Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

A real-world study of treatment patterns following disease progression in epithelial ovarian cancer patients undergoing poly-ADP-ribose polymerase inhibitor maintenance therapy.

BACKGROUND: The efficacy of subsequent therapy after poly-ADP-ribose polymerase (PARP) inhibitor maintenance treatment has raised concerns. Retrospective studies show worse outcomes for platinum-based chemotherapy after progression of PARP inhibitor-maintenance therapy, especially in BRCA-mutant patients. We aimed to describe subsequent therapy in ovarian cancer patients after PARP inhibitor-maintenance therapy and evaluate their response to treatment. We focused on chemotherapy for patients with a progression-free interval (PFI) of ≥ 6 months after prior platinum treatment, based on BRCA status. METHODS: We analyzed real-world data from Peking University Cancer Hospital, subsequent therapy after progression to PARP inhibitor-maintenance therapy for epithelial ovarian cancer between January 2016 and December 2022. Clinicopathological characteristics and treatment outcomes were extracted from medical records. The last follow-up was in May 2023. RESULTS: A total of 102 patients were included, of which 29 (28.4%) had a germline BRCA1/2 mutation and 73 (71.6%) exhibited BRCA1/2 wild-type mutations. The PARP inhibitors used were Olaparib (n = 62, 60.8%), Niraparib (n = 35, 34.3%), and others (n = 5, 4.9%). The overall response rate (ORR) was 41.2%, and the median time to second progression (mTTSP) was 8.1 months (95%CI 5.8-10.2). Of 91 platinum-sensitive patients (PFI ≥ 6 months) after progression to PARP inhibitor-maintenance therapy, 65 patients subsequently received platinum regimens. Among them, 30 had received one line of chemotherapy before PARP inhibitor-maintenance therapy. Analysis of these 30 patients by BRCA status showed an ORR of 16.7% versus 33.3% and mTTSP of 7.1 (95% CI 4.9-9.1) versus 6.2 months (95% CI 3.7-8.3, P = 0.550), for BRCA-mutant and wild-type patients, respectively. For the remaining 35 patients who had received two or more lines of chemotherapy before PARP inhibitor-maintenance therapy, ORR was 57.1% versus 42.9%, and mTTSP was 18.0 (95% CI 5.0-31.0) versus 8.0 months (95% CI 4.9-11.1, P = 0.199), for BRCA-mutant and wild-type patients, respectively. CONCLUSION: No differences in survival outcomes were observed among patients with different BRCA statuses. Furthermore, for patients who had undergone two or more lines of chemotherapy before PARP inhibitor maintenance therapy, no negative effects of PARP inhibitors on subsequent treatment were found, regardless of BRCA status.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

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.

A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis.

BACKGROUND: The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). METHODS: This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut). RESULTS: Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. CONCLUSIONS: Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).

A nomogram prediction model for the TP53mut subtype in endometrial cancer based on preoperative noninvasive parameters.

