8516 Background: Recent retrospective studies across 10 cancer types suggest increased efficacy of Early rather than Late Time-of-Day (ToD) infusions of immune checkpoint inhibitors (ICIs). This first randomized controlled phase III trial aimed to determine the relevance of ToD of immunochemotherapy for efficacy in patients (pts) with non-small cell lung cancer (NSCLC). Methods: Eligible pts received ICI pembrolizumab or sintilimab combined with chemotherapy, as 1 st line treatment for stage IIIC-IV NSCLC without driver mutation. Pts were randomly assigned in a 1:1 ratio to receive the initial four immunochemotherapy cycles either before 15:00 in the Early ToD group, or after 15:01 in the Late ToD group. We hypothesized an increase in median progression-free survival (PFS) from 6 months in the Late ToD group up to 10 months in the Early ToD group. A total of 210 pts was required to validate PFS differences, using a two-sided significance level (α, 0.05; β, 0.80). Secondary endpoints were overall survival (OS) and objective response rate (ORR). Results: From 09/2022 to 05/2024, 210 pts (median age, 61 y.o.; male sex, 90.5%; Stage IV, 80.5%) were randomized. The pts in each group had similar characteristics. After a median follow-up of 18.9 months (mo.), median PFS was 13.2 mo. [95% CI, 10.1-16.3] in the early ToD group and 6.5 mo. [5.9-7.1] in the late ToD group, with a hazard ratio (HR) of an earlier progression of 0.43 [0.31-0.60] ( P < 0.0001). Median OS was not reached in the early ToD group, whereas it was 17.8 mo. [14.2-21.5] in the late ToD group (HR of an earlier death, 0.43 [0.27-0.69]; P = 0.0003). ORR was 75.2% [66.8%-83.6%] for early ToD and 56.2% [46.5%-56.8%] for Late ToD ( P = 0.007). PFS, OS, and ORR were consistently improved in the early ToD group regardless of age, sex, performance status, tumor stage, histology, PD-L1 status, and ICI agent. Conclusions: In this randomized trial, all three efficacy endpoints of immunochemotherapy were significantly improved through Early vs Late ToD dosing in pts with previously untreated stage IIIC-IV NSCLC. The near doubling in PFS and OS in our trial support the need for further randomized trials to determine the relevance of ToD for ICI efficacy and their underlying circadian mechanisms in pts with various cancer types. Clinical trial information: NCT05549037 .

5611 Background: FRUSICA-1 (NCT03903705) was an open-label, single-arm, pivotal phase 2 study to evaluate the efficacy and safety of fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) in previously treated advanced EMC patients (pts) with pMMR (proficient mismatch repair) status. The primary results of FRUSICA-1 have demonstrated encouraging efficacy (objective response rate [ORR]: 35.6%; median progression-free survival [PFS]: 9.5 mo; median overall survival [OS]: 21.3 mo) in the overall population (Wu X, et al; 2024 ASCO). In this updated exploratory analysis (data cutoff: May 15, 2024), we evaluated the association between prior NACT/ACT and clinical outcomes in this study. Methods: Pts who had histologically confirmed advanced EMC with pMMR status confirmed by central lab and had progression on 1 standard systemic therapy were eligible. They received F (5 mg QD, 2 weeks on/1 week off, orally) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity. The efficacy subgroup analysis was performed by prior NACT/ACT (Yes vs No). Results: As of May 15, 2024, a total of 98 EMC pts with pMMR status were enrolled and received the treatment with the median follow-up of 22.0 mo (95%CI: 20.5, 23.7). Based on pts with or without prior NACT/ACT (Yes vs No = 47 pts vs 51 pts), the baseline demographics and disease characteristics were well balanced. Independent Review Committee (IRC)-assessed ORR (34.0% vs 31.4%) and disease control rate (DCR, 85.1% vs 82.4%) were comparable, respectively. Median duration of response (DoR) in pts with NACT/ACT was 11.1 mo while not reached for pts without NACT/ACT. Median PFS were 7.1 mo (95%CI: 4.7, 13.8) vs 9.5 mo (95%CI: 5.5, not estimable), respectively with two 95%CIs highly overlapped. The 6-mo PFS rates were also comparable at 56.8% vs 59.7%. Median OS pending maturity, the 18-mo OS rates were nearly identical (58.7% vs 59.1%). Conclusions: In this updated exploratory analysis of pts with advanced EMC enrolled in FRUSICA-1 study treated with F plus S, encouraging outcomes were achieved in the overall population, including patients who had received prior NACT/ACT and those who had not, with durable and clinically meaningful responses. Clinical trial information: NCT03903705 .

