (IHC 1+, 2+, 3+ and/or ISH+ and/or NGS confirmed mutation or amplification) who failed or were intolerant to standard treatment were enrolled from China and Australia. Pts received IBI354 at 2−12 mg/kg every three weeks (Q3W) or Q2W. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) per RECIST v1.1. Results: As of November 12, 2024, 92 pts were enrolled (median age, 58.0 years; Asian, 95.7%; White, 4.3%; ECOG PS 1, 73.9%; IHC 1+, 65.2%; IHC 2+, 29.3%). The median follow-up time was 11.0 months (range: 8.0−19.0). Median treatment duration was 24.1 (range: 3.1−60.3) weeks with 21 (22.8%) pts still on treatment. Treatment-related adverse events (TRAEs) occurred in 79 (85.9%) pts with grade ≥ 3 TRAEs in 27 (29.3%) pts. The most common TRAEs were anemia (51.1%), white blood cell count decreased (45.7%), neutrophil count decreased (40.2%), and nausea (35.9%). Serious TRAEs occurred in 10 (10.9%) pts. Interstitial lung disease or pneumonitis was observed in 1 (1.1%) pt, which was grade 2 and not related to IBI354 considered by the investigator. TRAEs led to dose reduction in 2 (2.2%) pts. No TRAEs led to treatment discontinuation or death. For efficacy-evaluable pts (who had at least 1 post-baseline tumor assessment) dosed at 12 mg/kg Q3W (n = 40), confirmed ORR and DCR reached 55.0% (95% CI: 38.5−70.7) and 90.0% (95% CI: 76.3−97.2), respectively. In 22 pts with confirmed response in 12 mg/kg Q3W dose group, the median DoR was not reached with events occurred in 6 (27.3%) pts, and 9-month DoR rate of 58.1% (24.2−81.2). The median PFS was 7.1 months (95% CI: 5.2−not reached) with events occurred in 21 (51.2%) pts. The median overall survival (OS) was not reached with events occurred in 12 (29.3%) pts, and the 9 month OS rate was 70.7% (95% CI: 54.3−82.2). For the pts with HER2 IHC 1+ OC dosed at 12 mg/kg Q3W (accounting for 67.5% [27/40] of efficacy-evaluable pts at 12 mg/kg Q3W), ORR and DCR reached 55.6% (95% CI: 35.3−74.5) and 88.9% (70.8−97.6), respectively. Conclusions: IBI354 was well tolerated with a manageable safety profile and showed promising efficacy in pts with locally advanced unresectable or metastatic OC, especially in pts with HER2 lower expression. Clinical trial information: NCT05636215 .

Mesothelin (MSLN) is an attractive therapeutic target for precision cancer treatments. However, MSLN can be cleaved and shed from tumor cells, resulting in the presence of soluble MSLN (sMSLN), which significantly hinders the efficacy of MSLN-targeted therapies. Here, we identify a MSLN-targeting designed ankyrin repeat protein (DARPin) M7, which specifically binds to the protease-sensitive C-terminal region of MSLN. Furthermore, we develop two auristatin-based DARPin-drug conjugates (DARPin-DCs), M7A-DC and M7GA-DC. We show that M7A-DC and M7GA-DC are effectively internalized by MSLN-positive cells, leading to the release of MMAE that induces lethal effects as well as bystander killing against MSLN-negative cells. Compared to ADCs, M7A-DC and M7GA-DC exhibit improved tumor spheroid penetration and cytotoxic activity in 3D models. Notably, M7GA-DC demonstrates enhanced tumor control and improved survival benefits in pancreatic cancer models with limited MSLN expression. Combination therapy with PD-1 blockade further promotes long-term immunological memory formation by activation of dendritic cells and reprogramming of the tumor microenvironment. These findings highlight the translational potential of DARPin-DC and its promising prospects for clinical combination with immunotherapies in the treatment of solid tumors, including refractory pancreatic cancer.

