tbuckley/cabot-search huggingface dataset:
Value of ctDNA-based molecular residual disease (MRD) in evaluating the adjuvant therapy effect in ovarian cancer.
Authors: Jingjing Wang, Keyao Chen, Yu Guo, Ying He, Shaochen Cheng, Li Sun, Jiaman Teng
Journal: Journal of Clinical Oncology (2024)

5525 Background: Ovarian carcinoma (OC) is the fifth leading cause of cancer-related mortality in women worldwide. Circulating tumor DNA (ctDNA) is a promising biomarker for ovarian cancer and can be detected using a noninvasive liquid biopsy. It reflects the status of molecular residual disease and post-surgery therapy effect in real-time. In this study, we examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding tumor specimens of different types of OC. Additionally, investigated whether mutations in plasma ctDNA can provide predictive insight into OC and provide a new perspective on the efficacy of postoperative adjuvant therapy. Methods: Stage I-IV ovarian cancer patients were recruited from 2022.11 to 2023.12. Tumor tissues were collected at excision and then subjected to whole exome sequencing(WES) for comprehensive somatic variant detection in 1000x depth. Personalized tumor-informed molecular residual disease (MRD) panel was designed for up to 40 loci including SNVs and InDELS. Plasma samples were collected at baseline and post-operation adjuvant therapy. Plasma samples performed on ctDNA-based MRD assay underwent 100,000x ultra-deep sequencing. Results: The cohort included 20 patients with high-grade serous carcinomas (HGSC), 5 with borderline tumors, 2 with clear cell carcinoma, 2 with mucinous carcinomas, 2 with endometrioid carcinoma, 1 with low-grade serous carcinomas, and 2 with other types. WES identified 2542 variants in 1906 genes, encompassing 2297 single nucleotide variants (SNVs) and 245 insertions/deletions (InDels), with missense mutations accounting for 84.5% of the major mutations. The most frequently mutated gene was TP53 (76.47%), followed by ZNF285 (44.12%), TTN (29.41%), TOPAZ1 (29.41%), THADA (23.53%), and UBE4A (20.59%). The mutation landscape showed no significant differences among subtypes. The baseline ctDNA detection rate is 88.23% for the entire cohort and 90% for HGSC patients. The consistency between plasma and tissue was verified by Pearson (p=2.7e-6) and Spearman (p=3.7e-7) correlation analyses. All HGSC patients underwent adjuvant therapy post-surgery (up to 8 cycles). 75% (15/20) of HGSC patients achieved complete response (CR), 20% (4/20) achieved partial response (PR), and 5% (1/20) showed progressive disease (PD). MRD monitoring showed a continuous decrease in postoperative ctDNA concentration, with 60% (9/15) of patients achieving MRD negativity. Among the patients with CR, 4 became MRD negative for the first time after surgery and maintained negativity after up to 6 cycles of adjuvant therapy. Conclusions: The results of this real-world study indicate that tumor-informed MRD can serve as a prognostic biomarker for OC, and would provide information about postoperative MRD status and long-term monitoring of adjuvant therapy for further precise treatment.
Trends in phase 3 gynecological clinical trials of targeted therapies: Study oversight and pharmaceutical involvement in the past 12 years.