3106 Background: AXL is a member of the TAM family activated by the high-affinity ligand Gas6. The Gas6/AXL signaling pathway plays a critical role in drug resistance, tumor proliferation, metastasis, invasion, epithelial-mesenchymal transition and immune regulation, implicating AXL as an important target in cancer treatment. TT-00973-MS is a highly selective and potent AXL inhibitor which exhibited significant anti-tumor activities in both SK-OV-3 and H1299 derived CDX model with AXL over-expression. Here is first time to present the first-in-human study of TT-00973-MS. Methods: Dose escalation is performed using“3+3”design. Adverse events (AE) are evaluated per CTCAE v5.0 criteria. Tumor responses are evaluated per RECIST 1.1. Pts receive TT-00973-MS once daily continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Results: As of the data cut-off date on December 24, 2024, 18 pts have received TT-00973-MS treatment in 2 mg (n = 1), 5 mg (n = 3), 10 mg (n = 3), 17 mg (n = 7), 25 mg (n = 4) at QD dose levels. Median age was 56.5 (37∼69), 8 (44.4%) were males, all had ECOG PS ≤1. 66.6% of pts had Stage III/IV disease. 50% had ≥3 prior lines of systemic therapies. 66.7% had prior immunotherapies. One DLT was observed in a subject at 17 mg QD dose level (Grade 3 peripheral motor nerve disorder). The MTD was not reached. Treatment-related AEs (TRAEs) were reported in all pts, grade 3 in 6 (33.3%), and no grade 4 or 5. The most common TRAE (≥30%) included increased blood lactate dehydrogenase (83.3%), increased aspartate aminotransferase (72.2%), increased alanine aminotransferase (66.7%), hypercholesterolaemia (55.6%), hypoalbuminaemia (38.9%), hypertriglyceridemia (33.3%) and proteinuria (33.3%). Fourteen pts were efficacy evaluable. Two confirmed partial remission (PR) were achieved in pts with renal pelvis cancer (n = 1) and ovarian cancer (n = 1). TT-00973-MS is slowly eliminated from body, with a half-life of about 55 h. After multiple dosing (QD), steady state was reached within 15 days, and the mean accumulation factor of AUC 0-24h was approximately 6. Preliminary PK analysis showed a linear increase on exposure. Plasma levels of soluble AXL (sAXL) increased to approximately 1.7 times (range: 0.9∼2.8) the baseline levels at C1D28. Conclusions: The preliminary findings from this phase I study demonstratedthat the AXL inhibitor TT-00973-MS monotherapy exhibits a well-tolerable safety profile, promising pharmacodynamic activity, with early signs of efficacy in pts with heavily pre-treated advanced solid tumors. Further studies are warranted to comprehensively evaluate the efficacy and safety of TT-00973-MS in large patient populations and specific tumor types. Clinical trial information: NCT05673538 .