BACKGROUND: The molecular subtypes of endometrial carcinoma are significantly correlated with survival outcomes and can guide surgical methods and postoperative adjuvant therapy. Among them, the TP53mut subtype has the worst prognosis and can only be determined by detection after surgery. Therefore, identifying preoperative noninvasive clinical parameters for early prediction of the TP53mut subtype would provide important guidance in choosing the appropriate surgical method and early warning for clinicians. Our study aimed to establish a model for the early prediction of the TP53mut subtype by using preoperative noninvasive parameters of endometrial cancer and screen out potential TP53mut patients. METHODS: Information and pathological specimens of 376 patients who underwent surgery for FIGO stage I-IV endometrial cancer in the Department of Gynecology, Peking University Cancer Hospital, from June 2011 to July 2020 were collected, and 178 cases were finally included in the study as the training dataset (part A). Thirty-six cases from January 2022 to March 2023 were collected as the validation dataset (part B). Molecular subtyping was performed using a one-stop next-generation sequencing (NGS) approach. Compared with the TP53mut subtype, the POLE EDM, MSI-H and TP53 wild-type subtypes were defined as non-TP53mut subtypes. Univariate Cox regression analysis and multivariate logistic analysis were performed to determine the preoperative clinical parameters associated with the TP53mut subtype. A nomogram prediction model was established using preoperative noninvasive parameters, and its efficacy in predicting TP53mut subtype and survival outcomes was verified. RESULTS: The TP53mut subtype was identified in 12.4% of the part A and 13.9% of the part B. Multivariate logistic regression analysis showed that HDL-C/LDL-C level, CA125 level, and cervical or lower uterine involvement were independent influencing factors associated with the TP53mut subtype (p = 0.016, 0.047, <0.001). A TP53mut prognostic model (TPMM) was constructed based on the factors identified in the multivariate analysis, namely, TPMM = -1.385 × HDL-C/LDL-C + 1.068 × CA125 + 1.89 × CI or LUI, with an AUC = 0.768 (95% CI, 0.642 to 0.893) in the part A. The AUC of TPMM for predicting TP53mut subtype in the part B was 0.781(95% CI, 0.581 to 0.980). The progression-free survival (PFS) and overall survival (OS) of patients with the TP53mut subtype were significantly worse than those of patients with the non-TP53mut subtype, as predicted by the model in the part A. CONCLUSIONS: TP53mut prediction model (TPMM) had good diagnostic accuracy, and survival analysis showed the model can identify patients with different prognostic risk.

Real-world study of bevacizumab treatment in patients with ovarian cancer: a Chinese single-institution study of 155 patients.

OBJECTIVE: The purpose of this study was to retrospectively assess the pattern, compliance, efficacy and safety of bevacizumab in Chinese ovarian cancer patients. METHODS: We reviewed the clinicopathological data of patients with histologically confirmed epithelial ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma, who were diagnosed and treated at the Department of Gynecologic Oncology of Peking University Cancer Hospital between May 2012 and January 2022. RESULTS: A total of 155 patients were eventually enrolled in this study, with 77 as first-line chemotherapy (FL) and 78 as recurrence therapy (RT) among which 37 patients were platinum sensitive and 41 were platinum resistant. Among the 77 patients in the FL group, 35 received bevacizumab during neoadjuvant chemotherapy (NACT) alone (NT), 23 received bevacizumab during both neoadjuvant and first-line chemotherapy (NT + FL) and 19 received bevacizumab during first-line chemotherapy alone (FLA). Among the 43 patients of NT and NT + FL groups undergoing interval debulking surgery (IDS), 38(88.4%) patients achieved optimally debulking and 24 (55.8%) patients had no residual disease after IDS. The patients in the FL group had a median progression free survival (PFS) of 15(95%CI: 9.951-20.049) months, and the 12-month PFS was 61.7%. In the RT group, the overall response rate (ORR) was 53.8%. According to multivariate analysis, the patients' platinum sensitivity had a significant impact on the PFS in the RT group. 13(8.4%) patients discontinued bevacizumab due to toxicity. Seven patients were in the FL group while 4 patients were in the RT group. The most common adverse event associated with bevacizumab therapy was hypertension. CONCLUSION: Bevacizumab is effective and well-tolerated in the real world setting of ovarian cancer treatment. Adding bevacizumab to NACT is feasible and tolerable. Receiving the regimen containing bevacizumab in the last preoperative chemotherapy did not result in increased intraoperative bleeding of IDS. Platinum sensitivity is the most important factor affecting the effectiveness of bevacizumab in recurrent patients.

Application of sentinel lymph node mapping in endometrial cancer: A survey among Chinese gynecological oncologists.