Authors: Qiao Ruan, Caitlin Ruth Johnson, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2024)

5503 Background: To determine the trends, progress, and pharmaceutical sponsorship of clinical trials in targeted therapy treatments for gynecologic cancers. Methods: From January 1st, 2011, to May 31st, 2023, all phase III gynecological clinical trials in targeted therapy treatment were identified from clinicaltrials.gov and reviewed using peer review publications. Characteristics of demographics and authorship were analyzed for comparison using Chi-square analyses and Fisher’s exact tests. P-values &lt;0.05 were considered statistically significant. Results: Over the 12-year period, we identified 18,424 patients enrolled across 30 clinical trials studying targeted therapy treatments for gynecologic cancers. Of these trials, 86.7%, 10.0%, and 3.3% involved ovarian, cervical, and endometrial cancers, respectively. Of patients enrolled in these trials, 77.0% identified as White, 13.3% as Asian, and 2.4% as Black; only 3.0% identified as Hispanic. Approximately 46.7% of first authors of publications for these trials were from the U.S. and 43.3% were from Europe. Furthermore, 23.4% of co-authors served or consulted on a committee board, 15.2% received grants/honoraria, and 10.0% were pharmaceutical employees. 73.3% of dedicated medical writers were funded by pharmaceutical groups. Additionally, 83.3% of trials were led by the pharmaceutical industry while 16.7% mainly funded by cooperative groups. 70.0% of clinical trials employed pharmaceutical group funding for study design, and 66.7% of trials had data analyzed by pharmaceutical groups. Clinical trials were then divided into three time periods based on time of publication (2011-2015, 2016-2019, and 2020-2023). Over these periods, diverse patient enrollment increased. There were statistically significant decreases in the proportion of White (80.7% vs. 82.6% vs. 70.3%; p&lt;0.0001) and Black (2.8% vs. 2.5% vs. 2.1%; p&lt;0.0001) patients while increases were found among Asians (6.4% vs. 10.3% vs. 20.5%; p&lt;0.0001) and Hispanics (2.3% vs. 0.7% vs. 12.3%; p&lt;0.0001). The proportion of authors receiving grants/honoraria support increased from 8.0% to 14.2% to 18.2% (p&lt;0.0001). Authors serving as industrial employees rose from 6.3% to 7.1% to 13.1% (p=0.02). Conversely, the proportion of authors acting as pharmaceutical advisory board members or consultants changed from 31.3% to 30.1% to 16.5% (p&lt;0.0001). However, authors without pharmaceutical affiliation remained stable at 49.1% to 53.6% to 48.9% (p=0.004). Conclusions: The number of trials over the last 12 years sponsored by industry increased, as well as pharmaceutical employee participation and grant support. Additionally, Asian and Hispanic participant enrollment significantly increased. Balancing the benefits of pharmaceutical partnership with study oversight and disclosure is important in protecting the interests of our patients.
Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): A final overall survival analysis of a multicenter, open-label, randomized, phase 3 trial.
Authors: Rongyu Zang, Jianqing Zhu, Jihong Liu, Rong Jiang, Xi Cheng, Yulian Chen, Huixun Jia, Tingyan Shi, Yi Guo, Yanling Feng, Dongsheng Tu, Yuqin Zhang, Xiao Huang, Shiyang Jiang, Wen Gao, Huijuan Yang, Ping Zhang
Journal: Journal of Clinical Oncology (2024)

5520 Background: Surgery for platinum-sensitive relapsed ovarian cancer is widely practiced but has contradictory outcomes of survival in previously published studies. Methods: This multicenter, open-label, randomized, phase 3 trial was performed in four primarily academic centers in China. Eligible patients were aged ≥18 years old with platinum-sensitive relapsed ovarian cancer and were predicted to have resectable disease according to the international model (iMODEL) combined with PET-CT, which was reported previously. Overall survival (OS) and progression-free survival were the co-primary end points in hierarchical testing and planned for the final analysis of OS with a two-sided alpha of 0.05, when 209 deaths happened. Results: Between July 19, 2012 and June 3, 2019, 357 patients were enrolled. Patients were randomly assigned to receive surgery (182 pts.) or control (175 pts.). Median follow-up was 82.5 m. The median OS was 58.1 m in the surgery group and 52.1 m in the control group (hazard ratio [HR] for death, 0.80; 95% confidence interval [CI], 0.61 to 1.05; P=0.109). Overall, 61/175 (35%) patients in the control group crossed to surgery in subsequent therapies. A sensitive analysis showed that adjusted HR for death for crossover to surgery was 0.76 (95% CI, 0.58 to 0.99) (Table). When excluding the center with the highest crossover rate, secondary cytoreduction provided a 21.0-m benefit of overall survival over a control therapy. The highest crossover surgery rate was 49% in patients with 4-19 sites of relapse. The hazard ratio for death in patients with 1-19 sites was 0.69 (95% CI, 0.46 to 1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73 m. Median time to second subsequent therapy was 34.8 m vs 28.1 m (HR 0.68; 0.55-0.87). 24 of 182 (13.2%) patients remained relapse free and alive over 60 m in the surgery group, as compared with 5 of 175 (0.6%) patients in the control group. Conclusions: Secondary cytoreduction did not increase overall survival in the intention-to-treat population but led to a longer duration of overall survival when the crossover effect was taken into consideration. These findings are arguably clinically meaningful and support the efficacy of secondary cytoreduction in specialized centers and selected patients. ClinicalTrial.gov: NCT01611766. Res Sponsor: Shanghai Gynecologic Oncology Group. Clinical trial information: NCT01611766 . [Table: see text]
Overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance monotherapy: Update from the L-MOCA trial.