Background: To observe dynamic changes of rectal injury in patients with locally advanced cervical cancer during curative pelvic radiotherapy using magnetic resonance imaging (MRI), and to explore non-invasive radiological methods for assessing radiation-induced rectal injury (RRI). Methods: A retrospective analysis was conducted on pelvic MRI images from 56 patients with locally advanced cervical cancer who underwent radical radiotherapy. MRI scans were conducted at four key stages: before radiotherapy, two weeks after starting external irradiation, upon completing external irradiation, and at the conclusion of brachytherapy. Thickness of the intestinal wall from the anorectal region to the sigmoid take-off at each scanning level was measured by RadiAnt DICOM Viewer software, and the average rectal wall thickness was calculated. Statistical analysis was performed using SPSS 26. Results: Out of the 56 patients undergoing pelvic radiation therapy, 30 (53.6%) reported symptoms of rectal injury, including diarrhea, increased frequency of stools, loose stools, abdominal pain, tenesmus, and difficulty in defecation, typically appearing during the 3rd to 5th week of treatment. Medication-preserved enemas were administered in the 5th week of radiotherapy and at the beginning of brachytherapy. In symptomatic patients, rectal wall thickness at two weeks of radiotherapy (7.76 f 0.96 mm) was significantly greater than that before radiotherapy (6.98 f 0.77 mm) (p < 0.01). Thickness continued to increase during external irradiation, reaching its peak at the end of external irradiation (7.99 f 0.83 mm), followed by a decrease at the end of brachytherapy (7.31 f 0.81 mm), which was significantly reduced compared with end-of-external-irradiation values (p < 0.01). Conclusions: Patients with locally advanced cervical cancer undergoing pelvic radiotherapy exhibit significant early and time-dependent rectal imaging changes prior to the onset of evident clinical symptoms of RRI. MRI may serve as a sensitive diagnostic tool for the early detection and prediction of radiation-induced rectal injury.

In light of the lack of reliable molecular markers for odontogenic myxoma (OM), the detection of copy number variation (CNV) may present a more objective method for assessing ambiguous cases. In this study, we employed multiregional microdissection sequencing to integrate morphological features with genomic profiling. This allowed us to reveal the CNV profiles of OM and compare them with dental papilla (DP), dental follicle (DF), and odontogenic fibroma (OF) tissues. We identified a distinct and robustly consistent CNV pattern in 93.75% (30/32) of OM cases, characterized by CNV gain events in chromosomes 4, 5, 8, 10, 12, 16, 17, 20, and 21. This pattern significantly differed from the CNV patterns observed in DP, DF, and OF. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated potential links between this CNV patterns and the calcium signaling pathway and salivary secretion, while Gene Ontology (GO) term analysis implicated CNV patterns in tumor adhesion, tooth development, and cell proliferation. Comprehensive CNV analysis accurately identified a case that was initially disputable between OF and OM as OM. Our findings provide a reliable diagnostic clue and fresh insights into the molecular biological mechanism underlying OM.

The future of artificial intelligence specialist doctors depends on foundational large language models (LLMs). However, there is currently a lack of evaluation studies on their Q&A capabilities in female malignancy. This cross-sectional study created a benchmark dataset consisting of 205 female malignancy Q&A to evaluate and compare the performance of 7 popular LLMs, with 3 human oncologists serving as a comparison. Only OpenAI o1, DeepSeek-R1, and Llama-3.1-405B achieved both accuracy and consistency rates exceeding 80%. Among these, Llama-3.1-405B demonstrated significantly higher accuracy than OpenAI o1 (P = .002) and potentially higher than DeepSeek-R1 (P = .059), with significantly lower latency (P < .001). After removing token limits, both OpenAI o1 and DeepSeek-R1 exhibited strong reasoning abilities, achieving accuracy rates of 98.5% and 95.6%, respectively, with no significant difference from Llama-3.1-405B (P > .05). The agreement between the models was fair, with an agreement rate of 0.318. Error analysis revealed that the highest error rates were associated with questions involving flexible medical scenarios and complex medical terminology. In female malignancy Q&A tasks, Llama-3.1-405B serves as a strong baseline model, while OpenAI o1 and DeepSeek-R1 show promise in inference, especially when token limitations are removed. However, their reasoning processes lack full consistency, likely due to differences in architectures and training methods. LLMs continue to face challenges in real-world medical scenarios and with complex medical terminology, highlighting the need for ongoing updates and the integration of clinical data to refine these models and improve their ability to address specialized medical needs.

