Search

Purpose: To evaluate safety, tolerability, and anti-tumor response of lete-cel, genetically modified autologous T-cells expressing a T-cell receptor specific for NY-ESO-1/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in human leukocyte antigen HLA-A*02-positive (HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-) patients with New York esophageal squamous cell carcinoma 1 (NY-ESO-1)- and/or LAGE-1a-positive non-small cell lung cancer (NSCLC)., Experimental Design: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multi-arm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent NSCLC., Results: Over 2500 patients were screened for target expression. In the multi-arm study, 738 (45%) of 1638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AEs) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not appear to increase toxicity over lete-cel alone. Limited anti-tumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients., Conclusions: Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Anti-tumor activity was observed in a limited number of patients.

Background: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported., Patients and Methods: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024)., Results: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed., Conclusions: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy., Methods: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS)., Results: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event., Conclusion: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222., Competing Interests: Conflicts of interest KK is listed as a coinventor on a patent entitled ‘Immunity to folate receptors’, which is owned by the Mayo Clinic and was previously licensed to Marker Therapeutics. KK reports receiving commercial research support from Marker Therapeutics. REO reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, Marker Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health. RMW reports grants or funding from Anixa Biosciences, Merck, OnTarget; consulting, DSMB, or advisory fees from Eisai, Sonnet Biotherapeutics, Genentech, Abbvie, Shattuck Labs, Merck, GSK/Tesaro, Legend Biotech, Novocure, Clovis, AstraZeneca, Regeneron, Mersana, Seagen; travel support from Eisai, Tapimmune/Marker Therapeutics; speakers bureau fees from GSK, CurioScience, Onclive; stock from Ovation Diagnostics. MSB is listed as a coinventor on pending patents entitled, “Combinations of Dendritic Cell-Based Vaccines” and “Checkpoint Inhibitors and Dendritic Cell-Based Vaccines and Uses Thereof;” reports institutional research support from Alkermes, Bristol-Myers Squibb, Genentech, Marker Therapeutics, Merck, nFerence, Pharmacyclics, Regeneron, Sorrento, TILT Biotherapeutics, Transgene, and Viewpoint Molecular Therapeutics; and is has served as a consultant/SAB member for Marker Therapeutics, Sorrento Therapeutics, TILT Biotherapeutics, and Viewpoint Molecular Targeting., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The treatment landscape of gynecologic cancers has expanded in recent years to include targeted and immune-based therapies. These therapies often have ocular side effects not seen with conventional chemotherapies, some of which can cause significant visual impairment if not recognized in a timely fashion. Clinicians must know how to appropriately identify, mitigate, and treat these ocular adverse events. Management often involves working with an interdisciplinary team of eye specialists, and it is important to know when to refer patients for specialized care. Proactive identification of eye specialists, especially in rural and community settings where access to care can be limited, may be necessary. Here, we discuss the management of common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers., Competing Interests: Conflicts of interest REO reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health. The other authors do not have potential conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result., Methods: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record., Results: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result., Conclusions: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results., (© 2024 American Cancer Society.)

Objective: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy., Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD)., Results: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups., Conclusion: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age., Competing Interests: Declaration of competing interest Dr. Valabrega reports consulting fees from GSK; honoraria from AstraZeneca, Eisai, GSK, and MSD; travel support from AstraZeneca and PharmaMar; and participation in advisory boards for AstraZeneca, Eisai, GSK, and MSD. Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, GSK, I-Mab, Immunogen, Incyte, Karyopharm, Merck, Mersana, Onconova, SeaGen, Sutro, and Toray; consulting fees from AstraZeneca, GOG Foundation, GSK, Merck, and Seagen; support for attending meetings from GOG Partners; and advisory board fees from Arquer Diagnostics, Atossa, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab, Immunogen, Lily, Merck, Mersana, Natera, Onconova, Regeneron, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutics. Dr. Oaknin reports institutional grants from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics AB, BMS, Clovis Oncology, Eisai, F. Hoffmann–La Roche, Immunogen, MSD de España SA, Millennium Pharmaceuticals, PharmaMar SA, Regeneron Pharmaceuticals, and Tesaro; consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, F. Hoffmann–La Roche, Genmab, GSK, ImmunoGen, Iteos, MSD de España SA, Mersana Therapeutics, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Shattuck Labs, Seagen, and Sutro Biopharma; honoraria from Asociación Colombiada de Ginecológos Oncólogos, AstraZeneca, ESO, GSK, Medscape, NSGO, Peerview, and Peervoice; individual travel support from AstraZeneca, PharmaMar, and Roche; and advisory board participation for Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, F. Hoffmann–La Roche, Genmab, GSK, ImmunoGen, Iteos, MSD de España SA, Mersana Therapeutics, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Seagen, Shattuck Labs, and Sutro Biopharma. Dr. Graybill reports consulting and speaker fees from GSK. Dr. Sánchez reports consulting fees from AstraZeneca, GSK, and MSD; honoraria from AstraZeneca, GSK, and MSD; and travel support from AstraZeneca, GSK, and MSD. Dr. McCormick reports personal fees for advisory boards for Clovis, GSK, ImmunoGen, and Merck. Dr. Baurain reports consulting fees from AstraZeneca, BMS, GSK, Immunocore, Merck, MSD, Novartis, Pfizer, Pierre-Fabre, Regeneron, Sanofi, and Sun Pharma. Dr. Tinker reports honoraria from AstraZeneca, Eisai, GSK, and Merck and travel support from GSK. Dr. Denys reports an institutional research grant from Gilead; consulting fees from Gilead and GSK; honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Leo Pharma, MSD, and Roche; travel support from AstraZeneca, Gilead, GSK, MSD, Pfizer, PharmaMar, Roche, and Teva; and participation on advisory boards for AstraZeneca, Eli Lilly, Gilead, GSK, Menarini, MSD, and Pfizer. Dr. O'Cearbhaill reports institutional research support from NIH/NCI Cancer Center Support Grant (P30 CA008748) and support grants from AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Fresenius Kabi, Immunogen, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health; and service as a noncompensated steering committee member for the DUO-O (olaparib) and PRIMA and Moonstone (niraparib) studies. Dr. Hietanen reports consulting fees from AstraZeneca, Eisai, GSK, and MSD and honoraria from AstraZeneca and GSK. Dr. Moore reports institutional grants from Angle Plc and Fujirebio Diagnostics and personal fees from Fujirebio Diagnostics. Dr. Knudsen has nothing to disclose. Dr. de La Motte Rouge reports receiving consulting fees from AstraZeneca, Clovis Oncology, Eisai, Gilead, GSK, MSD, Novartis, Pfizer, and Sanofi; receiving honoraria from AstraZeneca, GSK, MSD, NetCancer, and Pfizer; and travel support from Gilead, MSD, and Pfizer. Dr. Heitz reports honoraria from AstraZeneca, GSK, Roche, and Tesaro and consulting fees from AstraZeneca, GSK, Roche, and Tesaro. Dr. Levy has nothing to disclose. Dr. Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers' bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. Dr. González-Martín reports for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis. Ms. York is a current employee of GSK. Dr. Gupta is a former employee of GSK and Mersana Therapeutics and is currently an employee of Cullinan Oncology., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare oncologic outcomes of secondary cytoreductive surgery (SCS) before and after FDA approval of Poly(ADP-ribose) polymerase inhibitor (PARPi) and bevacizumab maintenance therapies for platinum-sensitive recurrent ovarian cancer (PS-ROC)., Methods: Patients who underwent SCS for first recurrence of PS-ROC from 1/1/2013-1/1/2020 were identified. Exclusion criteria included prior chemotherapy for recurrence, bowel obstruction procedures, and palliative surgery. Data were dichotomized pre/post 1/2017, relative to FDA approval of PARPi and bevacizumab maintenance for ROC. Second progression-free survival (PFS2), the primary endpoint, was estimated using Kaplan-Meier method., Results: Overall, 245 patients underwent SCS-131 (53%) pre- and 114 (47%) post-approval. Most patients had high-grade serous tumors (83% and 90%, respectively; p = 0.13). Deleterious BRCA1/2 alterations were identified in 27% (32/120) and 28% (32/113) of tested patients, respectively (p = 0.88). Disease-free intervals pre- and post-approval were: 6-12 months, 16% and 18%; 12-30 months, 56% and 59%; and >30 months, 28% and 24%, respectively (p = 0.73). Overall, 85% and 86% of patients, respectively, achieved complete gross resection (CGR; p > 0.99). PARPi maintenance use increased from 3.8% to 27% (p < 0.001) following approval, and bevacizumab from 1.5% to 12% (p < 0.001). Median PFS2 was 19 and 20.1 months, respectively. In the post group, 1-year PFS2 rate was 84.5% (95% CI, 75.7-90.4%) for patients with CGR vs 56.2% (95% CI, 29.5-76.2%) for those with residual disease; 3-year PFS2 rates were 31.3% (95% CI, 21.6-41.4%) and 12.5% (95% CI, 2.1-32.8%), respectively (p = 0.001)., Conclusions: CGR during SCS is associated with improved PFS2 compared to suboptimal resection. Prospective randomized trials are warranted to elucidate the role of SCS as more therapeutics become available., Competing Interests: Declaration of competing interest D.S. Chi reports personal fees from AstraZeneca, UptoDate, Biom'Up, Apyx Medical Group, and Verthemia; he also has stock in Verthemia. R.N. Grisham reports honoraria from GlaxoSmithKline (GSK), AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. R.E. O'Cearbhaill reports research funding paid to the institution from Bayer/Celgene/Juno, Arsenalbio, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Alkermes, Kite Pharma, Acrivon and Gynecologic Oncology Foundation, Lyell Immunopharma. She also reports honoraria for lectures from GSK, Curio/Onclive/PER/MJH/Aptitude Health, SITC, Gynecologic Oncology Canada, and the Society of Gynecologic Oncology. She also reports travel/meeting support from Hitech Health, Gathering Around Cancer, Ireland, and the GOG Foundation. She also reports unpaid Steering Committee participation for AstraZeneca, GSK, and Acrivon, as well as unpaid advisory roles for Carina Biotech and Link Therapeutics. She has served on the Advisory Boards of SeaGen, Tesaro/GSK, Regeneron, Immunogenicity, R-Pharm, Fresenius Kabi, Miltenyi, 2seventybio, and Bayer., (Copyright © 2024. Published by Elsevier Inc.)

Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8 + PD-1 + ) or terminally dysfunctional (CD8 + PD-1 + TOX + ) T cells and their interaction with programmed death ligand-1 (PD-L1) + cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 ., (© 2024. The Author(s).)

Objective: Romiplostim is used to treat chemotherapy-induced thrombocytopenia in a variety of tumor types; however, few studies have examined its use in breast and gynecologic cancers. We evaluated platelet response and durability of response to romiplostim in patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia., Methods: We retrospectively identified 33 patients with gynecologic or breast cancer who received romiplostim between 07/1/2021-07/31/2022 at an academic cancer center., Results: Thirty-three patients met inclusion criteria; 26 (79 %) had breast cancer, 4 (12 %) had ovarian cancer, and 3 (9 %) had endometrial cancer. Twenty patients (61 %) experienced treatment delays and 12 (36 %) required dose reductions prior to starting romiplostim for chemotherapy-induced thrombocytopenia, with some patients experiencing both. Eleven patients (33 %) did not undergo a dose reduction or delay prior to initiation of romiplostim. Median platelet count prior to romiplostim therapy was 53 k/mcL (range, 40.5-78.8). Median platelet count within 3 weeks following initiation of romiplostim was 147 k/mcL (range, 31-562). Twenty-one patients (64 %) achieved platelet correction within 3 weeks, of whom 10 (48 %) resumed anticancer therapy and maintained platelet levels above 100 k/mcL at 8 weeks. Twelve patients did not achieve platelet correction within 3 weeks of romiplostim initiation; 4 (33 %) required a treatment change secondary to persistent thrombocytopenia, 3 (25 %) required a treatment dose reduction, 3 (25 %) were deemed too ill to continue therapy, and 2 (17 %) required a treatment delay., Conclusions: Romiplostim facilitated the resumption of anticancer therapy in 64 % of patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SM is owner of Daboia Consulting LLC and reports consulting fees from Janssen Pharmaceuticals. JZ is on the data safety monitoring boards of Sanofi and CSL Behring; reports consulting fees from Calyx; participated in advisory boards with Pfizer and Bristol Myers Squibb (BMS); and receives royalties from UptoDate; CW reports consulting fees from Allmed. RO reports meeting/travel support from the Gynecologic Oncology Foundation, Curio, and Hitech Health; participation in the advisory boards of Tesaro/GlaxoSmithKline (GSK), Regeneron, Seattle Genetics, Fresenius Kabi, Bayer, and CarinaBiotech (non-compensated); non-compensated steering committee participation for Tesaro/GSK and AstraZeneca; and grant support paid to the institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, the Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, KitePharma, and the Gynecologic Oncology Foundation., (© 2024 The Authors.)

Objective: To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade., Methods: Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively., Results: During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1-9.9), and median overall survival was 21.7 months (95% CI, 14.9-not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival., Conclusions: Procedural interventions for patients with oligoprogression on immune checkpoint blockade therapy are feasible and demonstrate favorable outcomes. With expanding use of immune checkpoint therapy, it is important to investigate combined modalities to maximize therapeutic benefit for patients with gynecologic cancers., Competing Interests: Competing interests: Outside the submitted work, AI reports consulting fees from Mylan. CFF reports institutional research support from Seagen, Merck, BMS, AstraZeneca, Mersana, and Hotspot Therapeutics; consulting fees from BMS, Seagen, and Aadi Biosciences; honoraria for lectures from Onclive; meeting/travel support by Puma; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). DZ reports institutional research support from AstraZeneca, Merck, Plexxikon Synthekine, and Genentech; consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa Biotech, Kalivir, Xencor, and GSK; royalties from Merck; and stock options from Accurius Therapeutics, ImmunOS Therapeutics, and Calidi Biotherapeutics. VM reports meeting/travel support by Eisai and Merck; participation on Data Safety Monitoring or Advisory Board of Duality, Merck, Karyopharm, Exelexis, Eisai, Karyopharm, BMS, Clovis, Faeth Immunocore, Morphosys, AstraZeneca, Novartis, GSK, and Bayer (all unpaid); and study support to the institution by Merck, Eisai, AztraZeneca, Faeth, Karyopharm, Zymeworks, Duality, Clovis, Bayer, and Takeda. YLL reports institutional research funding from Repare Therapeutics, AstraZeneca, and GSK; honoraria from Total Health and Sarah Lawrence College; and travel/meeting support by AstraZeneca. DSC reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. EJ reports personal fees from Covidien/Medtronic. RO reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio, and Immunogen; and other from Hitech Health, all outside the submitted work; non-compensated steering committee membership for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies; a non-compensated advisor role for Carina Biotech; and funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. CK reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. All other authors have no potential conflicts of interest to disclose., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC., Methods: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset., Results: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01)., Conclusions: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype., Competing Interests: Declaration of Competing Interest YLL reports research funding from AstraZeneca, GSK and Repare Therapeutics outside of this work. KEB reports that an immediate family member is on the Scientific Advisory Board of Emendo Biotherapeutics, Karyopharm Therapeutics, Imago BioSciences, and DarwinHealth; is co-Founder of Isabl Technologies; and has equity interest in Imago BioSciences, Emendo Biotherapeutics and Isabl Technologies. BW reports research funding by Repare Theraputics. CA has received research grants from Abbvie, Clovis, Genentech, and Astra Zeneca and served on advisory boards for Abbvie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech. ZS reports an immediate family member who serves as a consultant in Ophthalmology for Adverum, Genentech, Gyroscope Therapeutics Limited, Neurogene, Optos Plc, Outlook Therapeutics, RegenexBio, and Regeneron. RO reports meeting/travel support from the Gynecologic Oncology Foundation, Curio, and Hitech Health; participation in the advisory boards of Tesaro/GlaxoSmithKline (GSK), Regeneron, Seattle Genetics, Fresenius Kabi, Bayer, and CarinaBiotech (non-compensated); non-compensated steering committee participation for Tesaro/GSK and AstraZeneca; and grant support paid to the institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, the Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, KitePharma, and the Gynecologic Oncology Foundation. AI reports consulting fees from Mylan. RG reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. DC reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. KO is a founder and shareholder of AnaNeo Therapeutics Incorporated. MFB reports receiving research funding from GRAIL and advisory board activities for Eli Lilly, AstraZeneca, and PetDx. All other authors have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody-drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer.