Authors: Qing-lei Gao, Jianqing Zhu, Weidong Zhao, Yi Huang, Ruifang An, Hong Zheng, Pengpeng Qu, Li Wang, Qi Zhou, Danbo Wang, Ge Lou, Jing Wang, John Low, Beihua Kong, Rutie Yin, Weiguo Lv, Jihong Liu, Wei Sun, Rongyu Zang, Ding Ma
Journal: Journal of Clinical Oncology (2024)

5559 Background: The open-label, single-arm, L-MOCA trial (NCT03534453) was the first study to demonstrate promising efficacy and tolerability of olaparib maintenance monotherapy in Asian patients with PSROC (median progression-free survival 16.1 months). Here we report the interim OS analysis. Methods: The study enrolled Asian patients with high-grade epithelial PSROC who had received ≥2 prior lines (L) of platinum-based chemotherapy and achieved complete or partial response. Patients were treated with oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. A prespecified descriptive analysis of OS, a secondary endpoint, was conducted after approximately 3 years of follow-up. OS was analyzed in the full analysis set (FAS; defined as patients who received olaparib) and in subgroups defined by biomarker status ( BRCAmutation /homologous recombination deficiency (HRD) status) and prior L of anticancer therapy. Results: By the date of data cutoff (16 Nov 2023), the median duration of follow-up was 40.0 months (range 0.5–64.2); 105 (46.9%) deaths occurred. In the FAS (N=224), the median OS was 54.4 months (95% CI 43.8–not evaluable [NE]). Median OS was not reached (NR; 51.9–NE) in the BRCA mutant ( BRCA m ) subgroup and 44.3 months (34.8–59.1) in the BRCA wild-type ( BRCA wt ) subgroup. In patients who had tumors with HRD, median OS was 59.1 (43.5–NE); among them, patients with HRD BRCA wt showed a median OS of 54.6 months (33.0–NE); in the homologous recombination proficiency (HRP) subgroup, median OS was 37.2 months (28.3–56.1). Adverse events of any grade occurred in 222 (99.1%) patients. The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low (3 [1.3%]). No new safety signals were identified. Conclusions: Olaparib showed promising OS benefit in Asian patients with PSROC, regardless of the BRCA mutation or HRD status, with a well-tolerated safety profile. Clinical trial information: NCT03534453 . [Table: see text]
Association of physical activity with self-reported quality of life after primary chemotherapy for ovarian cancer.