BACKGROUND:Cadonilimab is a bispecific antibody targeting PD-1 and CTLA-4, which has shown substantial clinical benefits in advanced cervical cancer. In the COMPASSION-16 trial, we aimed to evaluate the addition of cadonilimab to first-line standard chemotherapy in persistent, recurrent, or metastatic cervical cancer. METHODS:In this randomised, double-blind, multicentre, placebo-controlled phase 3 trial, women aged 18-75 years across 59 clinical sites in China with previously untreated persistent, recurrent, or metastatic cervical cancer were randomly assigned (1:1) to receive cadonilimab (10 mg/kg) or placebo plus platinum-based chemotherapy with or without bevacizumab every 3 weeks for six cycles, followed by maintenance therapy every 3 weeks for up to 2 years. Randomisation was performed centrally through an interactive web-response system. Stratification factors were the use of bevacizumab (yes or no) and previous concurrent chemoradiotherapy (yes or no). The dual primary outcomes were progression-free survival as assessed by blinded independent central review and overall survival in the full analysis set. This study is registered with ClinicalTrials.gov, NCT04982237; the study has completed enrolment and is ongoing for treatment and follow-up. FINDINGS:445 eligible women were enrolled between Sept 11, 2021, and June 23, 2022. Median progression-free survival was 12·7 months (95% CI 11·6-16·1) in the cadonilimab group and 8·1 months (7·7-9·6) in the placebo group (hazard ratio 0·62 [95% CI 0·49-0·80], p<0·0001); median overall survival was not reached (27·0 months to not estimable) versus 22·8 months (17·6-29·0), respectively (hazard ratio 0·64 [0·48-0·86], p=0·0011). The most common grade 3 or higher adverse events were decreased neutrophil count, decreased white blood cell count, and anaemia. INTERPRETATION:The addition of cadonilimab to first-line standard chemotherapy significantly improved progression-free survival and overall survival with a manageable safety profile in participants with persistent, recurrent, or metastatic cervical cancer. The data support the use of cadonilimab plus chemotherapy as an efficacious first-line therapy in persistent, recurrent, or metastatic cervical cancer. FUNDING:Akeso Biopharma.