Purpose: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC)., Methods: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR)., Results: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E)., Conclusion: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Cervical cancer is the most commonly diagnosed gynecologic cancer worldwide. Although the incidence has declined with increased screening and higher uptake of human papillomavirus (HPV) vaccination in high-income countries, this disease remains the second highest cause of cancer mortality among women in low- and middle-income countries. In this clinical practice statement, we describe therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with this disease. In addition to chemotherapy and radiation, therapeutic strategies for cervical cancer include immune checkpoint blockade, antiangiogenics, and antibody-drug conjugates. Optimal treatment for recurrent cervical cancer remains an area of unmet need, necessitating further exploration of rational and innovative treatment approaches, including cell and immune-based therapies. Importantly, development of effective therapies for cervical cancer must incorporate strategies to ensure universal equitable access to HPV vaccination, screening, and treatment. Important consequences of the disease and treatment that impact quality of life must also be addressed. Patients with cervical cancer are at increased risk for financial toxicity, which can lead to downstream detrimental effects on physical, financial, and career outcomes. Underrepresentation of racial and ethnic minorities in gynecologic oncology clinical trials highlights the urgent need for collaborative and focused initiatives to bridge the significant divide and alleviate inequalities in the prevention and treatment of cervical cancer., Competing Interests: Declaration of Competing Interest Dr. Girda reports personal fees from Merck. Dr. Randall reports personal fees from Seagen for an educational webinar at drug launch and speaker's bureau and personal fees from Merck for an unbranded educational video for cervical cancer. Her institute receives research funding for clinical research from Seagen and Merck. She reports personal fees from BluPrint Oncology, PER, CurioScience, Projects in Knowledge, AstraZeneca, Tesaro, Merck, Mersana, Agenus, Rubius Therapeutics, Myriad Genetics, EMD Serono, Genentech/Roche, Seattle Genetics, Novartis, and Eisai, all outside the submitted work. Dr. Chino reports grants from NIH/NCI, during the conduct of the study. Dr. Monk reports personal fees from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis, Easai, Elevar Therapeutics, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, Merck, Mersana, Novocure, Myriad, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, all outside the submitted work. Dr. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech. She reports grants from NIH/NCI. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. Dr. Farley has nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer., Experimental Design: Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records., Results: A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB >10 mut/Mb), 3 of which were also microsatellite instability-high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at >5 years follow-up., Conclusions: Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objective: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment., Methods: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment)., Results: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores., Conclusions: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC., Competing Interests: Declaration of Competing Interest LMR reports personal fees from GSK/TESARO for consultancy unrelated to this study; research grant (to institution): Seagen, Genmab, Merck, Akeso, Mersana, Incyte, GOG Foundation, Genentech; consulting fees: Agenus, Akeso, AstraZeneca, Clovis Oncology, Eisai, Elevar, EMD Serono/Merck, Genmab, Seagen, GOG Foundation, Hengrui, ImmunoGen, Iovance, Merck, Mersana, Myriad, Novocure, Pfizer, Regeneron, Roche/Genentech, GSK/Tesaro, Zentalis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Eisai, Myriad, Roche/Genentech, GSK/Tesaro. DMO reports grant funding (to the institution) from AbbVie; personal fees for an advisory board from AbbVie; support for manuscript preparation from GSK/TESARO. BJM reports consulting/advisory role and honoraria for AbbVie, ChemoCare, ChemoID, Eisai, Geistlich Pharma, Incyte, Mateon Therapeutics, Merck, Myriad Pharmaceuticals, Perthera, Precision Oncology, Samumed, Takeda, and VBL Therapeutics; consulting/advisory role, honoraria, and research funding (to the institution) from Advaxis, Amgen, Immunogen, NuCana BioMed and Pfizer; consulting/advisory role, speakers bureau, honoraria, and research funding (to the institution) from AstraZeneca, Roche/Genentech and TESARO; consulting/advisory role, speakers bureau and honoraria from Clovis Oncology; speakers bureau, honoraria and research funding (to the institution) from Janssen; consulting/advisory role for Cerulean Pharma, OncoMed, and OncoSec; a leadership role for US Oncology; honoraria from Agenus, Conjupro Biotherapeutics, Genmab, Immunomedics, OncoQuest, and PumaBiotechnology; research funding (to the institution) from Array BioPharma, Lilly, Morphotek, Novartis, and Regeneron. RLC reports consulting, grant and honoraria/reimbursement from AstraZeneca, Clovis Oncology, Janssen, Merck, and Roche/Genentech; consulting and honoraria/reimbursement from Arrivive, Eisai, Novocure, Oncomed/Mateo, and TESARO/GSK; consulting and grant from AbbVie, grant from Genmab. SG reports a consulting/advisory role for AstraZeneca, Immunogen, Rigel, and Sermonix Pharmaceuticals; research funding (to the institution) from AbbVie, AstraZeneca, Genentech/Roche, Iovance Biotherapeutics, Pfizer, PharmaMar, and GSK/TESARO; hold patents, royalties or other intellectual property with Sermonix Pharmaceuticals. SA reports research funding from AstraZeneca. LRD reports consulting/advisory role for Genentech/Roche, Merck, Inovio Pharmaceuticals, CUE Biopharma; institutional research funding from GSK, Millennium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, GSK/TESARO, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Merck, Genentech/Roche, Cerulean Pharma, Morab, Morphotek, Syndax, Ludwig Institute for Cancer Research, Leap Therapeutics. HD reports a consulting/advisory role for Eisai and Merck. RWH reports speaker's bureau from AstraZeneca, Clovis, and GSK. MH reports advisory board participation for Clovis Oncology, Janssen, Immunogen, Eisai, Seagen, and Tesaro; grant funding from Merck. HSC has nothing to disclose. NGC reports participation in advisory boards from AstraZeneca, GSK, Toray, Tarveda Therapeutics, Aadi. ACE is an employee and stockholder in Natera Inc. REO is funded in part by the NIH/NCI Cancer Center Support Grant P30 CA008748, reports personal fees for advisory boards from TESARO/GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, R-Pharm, Miltenyi, 2seventybio and Immunogen; reports personal fees from MJH Life Sciences, Onclive/PER and Curio; and reports non-compensated membership of steering committees for the PRIMA and DUO-O studies. SW reports a consulting/advisory role for Regeneron. AT, AS, LMN, AB and VS are employees of and hold stocks/shares in GSK. PAK reports personal fees from GSK/TESARO for consultancy unrelated to this study and personal fees for advisory board participation from AstraZeneca, Merck, and Pfizer., (Copyright © 2023. Published by Elsevier Inc.)

Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma., Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes., Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors., Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype., Competing Interests: Conflicts of interest Roisin O'Cearbhaill - reports personal fees from once off advisory boards from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Immunogen, R-Pharm, Miltenyi, 2seventybio and Bayer, outside the submitted work; received honoraria for lectures from Gynecologic Oncology Foundation, Curio, PER/MJH, SITC, Gynecologic Oncology Canada and support to attend meetings from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech, Acrivon, Link Therapeutics and Transgene. NRG representative for the ComboMATCH and iMATCH studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation, Acrivon and Lyell Immunopharma. Robert Soslow is a co-editor for the journal Modern Pathology. Dmitriy Zamarin has grants/contracts from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech. He has patient licensng fees through Merck. He has received consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa, Kalivir, Xencor and GSK. Patents planned, issued or pending include Merck for use of oncoltic NDV for cancer therapy. He also has stock options for Accurius, Immunos and Calidi Biotherapeutics. Kathleen Moore's institution receives research funding from PTC Therapeutics, Lilly, Clovis, Genentech, GSK and Verastem. Her Royalties/licenses are up to date. She received consulting fees from AstraZeneca, Aravive, Alkemeres, Aadi, Blueprint pharma, Clovis, Caris Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Iovance, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, OncXerna, Onconova, Tarveda, VBL Therapeutics and Verastem. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from PRIME, RTP, Medscape, Great Debates and Updates. She has received support for attending meetings and/or travel from AstraZeneca. She has a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid through GOG P Associate Director. Mark Shahin received grants or contracts from GSK, AstraZeneca and Merck. He also received consulting fees from GSK, AstraZeneca and Immunogen. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AstraZeneca, Merck, Eisai, Immunogen and SeaGen. He has a leadership or fiduciary role with UniteForHer. Premal Thaker's institution received grants/contracts from Merck and GSK. He has received consulting fees from Novartis for endometrial cancer, Merck, AstraZeneca, Clovis Oncology, GSK, Novocure, R-Pharm, Immunon, Zentalis and Aadi Bioscience. Andrea E. Wahner-Hendrickson has an NCI grant (P50 CA 136393) for Mayo Ovarian Cancer SORE (Co-project leader), TORL – Site PI Clinical Trial and Prolynx – IIT. She ha received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from George Washington University for Medical Oncology Board Review (CME) – ovary and uterine. She participates on a Data Safety Monitoring Board or Advisory Board at Mayo Clinic DSMB NCI CIRB (early emphasis). She has unpaid Leadership or fiduciary roles in other board, society, committee or advocacy group with Oxcia Advisory Board and MN ovarian cancer advisory board. Carol Aghajanian received clinical trial funding to institution (MSK): Abbvie – MSK PI, GOG 3005, AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator & MSK PI, DO81RC00001; ENGOT – ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3; Genentech/Roche – MSI PI, GOG 3015 (Imagyn050). She has received consulting fees from Abbvie – Advisory Board 5/8/20; Roche/Genentech – Advisory Board 8/21/20; Eisai/Merck – Advisory Board 9/12/20; AstraZeneca/Merck – Advisory Boards 9/30/20 & 10/14/20; and Repare Therapeutics – Advisory Board 10/15/20. She has participated on an Advisory Board – 6/30/21 (no consulting fee) for Blueprint Medicine. She also served as Leadership or fiduciary role in other board, society, committee or advocacy group for GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology Board of Directors (unpaid). Austin Miller, Heather Lankes, Deborah Delair, Sheila Segura, Shweta S. Chavan, Robert DeBernardo, and John Moroney have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To evaluate rates of germline pathogenic/likely pathogenic variants (PVs) and genetic counseling by ancestry in patients with epithelial ovarian cancer (EOC)., Methods: Patients with pathologically confirmed EOC who underwent clinical tumor-normal sequencing from January 1, 2015, to December 31, 2020, inclusive of germline analysis of ≥76 genes were included. Patients with newly identified PVs were referred for Clinical Genetics Service (CGS) counseling. Ancestry groups were defined using self-reported race/ethnicity and Ashkenazi Jewish (AJ) heritage. Genetic ancestry was inferred computationally using validated algorithms. Logistic regression models were built., Results: Of 1,266 patients, self-reported ancestry (AJ, 17%; Asian, 10%; Black/African American, 5.4%; Hispanic, 6.2%; non-Hispanic White, 57%; other, 0.16%; unknown, 4.0%) correlated with genetic ancestry (AJ ancestry, 18%; admixed, 10%; African, 4%; East Asian [EAS], 6%; European, 56%; Native American, 0.2%; South Asian [SAS], 4%; unknown, 2%). Germline PVs were observed in 313 (25%) patients, including 195 (15%) with PVs in EOC-associated genes. Those with PVs were younger at diagnosis (59 v 62 years; P < .001) and more likely to have high-grade serous ovarian cancer (83% v 72%; P = .009). PV prevalence varied between ancestry groups ( P < .001), with highest rates in the AJ (39.9%) and Asian (26.5%) groups and similar rates (>10%) across other ancestry groups. Use of genetic ancestry demonstrated similar findings and further characterized high rates of PV in EAS/SAS groups. Younger age, high-grade serous histology, and self-reported AJ or Asian ancestry were associated with PV in an EOC-associated gene. Rates of CGS counseling for newly identified PVs were high (80%) across ancestry groups., Conclusion: Rates of PV, particularly in EOC-associated genes, were high regardless of ancestry, with similar rates of counseling between groups, emphasizing the importance of universal genetic testing in all patients with EOC.