Cell-free extrachromosomal circular DNA (eccDNA) in the plasma provides an advantage for monitoring epithelial ovarian cancer (EOC) progression. We isolated eccDNA from plasma samples of 30 EOC patients before treatment (T0 time point) and 4 healthy individuals. We followed 16 EOC patients, collecting paired eccDNA samples between the 3rd and 4th course of chemotherapy (T1) and 6 months after the last course of chemotherapy (F). The patients were divided into three groups, including complete remission (CR) group, partial remission group (PR), and relapse group (RC). We compared the normalized eccDNA count per million mapped reads (EPM) among all the groups and assessed the distribution of eccDNA on each chromosome. Then, the eccDNA within the top 5 % coverage regions of each chromosome were annotated, and the top genes were analyzed for prognosis. We found that EOC patients exhibited significantly higher levels of eccDNA, with higher coverage in coding exon regions. Notably, circulating eccDNA was generally increased in the CR group, while decreased in the PR and RC group during treatment. Our results showed that the fold change of EPMs between the T1 and T0 distinguished PR and RC patients from CR patients, with area under the curve (AUC) of 0.71. Additionally, we identified two genes, SCARB1 and PDE10A, whose EPMs were able to predict prognosis in EOC patients, with AUCs of 0.86 and 0.83, respectively. Thus, our study offers valuable preliminary insights into a novel approach for predicting chemotherapy sensitivity in EOC patients, based on the trends of circulating eccDNA.

BACKGROUND:Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS:We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS:ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS:Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

5556 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload and is administered by intravenous infusion Q2W. Methods: This phase 1 study includes the dose-escalation of Ia and the dose-expansion of Ib. The phase Ia started with accelerated titration (0.015, 0.03mg/kg) and then switched to 3+3 design (0.12, 0.15, 0.17, 0.18, 0.20mg/kg). Phase Ib dose-expansion study includes 4 cohorts, platinum-resistant high-grade serous ovarian cancer (HGSOC), other sub-types of ovarian cancer such as clear cell ovarian cancer (OCCC) and low-grade serous ovarian cancer, metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective is to assess the safety and preliminary efficacy. Results: As of December 8, 2023, 240 patients (phase Ia: n=40; phase Ib: n=200) have been enrolled including 136 HGSOC,17 OCCC, 24 TNBC and 63 other tumor types. Majority of adverse events were mild to moderate. Common (≥50%) treatment-related AEs (TRAEs) were neutropenia, WBC decreased, AST increased, pyrexia, ALT increased and nausea. Grade 3/4 TRAEs (≥5%) were neutropenia (49%), WBC decreased (26.8%), AST increased (5.9%), ALT increased (5.9%), anaemia (5.4%). 41 HGSOC patients at dose of 0.15mg/kg with ≤3 prior treatment regimens, regardless of FRα expression levels were evaluable for efficacy assessment. 13 patients achieved partial response (PR) and 29 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 31.7% and 70.7%, respectively. For 19 patients with FRα expression level 0 to 49%, 6 patients achieved PR and ORR was 31.6%. The longest treatment duration exceeds 13 months. Conclusions: The current result showed that CBP-1008 demonstrated manageable safety profile. Promising antitumor activity was observed in ovarian cancer patients at dose of 0.15mg/kg, especially in platinum-resistant HGSOC patients with ≤3 prior treatment regimens. CBP-1008 has the potential to provide a better treatment option for ovarian cancer patients regardless of FRα expression levels. Clinical trial information: NCT04740398 .

Prognostic models play a crucial role in providing personalised risk assessment, guiding treatment decisions, and facilitating the counselling of patients with cancer. However, previous imaging-based artificial intelligence models of epithelial ovarian cancer lacked interpretability. In this study, we aimed to develop an interpretable machine-learning model to predict progression-free survival in patients with epithelial ovarian cancer using clinical variables and radiomics features. A total of 102 patients with epithelial ovarian cancer who underwent contrast-enhanced computed tomography scans were enrolled in this retrospective study. Pre-surgery clinical data, including age, performance status, body mass index, tumour stage, venous blood cancer antigen-125 (CA125) level, white blood cell count, neutrophil count, red blood cell count, haemoglobin level, and platelet count, were obtained from medical records. The volume of interest for each tumour was manually delineated slice-by-slice along the boundary. A total of 2074 radiomic features were extracted from the pre- and post-contrast computed tomography images. Optimal radiomic features were selected using the Least Absolute Shrinkage and Selection Operator logistic regression. Multivariate Cox analysis was performed to identify independent predictors of three-year progression-free survival. The random forest algorithm developed radiomic and combined models using four-fold cross-validation. Finally, the Shapley additive explanation algorithm was applied to interpret the predictions of the combined model. Multivariate Cox analysis identified CA-125 levels (P=0.015), tumour stage (P=0.019), and Radscore (P<0.001) as independent predictors of progression-free survival. The combined model based on these factors achieved an area under the curve of 0.812 (95% confidence interval: 0.802-0.822) in the training cohort and 0.772 (95% confidence interval: 0.727-0.817) in the validation cohort. The most impactful features on the model output were Radscore, followed by tumour stage and CA-125. In conclusion, the Shapley additive explanation-based interpretation of the prognostic model enables clinicians to understand the reasoning behind predictions better.