AIM: To gain a better understanding of the use of sentinel lymph node mapping by Chinese oncologists for endometrial cancer staging and analyze factors influencing its application. METHODS: Questionnaires were collected online before and by phone after the symposium to evaluate the general characteristics of oncologists who participated in the endometrial cancer seminar and factors associated with the application of sentinel lymph node mapping in endometrial cancer patients. RESULTS: Gynecologic oncologists from 142 medical centers participated in the survey. 35.4% of doctors employed sentinel lymph node mapping for endometrial cancer staging, 57.3% chose indocyanine green as the tracer. Multivariate analysis revealed that cancer research center (odds ratio = 4.229, 95% CI 1.747-10.237), physician familiarity with sentinel lymph node mapping (odds ratio = 126.188, 95% confidence interval 43.220-368.425) and the use of ultrastaging (odds ratio = 2.657, 95% confidence interval 1.085-6.506) were related to the doctors' selection of sentinel lymph node mapping. There was a significant difference in the surgical procedure for early endometrial cancer, the number of removed sentinel lymph node, and the reason for not adopting sentinel lymph node mapping before and after the symposium. CONCLUSIONS: The theoretical knowledge of sentinel lymph node mapping, the use of ultrastaging, and cancer research center are related to a higher acceptance of sentinel lymph node mapping. Distance learning is conducive to the promotion of this technology.

Circulating T-cell receptor diversity as predictive biomarker for PARP inhibitors maintenance therapy in high grade serous ovarian cancer.

OBJECTIVE: T-cell receptor (TCR) repertoire diversity is getting increasing attention as a predictive biomarker in cancer patients. However, the characteristics of the TCR together with its predictive significance for high grade serous ovarian cancer (HGSOC) patients receiving poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy remain unknown. METHODS: Twenty-seven patients with HGSOC were analyzed including 22 patients receiving PARPi maintenance therapy and 5 untreated patients as control. Peripheral blood samples were collected for TCR sequencing at baseline as well as one month and three months after the exposure to PARPi. To determine whether TCR diversity was related to PARPi efficacy, we compared the TCR repertoire between patients who had received PARPi and those who had not. RESULTS: For patients receiving PARPi treatment or not, we evaluated changes in clone abundance during PARPi maintenance and the similarity of the TCR repertoire before and after the treatment. The results revealed that patients receiving PARPi had TCR repertoires that were more stable than those of untreated cases. We next correlated TCR diversity with the efficacy of PARPi in the treatment group. The rising trend of TCR diversity after three months with PARPi treatment was associated with a longer PFS (21.7 vs 7.4 months, hazard ratio = 0.19, p < 0.001) and a better response to PARPi (91.7% vs 25.0%, p = 0.004). Furthermore, we discovered that the primary characteristic with predictive value for the effectiveness of PARPi is the considerable reduction of the high-frequency T cell clones. CONCLUSION: We suggested that the circulating TCR diversity could be a potential predictive biomarker for PARPi maintenance therapy in HGSOC.

A multicenter phase 2 trial of camrelizumab plus famitinib for women with recurrent or metastatic cervical squamous cell carcinoma.

This phase 2 study assesses the efficacy and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (anti-angiogenic agent) in women with pretreated recurrent or metastatic cervical cancer (ClinicalTrials.gov NCT03827837). Patients with histologically or cytologically confirmed cervical squamous cell carcinoma experiencing relapse or progression during or after 1-2 lines of systemic therapy for recurrent or metastatic disease are enrolled. Eligible patients receive camrelizumab 200 mg intravenously on day 1 of each 3-week cycle plus famitinib 20 mg orally once daily. The primary endpoint is the objective response rate. Secondary endpoints are duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. The trial has met pre-specified endpoint. Thirty-three patients are enrolled; median follow-up lasts for 13.6 months (interquartile range: 10.0-23.6). Objective responses are observed in 13 (39.4%, 95% confidence interval [CI]: 22.9-57.9) patients; the 12-month duration of response rate is 74.1% (95% CI: 39.1-90.9). Median progression-free survival is 10.3 months (95% CI: 3.5-not reached) and the 12-month overall survival rate is 77.7% (95% CI: 58.9-88.7). All patients experience treatment-related adverse events; grade ≥3 events occur in 26 (78.8%) patients. Treatment-related serious adverse events and deaths are observed in 9 (27.3%) and 2 (6.1%) patients, respectively. Camrelizumab plus famitinib shows promising antitumor activity with a manageable and tolerable safety profile in patients with pretreated recurrent or metastatic cervical squamous cell carcinoma. This combination may represent a treatment option for this population.

The first Chinese National Union of Real-world Gynaecological Oncology Research and Patient Management Platform: A retrospective study.