Purpose: To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016)., Methods: Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported., Results: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature., Conclusions: Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified., Competing Interests: Declaration of Competing Interest Dr. González-Martín reports support for the manuscript funding from GSK; grants or contracts from GSK and Roche; consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, and Sutro; honoraria fees from AstraZeneca, Clovis, GSK, PharmaMar, and Roche; and support for attending meetings from AstraZeneca, GSK, PharmaMar, and Roche. Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Genentech/Roche, Karyopharm, Merck, Mersana, GSK, Sutro, Toray, Incyte, Imab, Onconova, VBL Therapeutics, and Clovis Oncology; consulting fees from AstraZeneca, GSK, SeaGen, and Merck; advisory board fees from Eisai, Lily, Merck, Sutro Biopharma, Tesaro/GSK, Astra Zeneca, and GOG Foundation. Dr. Vergote reports institutional payments for corporate sponsorship research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Oncoinvent AS, Octimet Oncology, Sotio, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharmaceuticals, and Oncoinvent AS; honoraria payments from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Jazz Pharmaceuticals, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, MSD, Novartis, Novocure, Seagen (2021), and Sotio. Dr. Graybill reports advisory board and speaker fees from GSK. Dr. Lorusso reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck, and PharmaMar; and grants from Merck and PharmaMar. Dr. McCormick reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. Dr. Freyer reports personal fees from AstraZeneca, Biogaran, Bristol Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer Inc., Roche Holding AG, S.A.S., and Tesaro; grants from AstraZeneca, Mylan, and Roche Holding AG. Dr. Backes reports personal fees from Agenus, CEC Oncology, Clovis, Eisai, Merck, AstraZeneca and GSK. ImmunoGen, Myriad; grants from Clovis, Eisai, Immunogen, and Merck, Beigene, Natera. Dr. Heitz reports honoraria from Roche, AstraZeneca, GSK, NovoCure, and PharmaMar; advisory board fees from NovoCure; and leadership role with AGO study group. Dr. Redondo reports institutional grants from Eisai, PharmaMar, and Roche; honoraria fees from AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; advisory board roles at AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; and travel support from AstraZeneca, GSK, and PharmaMar. Dr. Moore reports personal fees from Abcodia Inc, Fujirebio Diagnostics Inc, and Humphries Pharmaceutical; and institutional grants from Angle Plc. Dr. Vulsteke reports medical writing support to GSK; consulting fees from Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo-Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr. O'Cearbhaill reports participating in advisory boards with 2seventy bio, Bayer, Carina Biotech, Fresenius Kabi, Immunogen, GSK, Miltenyi Biotec, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; travel fees from Hitech Health and Gathering Around Cancer, Ireland; service as a noncompensated steering committee member for the PRIMA and Moonstone (niraparib) and DUO-O (olaparib) studies; institutional research support grants from Acrivon Therapeutics, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Immunopharma, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune Inc, and TCR2 Therapeutics. Drs. Malinowska and Shtessel are employees of GSK. Ms. Compton is a former employee of GSK and currently receiving consulting fees from GSK. Dr. Mirza reports consulting and advisory role fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zai Lab; speakers’ bureau fees from AstraZeneca and GSK; institutional research funding from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). Dr. Monk reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novocure, Novartis, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 10 8 cells per m 2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 ., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Oral tyrosine kinase inhibitors (TKIs) have new indications for treatment in gynecologic malignancies. These targeted drugs have both unique and overlapping toxicities, which require careful attention and management. New combination therapies with immune-oncology agents have demonstrated promise in endometrial cancer. This review examines common adverse events associated with TKIs and provides readers with an evidence-based review on current uses and strategies for the management of these medications., Methods: A comprehensive review of the medical literature on TKI use in gynecologic cancer was undertaken by a committee approach. Details of each drug, its molecular target, and relevant data on both clinical efficacy and side effects were compiled and organized for clinical use. Information on drug-related secondary effects and management strategies for specific toxicities, including dose reduction and concomitant medications, were gathered., Results: TKIs can potentially offer improved response rates and durable responses for a group of patients who were previously without an effective standard second-line therapy. The combination of lenvatinib and pembrolizumab represents a more targeted approach to the drivers of endometrial cancer; however, there remains significant drug-related toxicity, and thus dose reduction and dose delay are frequently required. Toxicity management requires frequent check-ins and management strategies to help patients find the highest tolerable dose. TKIs are expensive and patient financial toxicity is as critical a measure of a drug's utility as any drug side effect. Many of these drugs have patient assistance programs, which should be fully utilized to minimize cost., Conclusions: Future studies are needed to expand the role of TKIs into new molecularly driven groups. Attention to cost, durability of response, and long-term toxicity management is needed to ensure all eligible patients have access to treatment., Competing Interests: Declaration of Competing Interest, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl)., Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event., Results: AUC statistics (range, 0.52-0.64) showed log(CrCl Jelliffe ) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively., Conclusion: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials., Competing Interests: Declaration of Competing Interest Dr. O'Cearbhaill reports support for this study from NCI/NIH P30 CA008748 and grants to Institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/Stemkens, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Kite Pharma, Acrivon and Gynecologic Oncology Foundation. Outside of the submitted work, Dr. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio. Dr. O'Cearbhaill reports receiving support to attend meetings and/or travel from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Dr. O'Cearbhaill participated on Data Safety Monitoring Board or Advisory Board for each of the following: AstraZeneca (DUO-0), GSK (moonstone, Prima), Acrivon, Carina Biotech, Link therapeutics, Tesaro/GSK, Regeneron, Seattle Genetics/Seagen, Immunogen, Bayer, R-Pharm, 2seventybio, Miltenyi and Fresenius Kabi. Dr. O'Cearbhaill also served as Vice-chair for the CPC, SGO as well a Chair, Developmental Therapeutics Committee for NRG Oncology. Dr. Aghajanian received research grants from AbbVie, Clovis, Genentech and Astra Zeneca and served on advisory boards for AbbVie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics and Roche/Genentech and received consulting fees for serving. Dr. Aghajanian served on the Blueprint Medicine Advisory Board (uncompensated). Dr. Aghajanian also serves on the GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) as well as the NRG Oncology Board of Directors (unpaid). Dr. Floor Backes wishes to report research grants from Immunogen, Clovis, Merck, Eisai, Natera and Beigene. Dr. Backes reports receiving consulting fees received from Eisai, Merck, Agenus, AstraZeneca, GlaxoSmithKline; Myriad, Clovis Oncology and Immunogen. Dr. Backes received honoraria for serving on advisory boards from Medlearning Group, CEC Oncology, OncLive, i3Health, and Medscape. Dr. Backes serves as Co-Chair of the NRG Oncology Developmental Therapeutics. Dr. Backes is a member of the Uterine Corpus Committee as well as a NCCN Ovary member and serves as an SGO Board Member. Dr. Michael Bookman reports payment to his Institution from Immunogen Data Monitoring Committee (unrelated to this project). Dr. David Cohn reports receiving honoraria from UpToDate as an Author as well as receiving payment for his role with Elsevier, Gynecologic Oncology as an Editor-in-Chief. Dr. Michael Friedlander reports that personally receiving consulting fees from AstraZeneca, Novartis, GSK and Incyclix (Nil). Dr. Friedlander also reports receiving honoraria from AstraZeneca and GSK and also received travel funding from AstraZeneca. Dr. Friedlander reports participating on Data Safety Monitoring Board/Advisory Board for AGITG IDSMB and ENDO-3. Dr. Friedlander reports that his Institution received grants from AstraZeneca, Beigene and Novartis. Dr. David Gershenson reports support from NRG Oncology with regard to this Study. Dr. Gershenson also acknowledges grants to his Institution from Novartis, GOG Foundation, and the NCI. Dr. Gershenson personally received royalties from Elsevier and UpToDate and consulting fees from Genentech (uncompensated) and Verastem. Dr. Gershenson received honoraria from University of Washington OB/GYN Grand Rounds and Yale University OB/GYN Grand Rounds and participating in a data safety monitoring/advisory board for