2528 Background: HB0028 is a bifunctional fusion protein consisting of an anti-PD-L1 IgG1 single domain antibody and TGF-β RII receptor extracellular domain (TGFβRII-ECD). This is the first dose escalation and expansion phase I/II study to evaluate the safety and preliminary anti-tumor activity of HB0028 in advanced solid tumors. Methods: In the phase I portion of the study, the patients (pts) with advanced solid tumor were enrolled, and an accelerated titration followed by a standard 3+3 design was applied to dose escalation. The objectives were toxicity evaluation, maximum tolerable dose (MTD), and recommended phase 2 dose (RP2D). Eligible pts with advanced solid cancers of any histologic subtype, and ECOG performance status ≤ 1 were treated with HB0028 (0.3mg, 1mg, 3mg, 10mg, 20mg, Q3W), until unacceptable toxicity or disease progression. Radiologic tumor assessments (by RECIST v1.1) were performed every 6 weeks while on treatment. Results: 16 pts [12 females and 4 males; ECOG 0/1, 9/7; median age 52 years (range 36 – 60)] were enrolled in phase I (0.3 mg/kg [n = 1], 1 mg/kg [n = 3], 3 mg/kg [n = 3], 10 mg/kg [n = 3], 20 mg/kg [n = 6]). Median number of prior lines of systemic therapy was 2 (range 1-4). 8(50%) pts received and progressed upon prior anti-PD-1/L1 therapy. All pts had measurable metastatic disease. No DLT and Death occurred. MTD was not reached. As of DEC 25,2023, among 16 patients' safety data are evaluable for toxicity. Any grade treatment‐related adverse events (TRAEs) occurred in 15 subjects (93.8%), with 2 subjects (12.5%) reported with ≥ Grade 3 (G3 Anemia and G3 γ-glutamyltransferase). The most common TRAEs (all grades) were AST increased (n = 4, 25%), anemia (n = 7, 43.8%) and infusion-related response (n = 5, 31.3%). Two SAEs (G2 AST increased and G3 Neoplastic fevers) were reported, only AST increased was considered as possibly related to study drug, but recovered shortly. The efficacy data cutoff date of DEC 25,2023, 16 patients are evaluable for radiologic response. 1 subject with cervical cancer in HB0028 20 mg/kg group had a partial response (PR), 3 subjects (liver cancer, lung cancer, left submandibular gland cancer) had stable disease (SD) and 12 subjects had progressive disease (PD). The ORR per RECIST 1.1 by investigator was 6.25% (1/16; 95% CI, 0%-30.2%), and the DCR was 25% (4/16; 95% CI, 7.3%-52.4%). Durable clinical benefit (SD for > 32 weeks) was seen in 1 subject with malignant tumor in the left submandibular gland. To date, 2 responders are still on treatment. Conclusions: HB0028 was generally well tolerated, and therapy provided modest antitumor activity in patients with heavily pretreated advanced solid tumors. Based on these data, a phase II prospective clinical trial is being planned in specific cancer. Clinical trial information: NCT06223308 .