OBJECTIVE: To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China. DESIGN: Retrospective study. SETTING: The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform). SAMPLE: Patient-centred data pool. METHODS: The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction. MAIN OUTCOME MEASURES: Recent treatment pattern shifts towards precision medicine for OC in China. RESULTS: Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China. CONCLUSION: The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.

Olaparib maintenance monotherapy in Chinese patients with platinum-sensitive relapsed ovarian cancer: China cohort from the phase III SOLO2 trial.

AIM: The phase III SOLO2 global study demonstrated the efficacy and safety of maintenance olaparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, in platinum-sensitive relapsed ovarian cancer patients with a BRCA mutation. This separate China cohort of SOLO2 investigated the efficacy and safety of maintenance olaparib in Chinese patients. METHODS: Patients received olaparib (300 mg twice daily, oral, tablets) or matched placebo. Primary endpoint was investigator-assessed progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1). Safety and tolerability were also assessed. RESULTS: Thirty-two patients were treated. Olaparib treatment led to an improvement in progression-free survival compared with placebo (hazard ratio = 0.44, 95% confidence interval: 0.17-1.19; median = 13.8 vs. 5.5 months). Results of secondary efficacy endpoints of time to first subsequent treatment/death and time to treatment discontinuation/death were consistent with progression-free survival results. Time to second progression/death and time to second subsequent treatment/death data were immature at data cutoff. The most common adverse events in the olaparib arm were nausea (81.8%), anemia (45.5%), and decreased appetite (36.4%). Grade ≥3 adverse events were experienced by 36.4% of olaparib and 10.0% of placebo patients. No adverse events led to discontinuation of treatment. There were six deaths (olaparib, five; placebo, one); one death in the olaparib arm was due to an unknown cause, all others were related to disease progression. CONCLUSIONS: Efficacy and safety findings in the China SOLO2 cohort support the use of olaparib (300 mg twice daily) as maintenance treatment for Chinese patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation.

Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study.

BACKGROUND: Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients with platinum-resistant ROC were enrolled to receive camrelizumab (200 mg every 3 weeks by intravenous infusion) and oral famitinib (20 mg once daily). All patients had disease progression during or <6 months after their most recent platinum-based chemotherapy. Primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 based on investigator's assessment. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), 12-month OS rate and safety profile. RESULTS: Of the 37 women enrolled, 11 (29.7%) patients had primary platinum resistant, 15 (40.5%) patients had secondary platinum resistant and 11 (29.7%) patients had primary platinum refractory disease. As the cut-off date of April 9, 2021, nine (24.3%) patients had achieved a confirmed objective response, the ORR was 24.3% (95% CI, 11.8 to 41.2) and the DCR was 54.1% (95% CI, 36.9 to 70.5). Patients with this combination regimen showed a median TTR of 2.1 months (range, 1.8-4.1) and a median DoR of 4.1 months (95% CI, 1.9 to 6.3). Median PFS was 4.1 months (95% CI, 2.1 to 5.7), and median OS was 18.9 months (95% CI, 10.8 to not reached), with the median follow-up duration of 22.0 months (range, 12.0-23.7). The estimated 12-month OS rate was 67.2% (95% CI, 49.4 to 79.9). The most common ≥grade 3 treatment-related adverse events were hypertension (32.4%), decreased neutrophil count (29.7%) and decreased platelet count (13.5%). One (2.7%) patient died of grade 5 hemorrhage that was judged possibly related to study treatment by investigator. CONCLUSION: The camrelizumab with famitinib combination appeared to show antitumor activity in heavily pretreated patients with platinum-resistant ROC with an acceptable safety profile. This combination might provide a novel alternative treatment strategy in platinum-resistant ROC setting and warranted further exploration. TRIAL REGISTRATION NUMBER: NCT03827837.

Evaluation of pelvic floor muscle function (PFMF) in cervical cancer patients with Querleu-Morrow type C hysterectomy: a multicenter study.