Onconova, Aadi and Springworks. Dr. Gershenson also served on the International Consortium for Low-Grade Serous Ovarian Cancer and NCCN Ovarian Cancer Panel (uncompensated). Dr. Gershenson also wishes to disclose having stock in managed accounts for Bristol Myers Squibb, Johnson & Johnson and Procter & Gamble. Dr. Michael Goodheart reports receiving consulting fees from GlasoSmithKlein GSK/Tesaro, Merck, AstraZeneca, Clovis Oncology, SeaGen and Eisai. Dr. Angeles Alvarez Secord reports clinical trial grants received from the following: AbbVie, Aravive, AstraZeneca, BoehringerIngelheim, Clovis, Eisai, Ellipses, I-MAB Biopharma, Immunogen, Merck, Oncoquest/Canaria Bio, Seagen Inc., TapImmune, Tesaro/GSK, VBL Therapeutics. Dr. Secord also wishes to report receiving clinical trial grant/translational research grant from Roche/Genentech as well as Consulting fee from Myriad. Dr. Secord also received support for attending meetings/travel from GSK, GOG Foundation and NRG. Dr. Secord also served on the Clinical Trial Steering Committees for Aravive, Genentech/Roche, VBL Therapeutics and Oncoquest/Canaria Bio without compensation. Dr. Secord personally received compensation from GOG Foundation and NRG Oncology paid compensation to Institution. Dr. Secord also served in Leadership roles for Society of Gynecologic Oncology and American Association of Obstetrics and Gynecology Foundation (uncompensated). Dr. Judith Smith received honoraria for Speaking at the HOPA Annual Meeting 2016 – Harmonization of Carboplatin Dosing, Dr. Smith serves as Chair on the NRG Oncology Pharmacy Subcommittee. Dr. Tewari also reports receiving honoraria from Eisai, AstraZeneca, Clovis, GSK/Tesaro, Merck and Seagen/Genmab. Dr. Krishnansu Tewari reports receiving consulting fees from Regeneron, Eisai, AstraZeneca, Clovis, GSK/Tesaro, Merck, Seagen/Genmab. Dr. Andrea Wahner Hendrickson reports receiving Clinical Trial support from Prolynx and Site PI Clinical Trial Support from both Amgen and TORL Biotherapeutics. Dr. Wahner Hendrickson reports serving on Oxcia Advisory Board (uncompensated). Dr. Wahner Hendrickson reports serving on an Advisory Board for the Mayo Clinic Data Safety Monitoring Board (uncompensated). Dr. Wahner Hendrickson also served on the NCCN Ovarian Cancer Committee (uncompensated). Dr. Robert Wenham reports personal and institutional grants received from Merck and Ovation Diagnostics. Dr. Wenham reports receiving consulting fees from Merck, Legend Biotech, Genentech, Ovation Diagnostics, GSK/Tesaro, Clovis, AstraZeneca, AbbVie, Legend Biotech, Regeneron, Seagen, Sonic Biotherapeutics, Shattuck Labs, Novacure, Eisai and Immunogen. Dr. Wenham also reports receiving Institutional Clinical Trial Fees from AbbVie, AstraZeneca, Regeneron and Eisai. Dr. Wenham reports serving on Advisory Board for Seagen and GSK/Tesaro. Dr. Wenham would like to disclose personally owning stock in Ovation Diagnostics. Dr. Peter Argenta, Dr. Heidi Gray, Dr. Roger Lee, Dr. Stuart Lichtman, Dr. Austin Miller, Dr. David Mutch, Dr. Aaron Praiss, Dr. Paul Sabbatini and Dr. Linda Van Le have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma., Methods: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations., Results: Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15)., Conclusions: gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members., Competing Interests: Declaration of Competing Interest B.Weigelt reports research funding and scientific advisory board participation from Repare Therapeutics, outside the submitted work. K. Offit is a founder and shareholder of AnaNeo Therapeutics Incorporated. Z.K. Stadler has an immediate family member who serves as a consultant in Ophthalmology for Alcon, Adverum, Gyroscope Therapeutics Ltd., Neurogene and RegenexBio, outside the submitted work. M.F. Berger reports receiving research funding from GRAIL and advisory board activities for Eli Lilly, AstraZeneca, and PetDx. Y.L. Liu reports research funding from AstraZeneca, GSK, and Repare Therapeutics. N.R. Abu-Rustum reports research funding paid to the institution from GRAIL. C. Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). D.S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. R.N. Grisham reports personal fees from AstraZeneca, Corcept, GlaxoSmithKline, MJH Life Sciences, Natera, PER, and SpringWorks. M.M. Leitao Jr. reports research funding paid to the institution from KCI/Acelity, ad-hoc speaker for Intuitive Surgical, Inc., and advisory board participation for JnJ/Ethicon and Takeda. V. Makker reports advisory board participation (unpaid) for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly, and Immunocore. R.E. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences, Curio, R-Pharm, GOG Foundation, and Onclive/PER. M. Rubinstein reports research funding from Merk, Zentalis, and AstraZeneca. M.L. Hensley reports advisory board participation at Aadi Bioscience, GSK, Thrive Bioscience, and Lilly; has an immediate family member who is employed by Sanofi; and served as a CME faculty speaker for Research to Practice. All other authors have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear., Methods: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort., Results: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy., Conclusions: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)., (Copyright © 2023 Massachusetts Medical Society.)

Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objective: To assess postoperative complications after secondary cytoreductive surgery (SCS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), we conducted an exploratory analysis of patients with platinum-sensitive recurrent ovarian cancer enrolled in a randomized phase II trial., Methods: Complications occurring within 30 days of surgery were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; only hemoglobin and platelet levels were assessed. Patients were grouped by CTCAE grade ≥ 3 and < 3 complications., Results: Among 83 eligible patients, 33 (40%) had grade ≥ 3 complications and 50 (60%) had grade < 3 complications; anemia and abdominal infections were the most common. There were no perioperative mortalities. Time to initiation of postoperative chemotherapy for patients with grade ≥ 3 and grade < 3 events was 34 days (range, 18-60) and 31 days (range, 21-43), respectively (P = .017). Median progression-free survival (PFS) did not significantly differ between patients with grade ≥ 3 and grade < 3 complications (11.2 months [95% CI: 9.3-14.4] vs 14.9 months [95% CI: 11.3-16.5], respectively; P = .186), nor did median overall survival (OS) (46.9 months [95% CI: 34-NE] vs 68.2 months [95% CI: 52.1-NE], respectively; P = .053)., Conclusion: Postoperative complications following SCS with or without HIPEC were associated with slight delays in chemotherapy initiation but did not significantly impact oncologic outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We investigated the feasibility, safety, and survival outcomes of intrathoracic cytoreduction during primary debulking surgery (PDS) for advanced ovarian cancer., Methods: We conducted a database review of patients with stage IIIB-IV ovarian (including fallopian tube and primary peritoneal) carcinoma who underwent PDS at our institution from 01/01/2006-9/30/2021. Patients who underwent intrathoracic cytoreduction as part of primary treatment were included. Patients who received neoadjuvant chemotherapy or surgery for reasons other than cytoreduction were excluded., Results: Among 178 patients identified for inclusion, complete gross resection (CGR) in the abdomen and thorax was achieved in 131 (74%); 45 (25%) had optimal cytoreduction, and 2 (1%) had suboptimal cytoreduction. Thirty-one patients (17%) had at least one grade ≥ 3 complication; 8 were possibly related to intrathoracic cytoreduction. There were no deaths within 30 days following surgery. Median length of follow-up among survivors was 53.4 months. Among all patients, the median PFS was 33.6 months (95% CI: 24.7-61.9) and the 3-year PFS rate was 48.9% (95% CI: 41.2%-56.2%). Median OS was 81.3 months (95% CI: 68.9-103). When stratified by residual disease status, median PFS was 51.8 months when CGR was achieved versus 16.7 months with residual disease (HR: 2.17; P < .001) and median OS was 97.6 months when CGR was achieved versus 65.9 months with residual disease (HR: 2.05; P = .003)., Conclusions: Intrathoracic cytoreduction during PDS for advanced ovarian cancer is both safe and feasible. CGR can be achieved in patients with intrathoracic disease if properly selected, and could significantly improve both PFS and OS., Competing Interests: Declaration of Competing Interest Outside of the submitted work, REO reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences, and Curio. AI reports consulting fees from Mylan. NAR reports grant funding from GRAIL paid to the institution. RG reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. DC reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. DJ reports consulting fees from AstraZeneca and serves on a clinical trial steering committee at Merck. BJP reports consulting fees from Intuitive Surgical, AstraZenenca, Medtronic, and CEEVRA. All other authors have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy., Competing Interests: Declaration of interests Indiana University has licensed technology to Charles River Laboratories and Genezen Inc. based on unrelated work developed by K.Co., L.D., and T-Y. L., who each receive royalties. P.A.S receives research funding from ATARA Biotherapeutics; Scientific Advisory Board and Consultant: ATARA Biotherapeuticcs, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion, Outpace Bio; research funding and intellectual property licensed to ATARA Biotherapeutics. M.B. has equity in