Epithelial ovarian cancer (EOC) is a lethal form of gynecological malignancy. Some EOC patients experience relapse after standard primary debulking surgery (PDS) and adjuvant chemotherapy (ACT). Identifying molecular residual disease (MRD) by circulating tumor DNA (ctDNA) detection can timely signal the potential for relapse. However, research on the usage of ctDNA for MRD detection in EOC is limited. Fifty-one EOC patients who received standard PDS and ACT were included. Targeted sequencing based on a panel of 1021 cancer-related genes, along with further validation using Enrich-rare-mutation sequencing, was performed on tumor tissues acquired during PDS and on plasma samples collected before and after PDS/ACT to identify variants reflecting tumor signals. Post-surgery MRD was associated with relapse (Log-rank p = 0.0006) and was identified as an independent prognostic factor (HR, 3.4; 95

Background Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix.Methods In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors.Findings 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0 & BULL;65 [95% CI 0 & BULL;48-0 & BULL;88], p=0 & BULL;0058; China HR 0 & BULL;53 [0 & BULL;37-0 & BULL;76], p=0 & BULL;0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0 & BULL;61 [95% CI 0 & BULL;39-0 & BULL;94], p=0 & BULL;024; China HR 0 & BULL;59 [0 & BULL;37-0 & BULL;95]; p=0 & BULL;029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0 & BULL;52 [95% CI 0 & BULL;32-0 & BULL;84]; p=0 & BULL;0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0 & BULL;17 [95% CI 0 & BULL;05-0 & BULL;50]; p=0 & BULL;0015).Interpretation This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery.

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.

OBJECTIVE:There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS:This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS:A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION:Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION:NCT03972722.

e17542 Background: Despite recent advances in cancer diagnostics and treatments, nearly 75% ovarian cancer patients relapse within two years of primary therapy and become candidates for treatment of recurrent diseases. A novel approach to post-surgical risk stratification for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes. Methods: We analyzed a cohort of 22 stage Ⅰ-Ⅳ ovarian cancer patients which were followed up at median 6 (range,3-15) times between July 2017 and December 2020. Among the 22 patients, stage I, II, III and Ⅳ comprised 9%, 5%, 50% and 36%, respectively. Tumor tissue and blood samples of all subjects were collected at Ruijin Hospital, Shanghai Jiao Tong University.Somatic mutations were identified by whole exome sequencing and assessed from plasma collected during treatment using personalized tumor-informed MRDtect assays with a median of 25（range,17-30） amplicons/assay targeting tumor-specific variants unique to each patient, sequenced at mean 200,000X depth. Plasma samples with ≥2 variants detected were considered MRD-positive and ctDNA levels were reported in mean tumor molecules per mL (MTM/mL) of plasma. Sequencing data were analyzed using PiVAT secondary analysis software and MRD positive was concluded when at least two variants were detected in plasma. Results: CtDNA was preoperatively detectable in 18 (85.7%) patients, and the positive rate became 38.8% (7/18) after surgery. Serial ctDNA analysis during surveillance after definitive treatment of the 22 patients with longitudinal collected plasma samples identified relapse with 100% sensitivity and 100% specificity. The median lead time from ctDNA detection in plasma to relapse detection by standard-of-care computed tomography was 135 days (range,45-387days). Variants from a total of 526 genes were selected from the WES results of these 22 patients. Among these 526 genes, 96% (505 genes) were selected for only one patient, 3.4% (18 genes) were selected for two patients and 0.2% (one gene) were selected for three patients. Compared with tumor-agnostic assay, tumor-informed assay is a more accurate route that is more consistent with the heterogeneity of tumor and can maximize the ability to reflect the real situation of each patient. Conclusions: Sensitive methods for risk stratification, therapeutic efficacy monitoring, and early relapse detection may have a major impact on treatment decisions and patient management for ovarian cancer patients. MRD can be used as an effective biomarker to prompt prognosis and recurrence risk, providing powerful assistance for accurate diagnosis and treatment for patients.