INTRODUCTION: To evaluate the pelvic floor muscle function (PFMF) of cervical cancer patients after type QM-C hysterectomy and to explore the relationship between decreased PFMF and related factors. METHODS: This was a multi-centered retrospective cohort study. 181 cervical cancer patients who underwent type QM-C hysterectomy were enrolled from 9 tertiary hospitals. Strength of PFMF were measured using neuromuscular apparatus (Phenix U8, French). Risk factors contributing to decreased PFMF were analyzed by univariate and multivariate ordinal polytomous logistic regression. RESULTS: Totally 181 patients were investigated in this study. 0-3 level of type I muscle fibre strength (MFSI) was 52.6% (95/181), 0-3 level of type IIA muscle fibre strength (MFSIIA) was 50% (91/181). Subjective stress urinary incontinence was 46% (84/181), urinary retention was 27.3% (50/181), dyschezia was 41.5% (75/181), fecal incontinence was 9% (18/181). ① MFSI: Multivariate ordinal polytomous logistic regression shows that the follow-up time (p < 0.05), chemotherapy and radiotherapy (p = 0.038) are independent risk factors of MFSI's reduction after type QM-C hysterectomy. ② MFSIIA: multivariate ordinal polytomous logistic regression shows that the follow-up time (p < 0.05) are independent risk factors of MFSIIA's reduction after type QM-C hysterectomy. The pelvic floor muscle strength (PFMS) increased after 9 months than in 9 months after operation, which showed that the PFMS could be recovered after operation. CONCLUSIONS: We advocate for more attention and emphasis on the PFMF of Chinese female patients with cervical cancer postoperation. PEKING UNIVERSITY PEOPLE'S HOSPITAL: PFMF after QM-C hysterectomy has not been analyzed by current study. The contribution is that patients with radical hysterectomy should do pelvic floor rehabilitation exercises in 3 months after operation. Clinical Trails NCT number of this study is 02492542.

Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study.

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.

Construction and Validation of a Platinum Sensitivity Predictive Model With Multiple Genomic Variations for Epithelial Ovarian Cancer.

Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or FAM175A LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 vs. 10.1 months, p < 0.05), or FAM175A LOH (16.5 vs. 9.2 months, p < 0.05), or negative WGD (16.5 vs. 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.

Assessment of Pelvic Floor Function and Quality of Life in Patients Treated for Cervical Cancer: A Multicenter Retrospective Study.

OBJECTIVES: Our study aimed to evaluate the quality of life (QoL) and pelvic floor function of cervical cancer (CC) patients after treatment. DESIGN: This was a cross-sectional observational cohort study. PARTICIPANTS: The participants included in this study were CC patients who underwent radical hysterectomy (RH) from 2012 to 2018 at 18 medical centers across China. METHODS: The validated versions of the Pelvic floor Distress Inventory-Short Form 20, Overactive Bladder Symptom Score, and Euro Qol Five-Dimension questionnaires were used to evaluate postoperative pelvic floor dysfunction (PFD) and QoL. RESULTS: A total of 689 CC patients were enrolled. The incidence of stress urinary incontinence (SUI), incomplete urinary emptying, and constipation were 32.7, 27.7, and 28.6%, respectively. Multivariate analysis confirmed that laparoscopic RH (LRH) and vaginal wall resection greater than 3 cm were risk factors for lower urinary tract symptoms (LUTS). LRH and chemotherapy were risk factors for SUI. Chemoradiotherapy and LRH were risk factors for overactive bladder (OAB). A high body mass index and LRH were risk factors for more severe defecation symptoms. ARH and large amount of operative blood loss were risk factors for poor QoL. CONCLUSION: PFD is common in CC patients after treatment. LRH seems to increase the postoperative distress, including LUTS and defecation symptoms. Postoperative urinary incontinence and OAB are more bothersome for patients undergoing chemotherapy and radiotherapy. We recommend evaluating pelvic floor function as a standard assessment during follow-up.

Real-world Experience of Olaparib Treatment in Patients with Ovarian Cancer: A Chinese Multicenter Study.