AlloVir, Marker Therapeutics, and Tessa Therapeutics; serves on the Scientific Advisory Board for Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Cell Genix, Kuur, Turnstone Biologics, Posedia, Tscan, and Bluebird Bio; and receives royalities from Takeda and Bellicum. K.Cu. is a consultant to Novartis and receives research support from Novartis, Cellectis, and Celgene. B.G. has equity in AlloVir, QBRegulatory LLC, and QBRegulatory, and provides consulting services to AlloVir, Marker Therapeutics, Tessa Therapeutics, Lokon Pharma and Proxima Clinical Research. H.H. has equity in AlloVir and Marker Therapeutics, and serves on the Scientific Advisory Board for Gilead Biosciences, Novartis, Tessa Therapeutics, Marker Therapeutics, Kiadis, PACT Pharma, Mesoblast, and receives research support from Tessa Therapeutics and Kuur Therapeutics. C.S.H. performs consulting and advisory board services for Neogene Therapeutics, Capstan Therapeutics, GlaxoSmithKline, and PACT Pharma; patents and royalties for NIH patents in cell and gene therapy and immunotherapy; research funding from Neogene Therapeutics and T-Cure Biosciences. J.K. has research support and royalty from Kite, a Gilead Company; and receives research funding from Bristol-Myers Squibb, Royalties: Kyverna. D.B.K. is a paid Scientific Advisory Board member for Allogene Therapeutics, ImmunoVec, Pluto Therapeutics, MyoGene Bio, Innoskel and an ad hoc consultant for Cimeio Therapeutics, TransformaTx, and Bluebird Bio. S.M. receives research funding from Allogene Therapeutics, Takeda Oncology, Juno Therapeutics, Bristol-Myers Squibb, Janssen Oncology, Fate Therapeutics and serves on the advisory panel for Legend Biotech, Evicore, Janssen Oncology, BioAscend, Optum Oncology, and EcoR1; and receives honoraria from Plexus Communication, OncLive, Physician Education Resource. R.O. receives compensation from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio/Onclive, R-Pharm, Immunogen, Hitech Health; non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies; non-compensated advisor for Carina Biotech. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb and Merck, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine and Tango; and has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. C.R. is Scientific Board Member for Novartis; research support from Tessa Therapeutics and Kuur Therapeutics. I.R. has equity or property rights with FloDesign Sonics, Takeda Pharmaceuticals, Fate Therapeutics, Mnemo Therapeutics, Juno Therapeutics; Services and Travel: Center for Commercialization of Cancer, Akron. C.S. is a consultant for Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite/a Gilead Company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, Ono Pharmaceuticals, MorphoSys, CSL Behring, Syncopation Life Sciences, CRISPR Therapeutics, and GSK; research funds: Juno Therapeutics, Celgene/BMS, Bristol-Myers Squibb, Precision Biosciences, Actinium Pharmaceuticals and Sanofi-Genzyme. S.S.: research funding: Sanofi-Aventis, Poseida Pharmaceuticals, Gilead Sciences, Inc, Prostate Cancer Foundation; Honoraria: Physician Education Resources, Janssen, Pfizer, Tolmar. D.A.W. holds intellectual property rights to the vector utilized in the trial reported in this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We previously developed preoperative and pre-chemotherapy modified versions of the male International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic model and assessed it in female patients with germ cell tumors (GCTs). We sought to validate these modified IGCCCG (mIGCCCG) models in a new cohort., Methods: We queried institutional databases for female patients with GCTs treated at Memorial Sloan Kettering Cancer Center from 1/1/1990-6/1/2020. The mIGCCCG model classifies patients with non-dysgerminomas as good, intermediate, or poor risk based on tumor markers using male IGCCCG cutoffs and absence/presence of non-pulmonary/peritoneal visceral metastasis. In dysgerminomas, good- and intermediate-risk groups are defined by absence/presence of non-pulmonary/peritoneal visceral metastasis. Progression-free survival (PFS) and overall survival (OS) were estimated for each group in the validation and combined original and validation cohorts. Associations between individual clinical factors and outcomes were evaluated., Results: Among 183 female patients with GCTs, clinical characteristics and outcomes were similar between the original (n = 93) and validation (n = 90) cohorts. In multivariable models, higher stage, older age, and non-dysgerminoma histology predicted worse PFS and OS (p < 0.05). Among 162 patients who received chemotherapy, preoperative and pre-chemotherapy mIGCCCG models were significantly associated with PFS and OS (p < 0.001 for all groups). With the preoperative model, 3-year PFS rates were 94%, 76%, and 50% in the good-, intermediate-, and poor-risk patients, respectively; OS rates were 96%, 86%, and 52%, respectively. Even within stage groups, mIGCCCG risk classifications were associated with clinical outcomes., Conclusions: A female-specific mIGCCCG risk model effectively stratifies patients and should be incorporated into clinical trials., Competing Interests: Conflict of Interest Statement Outside the submitted work, YL reports research funding from GSK, REPARE Therapeutics, and AstraZeneca; DF is a consultant/advisor for Cigna Research, and reports research funding from Decibel Therapeutics, Astellas Pharma, and Telix Pharmaceuticals; SF has received research support from AstraZeneca, Genentech/Roche, is a consultant/advisory board member for Merck, and owns stock in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, ByHeart, 76Bio, Vida Ventures, and Inconovir; JM reports research funding from Seagen, Sermonix, Pfizer, and Olema Pharmaceuticals, and has consulted for Seagen, Pfizer, Novartis, Sanofi, Genzyme, AstraZeneca, and GlaxoSmithKline in the past 2 years; RO reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio; RG reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER; CA has received research grants from Abbvie, Clovis, Genentech, and Astra Zeneca and served on advisory boards for Abbvie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech; DC reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE; and NAR reports research funding paid to the institution by GRAIL. The other authors do not have potential conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Objective: To assess long-term outcomes of patients with advanced-stage ovarian cancer by treatment type., Methods: Patients with newly diagnosed stage III-IV ovarian cancer who underwent primary treatment at our tertiary cancer center from 01/01/2015-12/31/2015 were included. We reviewed electronic medical records for clinicopathological, treatment, and survival characteristics., Results: Of 153 patients, 88 (58%) had stage III and 65 (42%) stage IV disease. Median follow-up was 65.8 months (range, 3.6-75.3). Eighty-nine patients (58%) underwent primary debulking surgery (PDS), 50 (33%) received neoadjuvant chemotherapy followed by interval debulking surgery (IDS), and 14 (9%) received chemotherapy alone, without surgery (NSx). Median PFS to first recurrence was 26.2 months (range, 20.1-36.2), 13.5 months (range, 12-15.1), and 4.2 months (range, 1.1-5.8) in the PDS, IDS, and NSx groups, respectively (P < .001). At first recurrence/progression, 80 patients (72.7%) were treated with chemotherapy, 28 (25.5%) underwent secondary cytoreductive surgery (CRS) followed by chemotherapy, and 2 (1.8%) received no treatment. Seven patients (4.6%) underwent palliative surgery for malignant bowel obstruction. Overall, 62.7% received 1-3 lines of chemotherapy. The 5-year OS rates were 53.2% (95% CI: 44.7%-61%) for the entire cohort, 71.5% (95% CI: 60.2%-80%) for the PDS group, 35.2% (95% CI: 22.2-48.5%) for the IDS group, and 7.9% (95% CI: 0.5%-29.9%) for the NSx group., Conclusion: The longitudinal treatment modalities and outcomes of patients with advanced ovarian cancer described here can be useful for patient counseling, long-term planning, and future comparison studies., Competing Interests: Declaration of Competing Interest Outside the submitted work, R. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio; D. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE; A. Iasonos reports consulting fees from Mylan. The other authors do not have potential conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: We assessed a conditional probability of survival (CPS) model to determine the probability of living 10 years after ovarian cancer diagnosis after having already survived 5 years., Methods: We identified patients newly diagnosed with high-grade epithelial ovarian cancer from 1/1/2001-12/31/2009 and treated at our institution. Patients with <3 years follow-up were excluded. CPS was defined as the probability of surviving additional years (y) based on the condition a patient had already survived a given time (x): S(x + y)/S(x). Confidence intervals were estimated using a variation of Greenwood's formula., Results: Of 916 patients meeting inclusion criteria, 473 (52%) were diagnosed from 2001 to 2005 and 443 (48%) from 2006 to 2009. Median age at diagnosis was 60 years (range, 25-95). The conventional 10-year OS rate for all patients was 29% (95% CI: 26%-32%)-75% (95% CI: 68%-82%) for stage I/II disease, 22% (95% CI: 19%-26%) for stage III, and 6.9% (95% CI: 3.9%-12%) for stage IV. For patients <65 years, the 10-year CPS for 5-year survivors was 65% (95% CI: 59%-70%); for those ≥65 years, it was 48% (95% CI: 38%-57%). For patients <65 years, the 10-year CPS for 5-year survivors by stage was: stage I/II, 89% (95% CI: 81%-94%); stage III, 58% (95% CI: 50%-66%); and stage IV, 26% (95% CI: 12%-42%). For patients ≥65 years, rates by