5562 Background: Niraparib maintenance therapy significantly prolonged progression-free survival (PFS) versus placebo in patients with newly diagnosed advanced ovarian cancer (aOC), but its antitumor activity remains unclear in those with measurable residual disease (MRD) after first-line platinum-based chemotherapy (1LCT). This study aims to report the efficacy, including antitumor activity, and safety of niraparib maintenance therapy in patients with MRD after 1LCT from the phase 3 PRIME trial (NCT03709316). Methods: In PRIME, adults with newly diagnosed aOC who had received cytoreductive surgery and responded to 1LCT were randomized 2:1 to receive niraparib or placebo with stratification by receipt of neoadjuvant chemotherapy, response to 1LCT, status of germline BRCA mutations, and tumor homologous recombination deficiency status. Tumor assessment was conducted at baseline and every 12 weeks thereafter by blinded independent central review (BICR) according to RECIST, version 1.1. Between 29 June 2018 and 11 November 2019, 384 patients were randomized (255 niraparib, 129 placebo). The data cut-off date was 30 September 2021. This post-hoc analysis reports BICR-assessed objective response rate (ORR) and PFS in patients with MRD at baseline. An initial response was confirmed ≥4 weeks later. Results: In total, 73 (19.0%) patients (47 niraparib, 26 placebo) had MRD at baseline. Baseline characteristics were well balanced between the two MRD groups. Complete and partial responses, both confirmed, were observed in 12 (25.5%) and 15 (31.9%) niraparib-treated patients and 3 (11.5%) and 5 (19.2%) placebo-treated patients, respectively, leading to a confirmed ORR of 57.4% with niraparib and 30.8% with placebo (odds ratio, 3.20; 95% confidence interval [CI], 1.11–9.11). ORRs by biomarker status are provided in the table. Median PFS (95% CI) was 22.3 (8.7–not estimable) months with niraparib versus 8.3 (5.6–11.0) months with placebo (hazard ratio, 0.36; 95% CI, 0.19–0.71). Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 28 (59.6%) niraparib-treated patients and 7 (26.9%) placebo-treated patients. TEAEs led to treatment discontinuation in three (6.4%) niraparib-treated patients and one (3.8%) placebo-treated patient. Conclusions: In patients with newly diagnosed aOC who had MRD after 1LCT, niraparib maintenance therapy tended to induce additional antitumor activity and led to a clinically meaningful increase in PFS versus placebo. Clinical trial information: NCT03709316 .[Table: see text]

Epithelial ovarian cancer (EOC) is classified into five major histotypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), endometrioid (ENOC), and mucinous (MOC). However, the landscape of molecular and immunological alterations in these histotypes, especially LGSOC, CCOC, ENOC, and MOC, is largely uncharacterized. We collected 101 treatment-naive EOC patients. The resected tumor tissues and paired preoperative peripheral blood samples were collected and subjected to target sequencing of 1021 cancer-associated genes and T cell repertoire sequencing. Distinct characteristics of mutations were identified among the five histotypes. Furthermore, tumor mutation burden (TMB) was found to be higher in CCOC and ENOC, but lower in LGSOC and HGSOC. Alterations associated with DNA damage repair (DDR) pathways and homologous recombination deficiencies (HRD) were prevalent in five histotypes. CCOC demonstrated increased level of T cell clonality compared with HSGOC. Interestingly, the proportion of the 100 most common T cell clones was associated with TMB and tumor neoantigen burden in CCOC, highlighting more sensitive anti-tumor responses in this histotype, which was also evidenced by the enhanced convergent recombination of T cell clones. These findings shed light on the molecular traits of genomic alteration and T cell repertoire in the five major EOC histotypes and may help optimize clinical management of EOC with different histotypes.

