Arcagy Gineco

Background:Patients with epithelial ovarian cancer (EOC) receiving neoadjuvant platinum-based chemotherapy (NACT) who remain ineligible for complete interval cytoreductive surgery (ICS) due to poor chemosensitivity (CA-125 KELIM™ score <1.0) have a poor prognosis (~20% 5-year survival). A weekly dose-dense carboplatin–paclitaxel regimen may improve outcomes in this high-risk subgroup.Objectives:To demonstrate the superiority of a salvage weekly dose-dense carboplatin–paclitaxel regimen over continuation of the standard 3-weekly regimen in poor-prognosis EOC patients after 3–4 cycles of standard NACT.Design:SALVOVAR is a pragmatic, open-label, multicenter, international, randomized phase III trial.Methods and analysis:Patients with stages III–IV high-grade EOC are eligible if they present (1) an unfavorable standardized KELIM score <1.0, and (2) a disease not amenable to complete ICS after 3–4 cycles of standard 3-weekly carboplatin–paclitaxel. Patients are randomized (1:1) to either the experimental arm (dose-dense carboplatin AUC5 day 1 plus paclitaxel 80 mg/m2 on days 1, 8, and 15, every 3 weeks) or the control arm (continuation of the standard regimen) for 3 cycles. Bevacizumab use is allowed at investigator discretion. Stratification factors include planned bevacizumab administration, BRCA mutation status, and KELIM strata. The two co-primary endpoints are (1) improvement in late complete cytoreduction rates (from 5% in the control arm to 20% in the experimental arm), and (2) overall survival (target hazard-ratio, 0.61). Total 250 patients will be randomized. Secondary endpoints include objective response rate, progression-free survival, and safety. Additional planned analyses include quality-of-life, cost-effectiveness, surgical standardization, human sciences, and biology studies.Ethics:The protocol was approved by the national ethics committee and health authorities.Discussion:SALVOVAR will evaluate whether chemotherapy densification improves outcomes in poorly chemosensitive advanced EOC. If positive, this pragmatic strategy could be implemented in large-scale studies, independent of resource setting.Trial registration:ClinicalTrials.gov NCT06476184 (June-2024). Available at: https://clinicaltrials.gov/study/NCT06476184

Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients. EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic BRCA mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m2 once weekly or pegylated liposomal doxorubicin 40-50 mg/m2 once every 28 days). Patients had 1-3 previous systemic therapies. Previous bevacizumab was required (unless contraindicated); previous poly(adenosine diphosphate-ribose) polymerase inhibitors were allowed. Primary end point was progression-free survival (PFS) per RECIST 1.1 (blinded independent review committee [BIRC]). Secondary efficacy end points included overall response rate (ORR; per BIRC), duration of response (per BIRC), and overall survival (OS; key secondary end point). A total of 358 patients (alpelisib + olaparib [n = 180], TPC [n = 178]) were included. The median follow-up time was 9.3 months. At data cutoff (April 21, 2023), 33 (18.3%) and 30 (16.9%) patients remained on treatment with alpelisib + olaparib and TPC, respectively. The median PFS (BIRC) was 3.6 versus 3.9 months (hazard ratio [HR], 1.14 [95% CI, 0.88 to 1.48]; one-sided P = .84) for alpelisib + olaparib versus TPC. The ORR was 15.6% (95% CI, 10.6% to 21.7%) versus 13.5% (95% CI, 8.8% to 19.4%). The median OS was 10.0 versus 10.6 months (HR, 1.22; 95% CI, 0.87 to 1.71). The safety profile of alpelisib + olaparib was consistent with that observed for the individual agents. The primary objective, PFS improvement, was not met in EPIK-O. No new or unexpected adverse events were observed. Biomarker analyses provided new insights for responders to alpelisib + olaparib.

BackgroundLung cancer is the leading cause of cancer-related death worldwide. The aim of the KBP-2020 study was to describe survival among patients diagnosed with lung adenocarcinoma in France in 2000, 2010, and 2020, outside academic medical centers.MethodsWe collected prospective data from all patients diagnosed with lung cancer in nonacademic public hospitals in France in 2020. We compared these data with those from similar studies performed in 2000 and 2010 to map the evolution of survival.ResultsThe KBP-2020 cohort comprised 5015 patients with lung adenocarcinoma. The 3-year overall survival (OS) rate was 38.6%, ranging from 21.3% among patients with metastatic disease at diagnosis to 84.0% for those with stage I disease at diagnosis. The median OS in the overall population more than doubled in 20 years, from 8.5 months in 2000 to 20.7 months in 2020. Female sex, higher performance status, and earlier disease stage were associated with an increased 3-year OS. Patients with metastatic lung adenocarcinoma with EGFR, ALK, or ROS1 molecular alterations who were treated with targeted therapy had a higher 3-year OS rate than such patients without these alterations — 36.0% versus 18.5%. Among those patients with metastatic disease without the above-noted molecular alterations, the 3-year OS rate was 36.2% with first-line immunotherapy versus 14.3% without immunotherapy, and median OS was 21.0 months versus 4.2 months.ConclusionsImprovements in the OS of patients with lung adenocarcinoma were seen over 20 years in this setting of nonacademic public hospitals in France. Targeted therapy and immunotherapy were associated with longer OS among patients with metastatic disease. (Le Nouveau Souffle and others; trial registration number, NCT04402099.)