stage were 78% (95% CI: 53%-91%), 42% (95% CI: 30%-53%), and 29% (95% CI: 7%-56%), respectively., Conclusions: For long-term survivors with high-grade epithelial ovarian cancer, CPS provides better prediction of survival than conventional methods., Competing Interests: Declaration of Competing Interest R.E.O. reports personal fees from Tesaro/GSK, personal fees from Regeneron, personal fees from Seattle Genetics, other from AstraZeneca Pharmaceuticals, personal fees from Fresenius Kabi, personal fees from Gynecologic Oncology Foundation, personal fees from Bayer, personal fees from Curio, advisor for Carina Biotech outside the submitted work; and non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), ARTISTRY7 (Arkemes) and DUO-O (AstraZeneca) studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie/StemCentrx, Merck, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation. N.A.R. reports research funding paid to the institution by GRAIL. R.N.G. reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER; D.S·C reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE; The other authors do not have potential conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab., Methods: Patients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011 to 03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. "Responders" had an immunogenic response to ≥ 3 antigens; "non-responders" to ≤ 2 antigens., Results: Twenty-one patients were treated on study. One developed a dose-limiting toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥ 3 and ≥ 2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). Four of 21 patients were alive > 5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-timepoint analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p = 0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02)., Conclusions: This is the longest follow-up of vaccine administration with bevacizumab in patients with ovarian cancer. The vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-timepoint analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all timepoint measurements, cytokine levels were not significantly associated with survival., Trial Registration: NCT01223235., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Gastric-type endocervical adenocarcinoma (GEA) is a rare form of cervical cancer not associated with human papilloma virus (HPV) infection. We summarize our experience with GEA at a large cancer center., Methods: Clinical and demographic information on all patients diagnosed with GEA between June 1, 2002 and July 1, 2019 was obtained retrospectively from clinical charts. Kaplan-Meier survival analysis was performed to describe progression-free survival (PFS) and overall survival (OS). Tumors from a subset of patients underwent next generation sequencing (NGS) analysis., Results: A total of 70 women with GEA were identified, including 43 who received initial treatment at our institution: of these 4 (9%) underwent surgery alone, 15 (35%) underwent surgery followed by adjuvant therapy, 10 (23%) were treated with definitive concurrent chemoradiation (CCRT), 7 (16%) with chemotherapy alone, and 3 (7%) with neoadjuvant CCRT and hysterectomy with or without chemotherapy. One-third (n = 14) of patients experienced disease progression, of whom 86% (n = 12) had prior CCRT. The median PFS and OS for patients with stage I GEA were 107 months (95% CI 14.8-199.2 months) and 111 months (95% CI 17-205.1 months) respectively, compared to 17 months (95% CI 5.6-28.4 months) and 33 months (95% CI 28.2-37.8 months) for patients with stages II-IV, respectively. On NGS, 4 patients (14%) had ERBB2 alterations, including 2 patients who received trastuzumab., Conclusions: GEA is an aggressive form of cervical cancer with poor PFS and OS when diagnosed at stage II or later. Further investigation is needed to identify the optimal management approach for this rare subtype., Competing Interests: Declaration of Competing Interest Outside the submitted work, B. Weigelt reports ad hoc membership in the scientific advisory board of Repare Therapeutics, outside the scope of the study. C. Friedman reports participation in the scientific advisory boards for Merck (LYNK-002) and Genentech (MyPathway) without compensation, consulting for Seagen and Bristol Myers Squibb, and institutional research funds from Genentech/Roche, Bristol Myers Squibb, Merck, AstraZeneca, and Daiichi. E. Jewell reports personal fee from Covidien/Medtronic. K. Cadoo reports grant funding from the Irish Cancer Society, MSD, and Immunogen; consulting fees from Nextcure, MJH Life Sciences, and GSK; payments/honoraria from GSK, AstraZeneca, and MSD; financial support to attend meetings from Roche, Pfizer, and MSD; advisory board participation at MSD, AstraZeneca, GSK, and Eisai; a voluntary advisory role at the National Cancer Control Programme Ireland; and a voluntary board member at ARC Cancer Support Centers. N. Abu-Rustum reports grant funding from GRAIL paid to the institution. S. issa Bhaloo reports stock or stock options in BioNTech, Moderna, Inc., Inovio, Relief Therapeutics Holding SA, Cansino Biologics, Inc., and Pfizer, Inc. M. Leitao reports personal fees from Medtronic, Intuitive Surgical, Inc., and JnJ/Ethicon. C. Aghajanian has received research grants from Abbvie, Clovis, Genentech, and Astra Zeneca and served on advisory boards for Abbvie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech. R. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio. C. Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. D. Zamarin is an inventor on a patent related to the use of oncolytic Newcastle Disease Virus for cancer therapy, and reports grant funding paid to the institution from AstraZeneca, Roche, Plexxikon, and Synthekine; consulting fees from Memgen, Celldex, Agenus, Astellas, AstraZeneca, Crown Biosciences, Roche, GSK, Hookpia, ImmunOS, Kalvir, Synlogic Therapeutics, Synthekine, Takeda, Targovax, Tessa Therapeutics, and Xencor; stock options in Accurius Therapeutics, Immunos Therapeutics and Calidi Biotherapeutics; and a Merck licensed patent (with personal payments and payments to the institution). All other authors have no potential conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To assess patient-perceived involvement in shared decision making among those diagnosed with breast or gynecologic malignancies undergoing chemotherapy associated with persistent chemotherapy-induced alopecia (pCIA). We also sought to identify factors that influence shared decision making., Methods: We recruited patients from the Gynecologic Medical Oncology and Breast Medicine Services at a large academic center for this prospective cohort study. All patients were scheduled to start chemotherapy between June 1, 2017 and December 31, 2017. Following medical consultation, including discussion of the risk of pCIA, patients completed the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Clinical and sociodemographic information was also collected. Univariate analysis was used to evaluate SDM-Q-9 total scores and their constituents for all variables., Results: Sixty-one patients completed the survey. The median total SDM-Q-9 score was 95.6 (95% CI: 90-100). Most patients (n = 57, 93%) reported a high level of involvement (SDM-Q-9 total score > 66). There was no difference in total scores between patients with breast compared with gynecologic cancer ( P  > .05). By individual item, the scores for item Q1 (" My doctor made clear that a decision needs to be made" ) were significantly lower for Black patients and those with advanced disease ( P  < .05)., Conclusions: Most patients indicated they were adequately involved in shared decision making regarding chemotherapy treatment options and their risk for pCIA. Patients from underrepresented populations and those with advanced disease may benefit from additional support from their clinicians to better address the anticipated psychosocial impacts of pCIA and facilitate the provision of optimal and equitable care., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Freites-Martinez reports consulting fees from Galderma, Leo Pharma, Pierre Fabre, and to the SHB law firm, which represents Sanofi Aventis U.S. Dr. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, R-Pharm, GOG Foundation, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio. Dr. Goldfarb reports grants from Paxman Coolers Ltd and Sprout Pharmaceuticals Inc paid to the institution; consulting from NanOlogy and Spectrum Pharmaceuticals; and participation in an advisory board for Sermonix Pharmaceuticals LLC, Revision Skincare, and Ms. Medicine. Dr. Lacouture reports grants, consulting fees, and honoraria from Johnson & Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, Oncoderm, NCODA, and Apricity, as well as receives research funding from Lutris, Paxman, Novocure, Johnson & Johnson, US Biotest, OQL, Novartis and AstraZeneca; royalties from Harborside Press; and leadership fees from Hoth, Lutris. Dr. Friedman reports grants paid to the institution from Daiichi, Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, and Mersana; consulting fees from Bristol-Myers Squibb, Seagen; honoraria from OncLive and Aptitude Health; uncompensated participation in advisory boards for Genentech/Roche for MyPathway and Merck for LYNK-002; and drugs from Genentech/Roche. All other authors have no potential conflicts of interest to disclose., (© 2022 The Authors. Published by Elsevier Inc.)

Purpose: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC)., Experimental Design: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected., Results: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation., Conclusions: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357., (©2022 American Association for Cancer Research.)