44 Background: The immunotherapy of sarcomas remains a challenge. As a breakthrough tool for cancer immunotherapy, the therapeutic cancer vaccine is in rapid development. In situ vaccination can be realized by intratumoral immune injection and radiotherapy. We have developed a bifunctional engineered Lactococcus lactis (FOLactis) expressing an encoded fusion protein of fms-like tyrosine kinase 3 ligand (Flt3L) and OX40 ligand (OX40L). We hypothesized that intratumoral injection of "FOLactis" combined with SBRT will realize tumor control and the synergetic application of PD-1 mAb systematically will further improve the effect of immunotherapy. Methods: This exploratory clinical study is designed as an open-label trial aimed at treating patients with advanced solid tumors who are unresponsive or intolerable to standard treatment. Patients will be treated with SBRT, intratumoral injection of "FOLactis", and PD-1 blockade. The primary endpoint was the objective response rate (ORR) of target lesions after 3 months and 6 months. The secondary endpoint included the disease control rate (DCR) of target lesions, progression-free survival (PFS), overall survival (OS), etc. Results: From July 2022 to December 2023, 30 patients were eligible for this trial (63% were sarcomas). 53.3% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb before respectively. The ORR and DCR of target lesions after 3 months were 27.6% and 93.1%, while these of systemic efficacy were 17.2% and 55.2%, respectively. In sarcomas, the ORR, DCR of target lesions were 11.1% and 88.9%, while these of systemic efficacy were 5.5% and 50%, respectively. Considering the deferred response in sarcomas, we also calculated the ORR after 6 months as the primary endpoint. The ORR, DCR of target lesions after 6 months were 56.3% and 100%, while these in sarcomas were 41.7% and 100%, respectively. Systemic median PFS were 2.87 months. Median PFS of target lesions and mOS has not reached. Among the evaluable target lesions, 6-month EFS was 50% in sarcomas (6/12) and 50% in all patients (8/16). Expression of CD4+, CD8+ T cells and dendritic cells was significantly increased between pre-treatment and post-treatment peripheral blood in responders. The most common treatment-related adverse events (TRAEs) were fever (83.3%), lymphocytopenia (53.3%), hypocalcemia (30%), neutrophilia (26.7%) and nausea (26.7%). Grade≥3 TRAE occurred in 11 patients, including lymphocytopenia (30%), fever (6.7%), leukopenia (3.3%), anemia (3.3%) and cardiac insufficiency (3.3%). Conclusions: In situ vaccination with“FOLactis", along with SBRT was tolerable and induced anti-tumor immunity, which would also augment systemic response when synergized with PD-1 mAb. This in situ vaccination is probably a promising option for advanced solid tumors. Clinical trial information: ChiCTR2200060660 .

Abstract Background: Neoantigens, derived from somatic mutations in tumor cells, have been identified as promising targets of immunotherapy. A personalized neoantigen/cancer-testis antigen (CTA) nanovaccine (PNVAC) platform has been established by us previously, and demonstrated its feasibility, safety and efficacy in preventing recurrence of high-risk resected gastric/gastroesophageal junction (G/GEJ) cancer in both preclinical and clinical studies. This study aims to explore the universality of PNVAC monotherapy or combined with anti-angiogenesis drugs or anti-programmed death 1 (PD-1) in patients with multiple advanced solid malignancies. Methods: Patient-specific neoantigens were selected based on tumor-specific mutations identified by whole-exome sequencing (WES) and RNA sequencing of paired blood and tumor tissues. Bioinformatic analysis for neoantigen prediction, including sequencing read filtering, human leukocyte antigen (HLA) typing and neoantigen filtering was performed. PNVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens designed to induce specific T cell responses. PNVAC is administrated to patients with metastatic solid tumors on days 1, 4, 8, 15, 22, 43 (prime phase) and 64, 85 and 169 (boost phase) alone, or combined with anti-angiogenesis or anti-PD-1 drugs. Safety, immunogenicity and clinical efficacy are evaluated. Results: Of the 30 enrolled patients, no treatment-related severe adverse events (AEs) occurred and the vast majority of AEs were limited to grade 1-2, only 1 patient developed grade 3 thrombocytopenia. The objective response rate (ORR) was 26.7% (8/30), including 2 cases of complete response (CR) and 6 cases of partial response (PR), and a disease control rate (DCR) of 66.7% achieved. The median progression-free survival (PFS) was 9.90 months (95% CI, 3.46-16.34 months), while the median overall survival (OS) was not reached (range, 0.80-43.53 months), and the estimated 1- and 2-year survival rates were 86.2% and 60.6%. Notably, among the 21 patients who had relapsed disease after previous ICB and/or anti-angiogenesis, disease control was asserted in 14 (66.7%) of them (7 of SD, 5 of PR, 2 of CR). ORR of this set was 33.3% (7/21), higher than that of all the enrolled patients (26.7%), and the set without prior ICB and/or anti-angiogenesis treatment (11.1%). For immune analysis, PNVAC elicited robust and persistent immune responses against neoantigens/CTAs. Additionally, peripheral T cells with a cytotoxic phenotype tended to increase after vaccination, and immune memory was also detected in some representative patients. Conclusions: These data supported the safety, immunogenicity, and efficacy of this regimen in patients with advanced solid malignancies, thus broadening the application and combined strategies of neoantigen-based vaccines. Clinical trial information: ChiCTR1800017319. Citation Format: Jia Wei, Qin Liu, Lijing Zhu, Jie Shao, Ju Yang, Guanghui Xu, Nandie Wu, Hanbing Wang, Rutian Li, Huizi Sha, Qiuping Xu, Jie Shen, Li Xie, Lifeng Wang, Juan Du, Lanqi Cen, Manman Tian, Lixia Yu, Baorui Liu. Personalized neoantigen/cancer-testis antigen nanovaccine for advanced solid tumors, a single-arm, open-label pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5001.