Authors: Larissa Alejandra Meyer, Amy K. Schneider, Haleh Aghajani, Maria del Sol Basabe, Leidy Huie Martinez, Gladys M Estrada, Maria Iniesta-Donate, Yue Liao, Charlotte C. Sun
Journal: Journal of Clinical Oncology (2024)

5574 Background: Patients (pts) with advanced stage ovarian cancer may proceed to maintenance therapy or routine surveillance following primary treatment. As part of a larger research study to assess real world experiences of pts, we explored whether physical activity was associated with self-reported quality of life (QOL). Methods: Pts were asked to wear a wrist health tracker and complete the FACT-Ovarian (FACT-O) survey at baseline and every 3 months for up to 24 months. Total FACT-O score, including well-being subscales for physical (PWB), social (SWB), emotional (EWB), functional (FWB), and ovarian cancer-specific QOL were calculated. Health tracker data corresponding to each FACT-O 7-day recall period were analyzed. Multilevel linear regression analysis examined the relationship between FACT-O and 7-day health tracker data. The potential moderating effect by age (&lt;60 vs. ≥ 60 yrs) was examined. Results: Data were analyzed for 77 pts with 250 total observations. Median age was 59 yrs (range 31, 82); 69% were White (6/53 pts self-identified as Hispanic), 4% Black, 9% Asian, 17% Other (13/14 pts self-identified as Hispanic). Of the 77 pts, 73% were married/partnered; median BMI 25.5; the majority had some college education. Pts completed a mean of 3 FACT-O surveys beyond baseline. Younger pts had better PWB (p&lt;.01) and FWB (p&lt;.01) than older pts, while older pts had better SWB (p&lt;.01). Compared to older pts, younger pts had more daily activity minutes (19.9 vs 10.2, p&lt;.01) and higher step counts (7035 vs 4689.8, p&lt;.01). Apart from SWB and FWB with activity minutes, activity minutes and step counts were positively associated with FACT-O overall and subscale scores (Table). Older pts had stronger positive associations between physical activity minutes and PWB (p&lt;.001), step counts and PWB (p&lt;.001); step counts and FWB (p=.004), while younger pts had stronger positive associations between step counts and ovarian cancer-specific QOL (p=.03). Positive associations between physical activity minutes and SWB (p&lt;.001) and EWB (p=.03), and ovarian cancer-specific QOL with activity minutes (p&lt;.001) were observed only in younger patients. Conclusions: We observed positive associations between health tracker physical activity data and pt-reported QOL. Stronger associations were observed in younger pts. Interventions aimed at increasing physical activity may have broader quality of life benefits for individuals with ovarian cancer. [Table: see text]
Oral cyclophosphamide plus bevacizumab in recurrent ovarian, fallopian tube and primary peritoneal cancer.
Authors: Mostafa Eyada, Victoria Michael, Bryan M. Fellman, Shrina Patel, Pamela T. Soliman, Jeffrey Andrew How, Amir A. Jazaeri, Nicole D. Fleming, Anil K Sood, Shannon Neville Westin, Travis T. Sims
Journal: Journal of Clinical Oncology (2024)

5517 Background: The combination of bevacizumab, cyclophosphamide and pembrolizumab is NCCN compendium listed based on a phase 2 trial that lacked a comparison arm. The objective of this study was to assess safety and efficacy of bevacizumab plus oral cyclophosphamide in patients with recurrent high-grade ovarian, fallopian tube and primary peritoneal cancer. Methods: This retrospective analysis included patients with recurrent platinum sensitive or resistant high-grade ovarian cancer treated with oral cyclophosphamide plus bevacizumab at a single institution. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks in combination with oral cyclophosphamide 50 mg daily. Patients with platinum free interval of 6 months or longer were considered to have a platinum sensitive disease. Objective response rate to chemotherapy (ORR = complete response (CR) + partial response (PR)) was calculated with 95% confidence interval (95% CI). Progression free survival (PFS) was calculated from initiation of chemotherapy to earliest date of progression or death and estimated using the methods of Kaplan and Meier. Adverse events were collected and graded using CTCAE v. 5.0. Results: One hundred patients were identified; 14 (14%) were platinum sensitive and 86 (86%) were platinum resistant. Median age