Objectives: To describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (SCNCC) and determine the staging system most predictive of outcome-the two-tier (limited-stage [LS] vs. extensive-stage [ES]) or International Federation of Gynecology and Obstetrics (FIGO) staging system., Methods: Patients with SCNCC evaluated at our institution from 1/1/1990-6/30/2021 were included. Medical records were reviewed for variables of interest. Appropriate statistical tests were performed to determine associations. Survival curves were created using the Kaplan-Meier method. Concordance probability estimates (CPEs) were calculated to evaluate the prediction probability of the staging systems., Results: Of 63 patients, 41 had LS and 22 ES SCNCC. Patients with ES disease were significantly older than those with LS disease (median, 54 and 37 years, respectively; p < 0.001). Smoking status, race, and history of HPV were not associated with stage or outcomes. Forty-eight patients had metastatic disease (24 [50%] at initial diagnosis). The most common first sites of metastasis were lung (n = 20/48, 42%), lymph nodes (n = 19/48, 40%), and liver (n = 13/48, 27%). Nine patients had brain metastasis (8 symptomatic at recurrence; 1 asymptomatic at initial diagnosis). Both staging systems were associated with progression-free and overall survival. Adjusted CPE found the FIGO staging system was more predictive of outcomes than the two-tier staging system., Conclusions: Providers should have a low threshold to obtain brain imaging for patients with SCNCC, especially in the presence of visceral metastases. FIGO staging should be used to classify SCNCC. Further research is necessary to understand prognostic factors of this rare disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence., Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population., Results: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37)., Conclusions: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance., Competing Interests: Declaration of Competing Interest REO reports participating in advisory boards with Bayer, Fresenius Kabi, GlaxoSmithKline, Immunogen, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; and service as a noncompensated steering committee member for the PRIMA (niraparib) and DUO-O (olaparib) studies; institutional research support grants from AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GlaxoSmithKline, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, Stem CentRx, Syndax, TapImmune Inc., and TCR2 Therapeutics. JAPF reports personal fees from Abilify Pharma, Amgen, AstraZeneca, Clinigen, Clovis, GlaxoSmithKline, and Roche; and institutional grants from GlaxoSmithKline. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Regeneron, Sorrento, Pfizer, Puma, US Oncology Research, and VBL; speaker's bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, TESARO/GSK; and is an investigator for US Oncology Research. IT reports personal fees from Celgene and Roche Pharma AG; institutional grants from Roche; and travel support from Roche. RGM reports personal fees from Abcodia Inc., Fujirebio Diagnostics Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc. MSS reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck, and Pacira Pharmaceuticals Inc.; and institutional grants from GlaxoSmithKline. DO reports personal fees from Agenus, Eisai, GlaxoSmithKline, and Immunogen; consultant/advisory board for Abbvie, Ambry, Amgen, Array Biopharma, Clovis, EMD Serono, Ergomed, Janssen/J&J, INC Research Inc., inVentiv Health Clinical, Iovance Biotherapeutics Inc., Myriad Genetics, Novacure, Regeneron, Tarveda, and VentiRx; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto Inc., Bristol Myers Squibb, Cerulean Pharma, GOG Foundation, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Stemcentrx Inc., Serono Inc., Tracon Pharmaceuticals, and Yale University. BMS reports consulting/advisory fees from Abbvie, AstraZeneca, Clovis, Eisai, Genentech, GlaxoSmithKline, GOG Foundation, Merck, and Myriad. FS reports personal fees from AstraZeneca, Clovis, GlaxoSmithKline, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GlaxoSmithKline, MSD, PharmaMar, and Roche. AK reports personal fees from AstraZeneca and GlaxoSmithKline. AGM reports consulting or advisory roles at Amgen, AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Merck & Co., Mersana, Immunogen, Roche, Sotio, and Takeda; speaker's bureau compensation from AstraZeneca, Clovis, GlaxoSmithKline, Merck & Co., and Roche; institutional research funding from Roche and GlaxoSmithKline; and travel support from AstraZeneca, GlaxoSmithKline, and Roche. CM, CV, JF, FF, WHB, SH, AD, KB, PMC, GA, and TL have nothing to disclose. IAM and DG are employees of GlaxoSmithKline. YL was an employee at GlaxoSmithKline at the time of the analysis; currently an employee of Adagio Therapeutics Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest Dr. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, Immunogen, MJH, SeaGen, Fresenius Kabi, and Curio, all outside the submitted work. Dr. Eskander reports grants and personal fees from AstraZeneca, personal fees from Myriad, personal fees from GOG Partners, grants and personal fees from Clovis Oncology, personal fees from GSK/Tesaro, personal fees from Merck, grants from Genentech Roche, personal fees from Iovance, all outside the submitted work. Dr. Gaillard reports grants from Abbvie, grants from Pfizer, grants from PharmaMar, grants from Iovance, grants from Tesaro, grants from Genentech/Roche, grants from Rigel, grants and personal fees from AstraZeneca, personal fees from Immunogen, personal fees from Sermonix, personal fees from Elevar Therapeutics, all outside the submitted work. In addition, Dr. Gaillard has a patent US 16/341,033 licensed, and a patent PCT/US2019/026669 licensed. All other authors have nothing to disclose.

Objective: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues., Methods: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting., Results: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues., Conclusions: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors., Competing Interests: Declaration of Competing Interest G. Zoppoli reports receiving travel grants from Roche, Novartis, and Pfizer, consultation fees from Pfizer, reagents from ThermoFisher Scientific and Cytiva Life Sciences, outside the submitted work. N.R. Abu-Rustum reports Stryker/Novadaq and GRAIL grants paid to the institution, outside the current study. J.S. Reis-Filho reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. J.S. Reis-Filho has stocks or stock options with REPARE Therapeutics and Paige.AI. D.S. Chi reports membership of the medical advisory boards of Bovie Medical Co. (now Apyx Medical), Verthermia Inc. and Biom ‘Up, to have/had stock options of Bovie Medical Co. (now Apyx Medical), Verthermia Inc., Intuitive Surgical Inc. and TransEnterix Inc., and to be the Chief Editor and shareholder of C Surgeries. D. Zamarin reports personal/consulting fees from Agenus, Hookipa Biotech, Western Oncolytics, Synthekine, Mana Therapeutics, Xencor, Memgen and Takeda, grants and personal fees from Merck and from Astra Zeneca, grants and non-financial support from Genentech, grants from Plexxikon and stock options from Calidi Biotherapeutics, outside the submitted work. D. Zamarin has a patent for use of Newcastle Disease Virus for cancer therapy, outside the submitted work. Dr. Aghajanian reports membership of advisory boards/personal fees from Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, Repare Therapeutics, and grants from Clovis, Genentech, AbbVie, Astra Zeneca, all outside the submitted work. R.E. O'Cearbhaill reports receiving honoraria/consulting/advisory role from GlaxoSmithKline, Fresenius, Seagen Inc., Carina Biotech and institutional research funding: Juno Therapeutics, Sellas Life Sciences, Ludwig Institute for Cancer Research, Stem CentRx, TapImmune Inc., TCR2 Therapeutics, Regeneron, Genmab, Atara Biotherapeutics, GlaxoSmithKline, AstraZeneca/Merck, Syndax, Genentech, Kite/Gilead, Gynecologic Oncology Group Foundation. Meal from AstraZeneca. B. Weigelt reports ad hoc membership of the scientific advisory board of Repare Therapeutics. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Endometrial stromal sarcomas (ESS) are rare, accounting for < 1% of all uterine malignancies. Treatment has been guided by small case series and retrospective studies. Endocrine therapy is used in both adjuvant and metastatic settings. Aromatase inhibitors (AIs) are widely used in clinical practice. We sought to evaluate clinical outcomes of AI use in the largest cohort of patients with LGESS to date., Methods: We performed a retrospective study of patients with LGESS treated with an AI at our institution from 1/1998-12/2020. Response was evaluated using RECIST 1.1. The Kaplan-Meier method was used to estimate median progression-free (PFS) and overall (OS) survival., Results: Forty patients were identified. Treatment was well tolerated, with 57.5% experiencing adverse effects. The most common were arthralgias (12 patients, 30%) and hot flashes (9, 22.5%). Two of 11 patients with RECIST-evaluable imaging experienced a partial response to treatment. Median PFS for the entire cohort was 79.2 months (95% CI 39.7 months to NE); the 5-year PFS rate was 59.6% (95% CI 41.8% to 73.6, p = 0.065). Median follow-up for the 29 survivors was 97.9 months (range: 12.6-226.7). The 5-year OS rate was 81.5% (95% CI 64.9-90.7%). One patient who discontinued AI after 10 years of treatment recurred 1 year later., Conclusion: AIs were well tolerated and offered periods of prolonged disease stability, even in the metastatic setting. Our study suggests, however, that response rates may be lower than previously reported. Data on optimal duration of treatment is needed, but the rarity of LGESS is an obstacle to conducting large clinical trials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)