Aim: In situ vaccination, a kind of therapeutic cancer vaccine, can be realized by radiotherapy and intratumoral immune injection. This study combines intratumoral injection, radiotherapy and PD-1 blockade for synergistic antitumor effect. Materials & methods: Patients with advanced solid tumors who are unresponsive or intolerant to standard treatment will be treated with hypofractionated radiotherapy, intratumoral injection of FOLactis, PD-1 blockade. The primary end point is to observe the efficacy and safety, with the secondary end point to evaluate abscopal effects and the correlation between the immunological rationale and efficacy. Discussion: The combined regimen will be utilized to trigger antitumor immunity and is expected to be feasible and effective and provide a novel option for the comprehensive treatment of cancer.

Background: To explore the feasibility of radiomic models using different magnetic resonance imaging (MRI) sequences combined with clinical information in evaluating the status of lymphovascular space invasion (LVSI) in cervical cancer. Methods: One hundred one cervical cancer patients were included from January 2018 to December 2020. All patients underwent 3.0T MRI examination including T2 weighted imaging (T2WI), diffusion weighted imaging (DWI) and contrast-enhanced T1 weighted imaging (T1WI + C) enhanced sequences. Age, preoperative squamous cell carcinoma (SCC) associated antigen value and the depth of muscular invasion were collected. The 101 patients were divided into training set and validation set. Three different models were developed using T2WI, DWI and T1WI + C parameters respectively. One model was developed combining the three different sequences. The diagnostic performance of each model was compared via receiver operating characteristic curve analysis. Results: Forty-eight cases were pathologically confirmed with lymphovascular space invasion. The average SCC value of the LVSI positive group (10.82 ± 20.11 ng/mL) was higher than that of the negative group (6.71 ± 14.45 ng/mL), however there was no significant statistical difference between the two groups. No clinical or traditional imaging features were selected by spearman correlation analysis. Among the corresponding radiomic models, the machine learning model based on multi-modality showed the best diagnostic efficiency in the evaluation of LVSI (receiver operating characteristic (ROC) curve of multimodal radiomics in the training set (area under the ROC curve (AUC) = 0.990 (0.975–0.999)) and in the validation set (AUC = 0.832 (0.693–0.971)). Conclusions: The diagnostic efficacy of radiomics is superior to conventional MRI parameters and clinical parameters. The radiomics-based machine learning model can help improve accuracy for the preoperative evaluation of LVSI in cervical cancer.