目的 通过2014年-2018年湖南省肿瘤登记数据,分析湖南省恶性肿瘤发病与死亡特征及流行趋势,为制定肿瘤防控策略提供工作依据.方法 收集整理2014年-2018年湖南省32个肿瘤登记点报告的发病与死亡资料,统计分析恶性肿瘤的发病率、死亡率、中国人口标化率(中标率)、年龄别发病率与死亡率、累积发病率与死亡率及年度变化百分比(APC)等指标.结果 2014年-2018年湖南省肿瘤登记地区恶性肿瘤发病率为225.56/10万,中标发病率为156.41/10万;恶性肿瘤死亡率为147.32/10万,中标死亡率为95.78/10万.恶性肿瘤发病与死亡变化趋势显示:中标发病率由2014年的142.27/10万上升至2018年的172.28/10万,APC为5.1％,上升趋势有统计学意义(t=12.30,P=0.001);中标死亡率由2014年的92.44/10万上升至2018年的99.16/10万,APC为2.1％(t=4.54,P=0.020).男性恶性肿瘤中标发病率和中标死亡率均高于女性.恶性肿瘤年龄别发病率在0～39岁处于较低水平,55～59岁年龄组开始快速上升,75～79岁年龄组达到最高峰;年龄别死亡率在0～44岁处于较低水平,55～59岁年龄组开始快速上升,80～84岁年龄组升至峰值.2014年-2018年湖南省肿瘤登记地区恶性肿瘤发病率前5位依次为肺癌、女性乳腺癌、肝癌、子宫颈癌和结直肠肛门癌;死亡率前5位依次为肺癌、肝癌、结直肠肛门癌、胃癌和女性乳腺癌.结论 湖南省恶性肿瘤的发病和死亡均呈逐年上升趋势,应高度重视恶性肿瘤的防治,做好重点癌症的筛查与早诊早治工作.

Abstract Purpose: Phase I results of this phase I/II study showed that pamiparib 60 mg twice a day had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer. Patients and Methods: This open-label phase II study was conducted in China and enrolled adult (≥18 years) patients with platinum-sensitive ovarian cancer (PSOC; disease progression occurring ≥6 months after last platinum treatment) or platinum-resistant ovarian cancer (PROC; disease progression occurring <6 months after last platinum treatment). Eligible patients had known or suspected deleterious germline BRCA mutation (gBRCAmut) and had previously received ≥2 lines of therapy. Pamiparib 60 mg orally twice a day was administered until disease progression, toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST version 1.1. Results: In the total patient population (N = 113; PSOC, n = 90; PROC, n = 23), median age was 54 years (range, 34–79) and 25.6% of patients received ≥4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2–21.5). Eighty-two patients with PSOC and 19 patients with PROC were evaluable for efficacy. In patients with PSOC, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% [95% confidence interval (CI), 53.3–74.9]. In patients with PROC, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6–56.6). Frequently reported grade ≥3 adverse events were hematologic toxicities, including anemia and decreased neutrophil count. Conclusions: Pamiparib 60 mg twice a day showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCAmut, and had a manageable safety profile.

