Li Chen

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)

Abstract Purpose: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody–drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC). Patients and Methods: Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. Results: The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03; HR = 2.02 (1.06–3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment. Conclusions: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.

Molecular and Immune Correlates of Response to First-Line De-escalated Chemotherapy plus Penpulimab and Anlotinib in Advanced Cervical Cancer

Abstract The standard of care for advanced cervical cancer includes chemotherapy, antiangiogenic, and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. Deescalation chemotherapy together with immunotargeted therapies has been proven effective and less toxic in other cancers. In this study, we conducted a multicenter, single-arm, phase II study of first-line deescalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in patients with PD-L1–positive, persistent, recurrent, or metastatic cervical cancer. Of 32 efficacy-evaluable patients, 30 (93.8%, 95% confidence interval, 79.2%–99.2%) had an investigator-confirmed objective response. Single-nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells, and activated germinal center B cells portended optimal treatment response. Patients with a high tertiary lymphoid structure-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in patients with metastatic, persistent, or recurrent cervical cancer. Significance: We recruited 34 patients with advanced cervical cancer receiving two cycles of platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab, and showed safety and efficacy of this deescalation regimen. This work highlights the potential for personalized treatment strategies and feasibility of reduced-toxicity regimens.

Development of a nomogram for predicting positive margins after cold knife conization in patients with high-grade squamous intraepithelial lesions

The objective was to develop a nomogram for predicting positive margins after cold knife conization (CKC) in patients with high-grade squamous intraepithelial lesion (HSIL). This retrospective study included patients who underwent CKC at Baoding No. 1 Central Hospital between December 2013 and March 2024. Patients were divided into training (between December 2013 and December 2022) and validation (between January 2023 and March 2024) sets. The least absolute shrinkage and selection operator regression was applied to filter and select relevant variables. Multivariable logistic regression was used for nomogram construction. The model performance was evaluated using various methods, including receiver operating characteristics, decision curve analysis, and calibration analysis. The training and validation sets included 985 and 227 patients, respectively. Age (OR = 1.046, 95% CI: 1.028–1.064, P < .001), cervical intraepithelial neoplasia quadrants by punch biopsy (OR = 1.561, 95% CI: 1.348–1.808, P < .001), HSIL type (OR = 1.711, 95% CI: 1.102–2.657, P = .017), and gland involvement (OR = 1.552, 95% CI: 1.073–2.247, P = .020) were associated with positive margins and used for nomogram construction. The predictive model yielded area under the curves of 0.744 and 0.754 in the training and validation sets, respectively. Decision curve analysis indicated a net benefit when using the nomogram, and the calibration curves demonstrated a good fit. This study constructed a nomogram model for predicting positive margins after CKC in patients with HSIL. This nomogram may enable early and accurate patient evaluation, potentially improving clinical outcomes.

The impact of plan complexity on dose delivery deviations resulting from multileaf collimator positioning errors in volumetric modulated arc therapy

Abstract Objectives This study aimed to assess the effect of plan complexity on dosimetric alterations induced by multileaf collimator (MLC) misplacements in volumetric modulated arc therapy (VMAT). Methods Volumetric modulated arc therapy plans for 14 cervical and 10 lung cancer cases were reoptimized utilizing 3 distinct aperture shape controller (ASC) settings (none, very high, and very low), resulting in 3 plan groups: ASC-none, ASC-vh, and ASC-vl. Four types of MLC position errors were simulated: total shifts (Type 1), open/closed (Type 2), right-side shifts (Type 3), and left-side shifts (Type 4). Plan complexity was assessed using the small aperture score (SAS). Dose deviations resulting from various MLC positioning errors and SAS values were calculated and compared among the 3 ASC groups. Results The variations in planning target volume (PTV) D95% for cervical cancer were approximately 0.6%, 3.7%, 1.9%, and 1.8% per millimetre for Types 1-4 errors, respectively. In the case of lung cancer, the changes were 2.3%, 9.3%, 5.3%, and 4.6% per millimetre. The ASC-vh and ASC-vl groups exhibited significantly reduced dose changes and SAS values in response to MLC errors, as compared to the ASC-none group (P < .05). Conclusions Highly complex plans exhibit greater dose sensitivity to MLC positional errors. The application of ASC proves effective in reducing plan complexity and mitigating the influence of MLC errors on dose deviation. Advances in knowledge By elucidating the relationship between dosimetric impacts from MLC errors and plan complexity, this study offers valuable guidance for the design of radiotherapy plans, helping to enhance the accuracy and effectiveness of VMAT treatments.

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.