was 58 (38-80). The majority of patients had high-grade serous histology (95%) and stage III or IV at diagnosis (95%). The median number of previous treatments was 3 (range 1-9). Thirty-three patients (33%) received bevacizumab in a prior regimen. A median of 5 (range 2-34) cycles of bevacizumab with daily oral cyclophosphamide were administered. ORR was 40.4% (95% CI: 30.7-50.7) with 4% CR, 36% PR, 20% SD, 39% PD. ORR among patients who received bevacizumab in a prior regimen was 12 (36%) compared to ORR of 24 (42%) among patient who never received bevacizumab in a prior regimen (P = 0.59). The median PFS was 4.6 months (95% CI: 3.42-5.9). There was no relationship between platinum status or platinum free interval and response to this regimen, although the population was predominantly platinum resistant. Seventy-six (76%) of patients had documented adverse events. Most common grade 3-4 toxicities included hypertension (3%), thrombocytopenia (3%), and hemorrhagic cystitis (1%). Conclusions: Bevacizumab in combination with oral cyclophosphamide was well tolerated and active, with a response rate of 40% in patients with recurrent platinum resistant high-grade ovarian cancer.
Combination of cemiplimab and ISA101b vaccine for the treatment of recurrent/metastatic HPV16 cervical cancer.
Authors: Domenica Lorusso, Ana Oaknin, Giuliano Santos Borges, Fernanda Damian, P. B. Ottevanger, Toon Van Gorp, Carlos Eduardo Paiva, Judith R. Kroep, Yong Man Kim, Hee Seung Kim, Jae-Kwan Lee, Cornelis JM Melief, Leon Hooftman, Shaheda Jamil Jamil, Suk-Young Yoo, Frank A. Seebach, Israel Lowy, Matthew G. Fury, Melissa Divya Mathias, Nicoletta Colombo
Journal: Journal of Clinical Oncology (2024)

5522 Background: Cemiplimab + ISA101b vaccine is being studied in HPV16-positive cancers in several phase 2 clinical trials. Here, we present the clinical efficacy and safety results of a phase 2 study of cemiplimab + ISA101b vaccine in patients with recurrent HPV16 cervical cancer who had disease progression after first-line chemotherapy (NCT04646005). Methods: Patients received cemiplimab 350 mg administered intravenously every 3 weeks + 3 doses of ISA101b vaccine 100 µg/peptide administered by subcutaneous injection on Days 1, 29, and 50. The primary endpoint was objective response rate (ORR) as measured by RECIST version 1.1. Secondary endpoints included duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety. Efficacy and safety endpoints were assessed in the full analysis set (patients who received ≥1 dose). Baseline PD-L1 expression was assessed by immunohistochemistry using anti–PD-L1 clone SP263. Results: This single arm study included 113 patients (Table). Median duration of follow-up was 4.9 months (interquartile range [IQR]: 3.0–7.5); median duration of treatment exposure was 10.0 weeks (IQR: 9.7–10.3) for ISA101b and 18.2 weeks (IQR: 9.0–27.6) for cemiplimab. At data cutoff (May 22, 2023), 90 patients discontinued treatment for reasons including disease progression (66.4%), death (7.1%), and an adverse event (AE; 3.5%) and 20.4% of patients were still on treatment. ORR (95% CI) was 16.8% (9.9–23.7). ORR by PD-L1 expression in tumor cells was 12.5% for patients with PD-L1 &lt;1% and 22.4% for patients with PD-L1 ≥1%, per investigator assessment. Median (95% CI) DOR was 5.6 (3.5–not estimable) months. Median (95% CI) OS and PFS were 13.3 (10.8–16.3) months and 3.0 (1.7–4.0) months, respectively. At 6 and 12 months, the estimated survival probabilities (95% CI) were 80.5% (71.7–86.9) and 54.5% (42.1–65.3), respectively, for OS, and 20.5% (13.4–28.6) and 7.8% (3.3–15.0), respectively, for PFS. Treatment-emergent AEs occurred in 92.9% of patients, with the most common being injection-site reaction (38.9%), anemia (25.7%) and nausea (22.1%). Six (5.3%) patients died due to a treatment-emergent AE. Conclusions: Results from this phase 2 study of cemiplimab + ISA101b in patients with recurrent HPV16 cervical cancer show clinical benefit, especially in patients with high PD-L1 expression, and no unexpected safety signals, supporting further research. Clinical trial information: NCT04646005 . [Table: see text]
Post hoc analysis of progression-free survival (PFS) and overall survival (OS) by mechanism of mismatch repair (MMR) protein loss in patients with endometrial cancer (EC) treated with dostarlimab plus chemotherapy in the RUBY trial.