Objectives: Niraparib, a potent poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor, demonstrated statistically significant improvement in progression-free survival (PFS) in advanced ovarian cancer (OC) patients (pts) with complete or partial response (CR/PR) after first-line platinum-based chemotherapy (1L CT) regardless of biomarker status in the global phase 3 PRIMA study. The PRIME study was conducted to evaluate the efficacy and safety of niraparib using an individualized starting dose as a maintenance treatment following CR/PR to 1L CT in Chinese pts with advanced OC. Methods: In this double-blind, placebo (PBO)-controlled, multicenter phase 3 study, pts with newly diagnosed, advanced (stage III-IV) OC (including high-grade serious or endometrioid ovarian, primary peritoneal, or fallopian tube cancer) with CR/PR to 1L CT were randomized 2:1 to niraparib or PBO once-daily. A starting dose of 200 mg once daily (QD) was used, except in pts with a baseline body weight of ≥ 77 kg and platelet count ≥ 150,000/μL who received 300 mg QD. Pts were stratified by gBRCA status (mutated [m]/non-gBRCAm), tumor HRD status (HRDpos, HRDneg [including not determined, missing] by BGI Genomics assay, receipt of neoadjuvant chemotherapy (yes/no), and best response to 1L CT (CR/PR). All randomized pts remained on assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, or lost to follow-up. The primary endpoint was PFS assessed by blinded independent central review, analyzed using a stratified log-rank test and a Cox proportional hazards model. The secondary endpoint included overall survival (OS). All efficacy outcome measures were analyzed based on the intention-to-treat (ITT) population. Results: Of the 384 randomized pts (niraparib, n=255; PBO, n=129); 125 (32.6%) were gBRCAm, 257 (66.9%) were HRd population (HRDpos/non-gBRCAm or gBRCAm) (data cutoff [DCO], 30 September 2021). The median follow-up was 27.5 months. Median PFS was significantly longer among pts who received niraparib compared with PBO (24.8 vs 8.3 months; hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.34–0.60; P<0.001; Figure 1). All subgroup analysis demonstrated consistent treatment benefit with HRd population (HR 0.48) and HRp (HR 0.41). OS data was immature (as of DCO, number of OS events: 65[16.9 %] occurred; HR, 0.63; 95% CI, 0.38-1.03). The most common grade ≥ 3 adverse events in niraparib arm were anemia (18.0%), neutrophil count decreased (17.3%), and platelet count decreased (14.1%), 1.6%, 1.6%, and 0.8% in placebo arm, respectively. Objectives: Niraparib, a potent poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor, demonstrated statistically significant improvement in progression-free survival (PFS) in advanced ovarian cancer (OC) patients (pts) with complete or partial response (CR/PR) after first-line platinum-based chemotherapy (1L CT) regardless of biomarker status in the global phase 3 PRIMA study. The PRIME study was conducted to evaluate the efficacy and safety of niraparib using an individualized starting dose as a maintenance treatment following CR/PR to 1L CT in Chinese pts with advanced OC. Methods: In this double-blind, placebo (PBO)-controlled, multicenter phase 3 study, pts with newly diagnosed, advanced (stage III-IV) OC (including high-grade serious or endometrioid ovarian, primary peritoneal, or fallopian tube cancer) with CR/PR to 1L CT were randomized 2:1 to niraparib or PBO once-daily. A starting dose of 200 mg once daily (QD) was used, except in pts with a baseline body weight of ≥ 77 kg and platelet count ≥ 150,000/μL who received 300 mg QD. Pts were stratified by gBRCA status (mutated [m]/non-gBRCAm), tumor HRD status (HRDpos, HRDneg [including not determined, missing] by BGI Genomics assay, receipt of neoadjuvant chemotherapy (yes/no), and best response to 1L CT (CR/PR). All randomized pts remained on assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, or lost to follow-up. The primary endpoint was PFS assessed by blinded independent central review, analyzed using a stratified log-rank test and a Cox proportional hazards model. The secondary endpoint included overall survival (OS). All efficacy outcome measures were analyzed based on the intention-to-treat (ITT) population. Results: Of the 384 randomized pts (niraparib, n=255; PBO, n=129); 125 (32.6%) were gBRCAm, 257 (66.9%) were HRd population (HRDpos/non-gBRCAm or gBRCAm) (data cutoff [DCO], 30 September 2021). The median follow-up was 27.5 months. Median PFS was significantly longer among pts who received niraparib compared with PBO (24.8 vs 8.3 months; hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.34–0.60; P<0.001; Figure 1). All subgroup analysis demonstrated consistent treatment benefit with HRd population (HR 0.48) and HRp (HR 0.41). OS data was immature (as of DCO, number of OS events: 65[16.9 %] occurred; HR, 0.63; 95% CI, 0.38-1.03). The most common grade ≥ 3 adverse events in niraparib arm were anemia (18.0%), neutrophil count decreased (17.3%), and platelet count decreased (14.1%), 1.6%, 1.6%, and 0.8% in placebo arm, respectively.