Background: Patients (pts) with advanced cervical cancer who progressed on first-line treatment have no standard therapy and derive limited benefit from currently available treatment. More effective therapeutic strategies are required. This phase II trial was conducted to evaluate the efficacy and safety of IBI310 (anti-CTLA-4 mAb) plus sintilimab (sint) versus sint in pts with recurrent/metastatic cervical cancer. Here we present the efficacy and safety results for pts in sint plus placebo group. Methods: Pts aged 18-75 years, with histologically or cytologically confirmed cervical cancer who had progressed on or been intolerant to first-line or above platinum-based chemotherapy were enrolled. Pts in sint plus placebo group received sint (200mg) plus placebo IV Q3W for 4 cycles followed by sint monotherapy till disease progression, intolerable toxicity, withdrawal of informed consent, death, or for up to 24 months. The primary endpoint was objective response rate (ORR) assessed by IRRC per RECIST V1.1. The data cutoff date was April 20, 2022. Results: Overall, 101 pts were enrolled and received at least one dose of assigned treatment (median age of 53.0 years, 71.3% pts with PD-L1 CPS ≥1, 91.0% pts with squamous-cell carcinoma, and 36.6% pts with ≥2 lines of prior systemic therapy). The median treatment exposure was 18.0 weeks. The IRRC-assessed confirmed objective response rate (ORR) was 24.5% (95%CI: 16.4%-34.2%), disease control rate was 56.1% (95%CI: 45.7%-66.1%), and median duration of response was not reached. Pts with PD-L1 CPS ≥1 showed numerically higher ORR versus those with CPS <1 (32.9% vs 17.2%). With a median follow-up of 8.3 months, median PFS was 2.7 months (95%CI: 1.5-4.3). Median overall survival (OS) was not reached; OS rate was 89.6% (95%CI: 80.9%-94.5%) at 6 months and 65.5% (95%CI: 50.9%-76.7%) at 12 months. Treatment-related adverse events (TRAEs) occurred in 75.2% pts, with the most common being anaemia (13.9%), hypothyroidism (12.9%), white blood cell count decreased (12.9%), and hyperthyroidism (10.9%). 18.8% pts experienced CTCAE Grade 3 or higher TRAEs (no TRAE leading to death occurred). TRAEs leading to drug discontinuation occurred in 1 pt (myocarditis, grade 2). Conclusion: This study demonstrated favorable antitumor activity and acceptable safety with sintilimab alone over available therapies in ≥2 line advanced cervical cancer. ClinicalTrials.gov identifier: NCT04590599 Citation Format: Qinglei Gao, Jing Wang, Qin Xu, Ying Tang, Jieqing Zhang, Baoping Chang, Bairong Xia, Wei Duan, Danbo Wang, Lijing Zhu, Ruifang An, Guonan Zhang, Yaling Tang, Jianli Huang, Xiang Zhang, Hui Qiu, Wenting Ji, Li Li, Jianqing Zhu, Ding Ma. Efficacy and safety of sintilimab (anti-PD-1 mAb) for advanced cervical cancer: Results from a Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT079.

BACKGROUND:Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS:This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS:Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION:Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING:Akeso Biopharma. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

Objective We report the efficacy and safety of serplulimab, a novel humanized anti–programmed death-1 antibody, plus nanoparticle albumin-bound (nab)-paclitaxel in previously treated patients with programmed death ligand-1 (PD-L1)–positive advanced cervical cancer. Methods Patients diagnosed with PD-L1–positive (combined positive score ≥1) cervical cancer were enrolled in this single-arm, open-label, phase II study. They were given serplulimab 4.5 mg/kg for up to 2 years (35 dosing cycles) plus nab-paclitaxel 260 mg/m 2 for up to six cycles once every 3 weeks. Primary endpoints were safety and objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST version 1.1. Secondary endpoints included ORR assessed by the investigator, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Between December 2019 and June 2020, 52 patients were screened and 21 were enrolled. IRRC-assessed ORR was 57.1% (95% confidence interval [CI] 34.0–78.2%); 3 (14.3%) patients achieved complete response and 9 (42.9%) partial response. The median DOR was not reached (NR) (95% CI 4.1–NR). IRRC-assessed median PFS was 5.7 months (95% CI 3.0–NR), and median OS was 15.5 months (95% CI 10.5–NR). Investigator-assessed ORR was 47.6% (95% CI 25.7–70.2%). Seventeen (81.0%) patients experienced grade ≥3 treatment-emergent adverse events. Grade ≥3 adverse drug reactions were reported in 7 (33.3%) patients. Immune-related adverse events occurred in 12 (57.1%) patients. Conclusions In previously treated patients with PD-L1–positive advanced cervical cancer, serplulimab plus nab-paclitaxel provided durable clinical activity and a manageable safety profile. Clinical trial registration ClinicalTrials.gov , identifier NCT04150575.