Authors: Mansoor Raza Mirza, Sudarshan Sharma, Henrik Roed, Lisa M. Landrum, Lucy Gilbert, Michael A. Gold, Zoltán Novák, Mitchell Edelson, Mihai Meirovitz, John Paul Diaz, Greet Huygh, Joseph Buscema, Bhavana Pothuri, Helen Dinkelspiel Eshed, Robert L. Coleman, Brian M. Slomovitz, Rumen Kostadinov, Shadi Stevens, Graziana Ronzino, Matthew A. Powell
Journal: Journal of Clinical Oncology (2024)

5606 Background: MMR deficiency (dMMR) is caused by aberrant expression of MMR proteins that mediate DNA repair. The loss can be explained by epigenetic regulation (epi-dMMR; MLH1 promoter hypermethylation preventing MLH-1 expression) or mutation (mut-dMMR; MMR proteins lost through deleterious mutations) accounting for 70%–75% and 25%–30% of dMMR/microsatellite instability–high (MSI-H) EC, respectively. The GARNET trial showed that mechanism of MMR loss did not influence response of EC to monotherapy with dostarlimab (DOST), an anti-PD-1. No data exist examining OS by mechanism of MMR loss in patients (pts) with EC receiving immunotherapy. Here, we report analyses of PFS and OS in pts with primary advanced or recurrent EC (pA/rEC) in Part 1 of the RUBY trial (NCT03981796) by mechanism of MMR protein loss. Methods: Pts with pA/rEC were randomized 1:1 to receive DOST or placebo (PBO), plus carboplatin-paclitaxel (CP), followed by DOST or PBO monotherapy for up to 3 years. MMR protein status was assessed by immunohistochemistry. MMR loss of function gene mutations were determined by Personalis ImmunoID NeXT whole-exome sequencing assay. MMR protein loss without mutations in MMR genes was a surrogate indicator for epi-dMMR. Post hoc PFS and OS analyses utilized data from the data cut at which each endpoint was met (PFS at Sep 28, 2022; OS at Sep 22, 2023). Results: Part 1 of the RUBY trial included 118 pts with dMMR/MSI-H pA/rEC (DOST+CP = 53; PBO+CP = 65); 39 pts (73.6%) in the DOST+CP arm and 52 pts (80.0%) in the PBO+CP arm had MMR gene mutation data available. Substantial PFS and OS benefits were observed with DOST+CP vs PBO+CP in pts with mut-dMMR or epi-dMMR (Table). No significant differences were seen in PFS or OS in pts with mut-dMMR vs pts with epi-dMMR. Conclusions: DOST+CP led to substantial PFS and OS benefits compared with PBO+CP indMMR/MSI-H pA/rEC, regardless of mechanism of MMR protein loss. A limited number of pts with mut-dMMR treated with DOST+CP were available for analysis; however, the results support that mechanism of MMR loss does not appear to be a significant predictor of clinical benefit for dostarlimab treatment in pts with dMMR pA/rEC in Part 1 of the RUBY trial. Clinical trial information: NCT03981796 . [Table: see text]