The objective of this study was to evaluate the real-world application, efficacy, and safety data of olaparib for maintenance therapy and active treatment in patients with ovarian cancer in China. Patients with ovarian cancer from 17 institutions in China treated with olaparib as maintenance or active therapy from January 2018 to March 2020 were included in this study. The medical records were reviewed, and follow-up information was collected for analysis of the patients' clinicopathologic characteristics as well as the effectiveness and safety of olaparib. A total of 251 patients receiving olaparib were included, with 84 as maintenance therapy after first-line chemotherapy (FL-M), 97 as maintenance therapy after platinum-sensitive recurrence (PSR-M), and 70 as active treatment (AT). The probability of progression-free survival (PFS) at 12 months was 87.6% in the FL-M group and 63.8% in the PSR-M group. According to the multivariate analysis, complete response (CR) to chemotherapy for the PSR-M patients was the only factor affecting the PFS (HR = 0.414, P = 0.014), and platinum sensitivity was the only factor affecting PFS improvement in the AT group (HR = 0.317, P = 0.009). In the AT group, the objective response rate was 37.1%, the CR rate was 7.1%, and 30% of the patients had stable disease. Eight (3.2%) patients discontinued olaparib due to toxicity. Anemia was the most common adverse event. In conclusion, olaparib is effective and well tolerated in the real-world setting of ovarian cancer treatment. Platinum sensitivity is positively correlated to the effectiveness of olaparib in both maintenance and active treatment.

Evaluation of the sexual quality of life and sexual function of cervical cancer survivors after cancer treatment: a retrospective trial.

OBJECTIVE: The purpose of this study was to explore the factors influencing the sexual quality of life of patients with cervical cancer who underwent radical hysterectomy. METHODS: This multicenter retrospective cohort study was conducted from June 2013 to June 2018 at nine hospitals in China. In total, 204 women diagnosed with stage IA to stage IIB cervical cancer who underwent radical hysterectomy completed the questionnaire. Sexual function was measured with the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ). All analyses were performed with R version 3.4.3 statistical software packages. A two-sided significance level of 0.05 was used to evaluate the statistical significance. RESULTS: The mean sexual quality of life score was 37.21 ± 17.28, where a higher PISQ score indicates a better sexual quality of life, and we identified the factors associated with sexual dysfunction. The average follow-up time was 29.0 ± 16.0 months. In addition to radical hysterectomy, 182 (89.2%) patients underwent ovarian suspension, 93 (45.6%) underwent chemotherapy, and 74 (36.3%) underwent concurrent radiotherapy. The univariate analysis confirmed that age represents a protective factor for sexual function (odds ratio (OR) 6.0, 95% confidence interval (CI) 1.1-10.8, p = 0.017). The patients who underwent ovarian suspension were more likely to experience a good sexual quality of life (OR - 7.2, 95% CI [- 14.8, - 0.4], p = 0.035) compared to those who did not undergo ovarian suspension. A significant negative association was observed between radiotherapy and the behavioral-emotive, physical and partner-related domains of the PISQ (behavioral-emotive, OR - 1.5, 95% CI [- 2.6, - 0.4], p = 0.011; physical, OR - 0.9, 95% CI [- 1.5, - 0.3], p = 0.006; partner-related, OR - 0.7, 95% CI [- 1.3, 0.0], p = 0.043). Chemotherapy and radiotherapy were common risk factors for sexual dysfunction, and radiotherapy exerted a stronger effect than chemotherapy. CONCLUSIONS: This study shows that the sexual function of cervical cancer patients tends to be related to age, radiotherapy, and chemotherapy. However, across these factors, patients with preserved ovaries tend to return to a satisfactory sexual quality of life after recovering from surgery.

A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells.

Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties across different tumors remain elusive. Here, by performing a pan-cancer analysis of single myeloid cells from 210 patients across 15 human cancer types, we identified distinct features of TIMs across cancer types. Mast cells in nasopharyngeal cancer were found to be associated with better prognosis and exhibited an anti-tumor phenotype with a high ratio of TNF+/VEGFA+ cells. Systematic comparison between cDC1- and cDC2-derived LAMP3+ cDCs revealed their differences in transcription factors and external stimulus. Additionally, pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types, and the composition of TIMs appeared to be associated with certain features of somatic mutations and gene expressions. Our results provide a systematic view of the highly heterogeneous TIMs and suggest future avenues for rational, targeted immunotherapies.