Mutant p53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label, randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor ganetespib (G) with paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602). Patients were randomized 2:1 to receive G + P or P alone until progression. Primary endpoints were progression-free survival (PFS) and PFS rate at 6 months. Exploratory endpoints were biomarkers based on p53 and HSP90. A total of 133 patients were enrolled. The median PFS was 3.5 (G + P) and 5.3 months (P) (HR = 1.3; 95% confidence interval, 0.897-1.895; P = 0.16), and PFS rates at 6 months were 22% (G + P) and 33% (P). No significant differences were found in overall survival, objective response rate, and post-progression PFS between arms. The most frequent adverse events were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%). Serious adverse events were more common in G + P (39.5% vs. 23.3%). Gastrointestinal perforation was a new safety finding. Despite a high TP53 mutation frequency, HSP90-p53 complexes were detected in only 39.6% of the cases and were also detected stably during treatment. In vitro, no synergistic effects of G + P were observed, and mutant p53 depletion did not sensitize ovarian cancer cells to treatment. Although no major safety findings were observed, G + P did not lead to survival benefit. Our companion diagnostic program confirmed that G + P do not favorably cooperate in killing ovarian cancer cells.

IntroductionLow grade serous ovarian cancer (LGSOC) is a rare, clinically distinct cancer commonly driven by RAS/MAPK pathway alterations. Avutometinib ([A] oral RAF/MEK clamp) + defactinib ([D] oral FAK inhibitor) is being investigated in recurrent LGSOC. We report the primary analysis of A±D from RAMP 201.MethodsPatients with recurrent, measurable LGSOC after at least one line of platinum chemotherapy were enrolled. Patients were randomized to A (4.0mg BIW) monotherapy or A (3.2mg BIW) + D (200mg BID). A+D was selected for expansion. Subsequently a 1.6mg dose of A +D was evaluated. The primary endpoint is ORR per RECISTv1.1 by BICR.ResultsAt the 30June2024 visit cutoff, 115 patients were enrolled to A (3.2mg BIW) + D (200mg BID). Median age was 54 (range, 21-87) and patients had a median of 3 (range, 1-9) prior lines of therapy. Prior therapies included endocrine (86%), bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR of 31% was observed (44% KRAS mt; 17% KRAS wt); median DOR, 31.1mo and median PFS, 12.9mo. The most common non-laboratory treatment-related AEs (all grades, grade ≥3) were nausea (67.0%, 2.6%) and diarrhea (58.3%, 7.8%). The most common laboratory abnormality was increased blood creatinine phosphokinase (60.0%, 24.3%). Discontinuations due to AEs were infrequent (10%). Results from all cohorts will be presented.Conclusion/ImplicationsA+D was well tolerated allowing prolonged exposure to therapy. ORR and durable responses observed are clinically meaningful in this heavily pretreated population and support the potential of A+D as a new standard of care for recurrent LGSOC. LB007/#1548 Table 1

BackgroundCA-125 alone is widely used to diagnose progressive disease (PD) in platinum-sensitive recurrent ovarian cancer (PSROC) on chemotherapy. However, there are increasing concerns regarding its accuracy. We assessed concordance between progression defined by CA-125 and RECIST using data from the CALYPSO trial.MethodsWe computed concordance rates for PD by CA-125 and RECIST to determine the positive (PPV) and negative predictive values (NPV).ResultsOf 769 (79%) evaluable participants, 387 had CA-125 PD, where only 276 had concordant RECIST PD (PPV 71%, 95% CI 67–76%). For 382 without CA-125 PD, 255 had RECIST PD but 127 did not (NPV 33%, 95% CI 29–38). There were significant differences in NPV according to baseline CA-125 (≤100 vs >100: 42% vs 25%, P < 0.001); non-measurable vs measurable disease (51% vs 26%, P < 0.001); and platinum-free-interval (>12 vs 6–12 months: 41% vs 14%, P < 0.001). We observed falling CA-125 levels in 78% of patients with RECIST PD and CA-125 non-PD.ConclusionApproximately 2 in 3 women with PSROC have RECIST PD but not CA-125 PD by GCIG criteria. Monitoring CA-125 levels alone is not reliable for detecting PD. Further research is required to investigate the survival impact of local therapy in radiological detected early asymptomatic PD.

Simple SummaryGenomic instability (GI) caused by homologous repair deficiency (HRD) is a novel highly clinically relevant biomarker that cannot only identify patients suffering from high-grade serous ovarian cancer that may benefit from poly-ADP ribose polymerase (PARP) inhibitors but also helps in functionally annotating mutations found within genes of the homologous repair pathway. Tumors in which GI plays a role in therapeutic considerations currently include ovarian, breast, prostate, and pancreatic cancer. Therefore, we developed, implemented, and clinically validated a comprehensive custom Agilent XT HS2 hybrid capture next-generation sequencing (NGS) assay that allows in addition to the analysis of homologous recombination repair (HRR) pathway and relevant cancer genes, complex BRCA1 and BRCA2 alterations including large deletions and the evaluation of the GI-Score (GIS) status on one single tumor sample. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS v1 assay was validated as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative on a subset of the ENGOT PAOLA-1 clinical trial samples. Patients identified as HRD-positive using the NOGGO GIS v1 assay showed a benefit of progression-free survival (PFS) and overall survival (OS) with comparable hazard ratios to the Myriad MyChoice assay.The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution’s specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25–85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The “NOGGO GIS v1 assay” performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

Correction to: British Journal of Cancer, published online 16 November 2020 The original version of this article contained an error in an affiliation. Upon careful review of the paper, the authors noticed that the affiliation for Goran Malenkovic was not written correctly. The authors only submitted the following affiliation Gynecologic Oncology Department Clinic for Operative Oncology, Institute of Oncology of Vojvodina, Serbia but they missed to notice that the Faculty of Medicine Novi Sad, University of Novi Sad, Serbia should also be in the affiliation.