Edinburgh Cancer Research Centre

Chronic kidney disease (CKD) leads to bone loss and bone marrow adipose tissue (BMAT) accumulation. Sclerostin and dickkopf-1 (DKK1) are two inhibitors of Wnt signalling, which suppress bone formation, promote bone marrow adipogenesis, and are elevated in CKD. However, therapies targeting sclerostin have shown limited efficacy in improving bone health in CKD animal models. Herein, we explored whether dual inhibition of sclerostin and DKK1 via a rodent bispecific antibody (rbsAb) could prevent bone loss and suppress BMAT accumulation in a CKD mouse model. CKD was induced using an adenine-supplemented diet in male mice, with CKD and control mice treated weekly for 6-weeks with vehicle or 30 mg/kg body weight of rbsAb. Circulating sclerostin and DKK1 were ~ 2- and ~ 3-fold higher, respectively, in CKD mice compared to controls. Proteomic profiling by LC-MS/MS and functional enrichment analysis suggested that in CKD mice, adipogenesis, osteoclast differentiation and bone resorption were increased whereas osteoblast differentiation was inhibited. These changes were prevented by antibody treatment. MicroCT revealed that long bones of CKD mice were characterised by lower bone mineral density, trabecular and cortical bone, and impaired biomechanical properties, but their vertebrae were unaffected. RbsAb treatment prevented cortical and trabecular bone loss and restored biomechanical properties. BMAT, as visualised by microCT imaging of osmium-stained bones, was elevated in CKD but reduced to control levels by rbsAb treatment. In conclusion, dual inhibition of sclerostin and DKK1 improved bone integrity and suppressed BMAT in experimental CKD, suggesting a promising therapeutic avenue for renal osteodystrophy.

ABSTRACT Importance Non-inferiority trials are becoming increasingly popular in abdominal surgery. The non-inferiority margin is critical in the interpretation and conclusion of these trials. Objective This systematic review aims to assess the methodological and reporting quality of non-inferiority randomized controlled trials in abdominal surgery. Evidence Review Non-inferiority trials were systematically identified by searching Ovid Medline, Embase and the CENTRAL databases from 2006 until December 2025. Randomized controlled trials in adult patients with any type of abdominal surgical intervention in at least one trial arm and a sample size ≥100 were eligible for inclusion. The primary outcome was the definition of the non-inferiority margin. Secondary outcomes were the reporting of the non-inferiority margin, the robustness of its estimation, the uncertainty of the point estimate and the adequacy of conclusions. Findings A total of 11’045 trials were identified, of which 101 were eligible, enrolling 44’370 patients. Most trials provided a rationale for the non-inferiority design, while six (5.9%) trials did not. Previous literature was commonly used (n=56; 55.4%), but the non-inferiority margin was most often based on a clinical fixed margin or on historical comparison of the treatment and the active comparator. Based on the margin, investigators tolerated substantially worse outcomes of the treatment compared to the comparator. Conclusions were appropriate based on the confidence interval and the predefined non-inferiority margin in 88 (87.1%) of trials. The clinical judgement of the conclusion was overall adequate. Confidence interval estimations were reported in 16 (15.8%) of trials. Simulation studies were limited by the reporting quality. Conclusions and Relevance Clinical fixed margins are commonly used in abdominal surgery non-inferiority randomized controlled trials, however, substantial shortcomings in reporting limit the interpretability and reproduction of study findings. Based on the findings of this study, guidance on surgical-specific non-inferiority margin definitions is needed. KEY POINTS Question How are non-inferiority margins estimated in surgical randomized controlled trials? Findings In this systematic review, non-inferiority margins were nearly always numerically defined, but reporting of how they were estimated was poor. Most frequently, clinical fixed margins were utilized and previous evidence was either ignored or not included at the design stage. The selected margins often tolerated substantially worse outcomes in the treatment group compared to the comparator. Meaning Improved reporting and guidance on the conduct of surgical non-inferiority trials are required.

4514 Background: KEYNOTE-564 (NCT03142334) established pembro monotherapy as the first adjuvant regimen to significantly improve both disease-free survival (DFS) and overall survival (OS) vs placebo (pbo) after surgery for participants (pts) with ccRCC at increased risk of recurrence. We present results from the fourth prespecified interim analysis with a minimum follow-up of 5 yrs. Methods: KEYNOTE-564 is a randomized, double-blind, pbo-controlled, phase 3 study, which enrolled adults with ccRCC with intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0 M0) or high (pT4 any Gr, N0 M0, or any pT and Gr, N+ M0) risk of recurrence or M1 with no evidence of disease (NED) who had nephrectomy and/or metastasectomy ≤12 wks prior to 1:1 randomization to pembro 200 mg or pbo IV Q3W. Treatment continued for ~1 yr (17 cycles) or until recurrence, intolerable AEs, or physician decision to discontinue treatment. The primary endpoint was DFS by investigator; the key secondary endpoint was OS. The study met its DFS and OS objectives at earlier analyses; thus, no subsequent formal statistical testing occurred. AEs were collected for 30-90 days after treatment cessation depending on severity, with serious treatment-related AEs collected regardless of timing. Results: A total of 994 pts were randomized to pembro (n = 496) or pbo (n = 498). The median follow-up time to data cutoff date of 25 Sept 2024 was 69.5 mo (range, 60.2−86.9). All pts completed or discontinued study treatment ≥3 years earlier. 188 DFS events in the pembro group and 241 in the pbo group had occurred. Median DFS was not reached (NR) vs 68.3 mo, respectively (HR 0.71, 95% CI 0.59−0.86); estimated DFS rate at 5 yrs was 60.9% vs 52.2%. 68 OS events in the pembro group and 99 in the pbo group had occurred. Median OS was NR in both arms (HR 0.66, 95% CI 0.48−0.90); estimated OS rate at 5 yrs was 87.7% vs 82.3%, respectively. DFS and OS outcomes were consistent across key subgroups, including by prespecified risk and sarcomatoid features (Table). No new serious treatment-related AEs have been reported for ≥3 years. Conclusions: With ≥5 yrs of follow-up, the benefits observed with adjuvant pembro vs pbo are consistent with prior analyses, including in all subgroups. No new serious treatment-related safety signals occurred. Adjuvant pembro remains a standard-of-care option for patients with ccRCC at increased risk of recurrence. Clinical trial information: NCT03142334 . All pts Prespecified risk subgroups Sarcomatoid features Intermediate-high High M1 NED Present Absent N 994 855 77 57 111 829 DFS events 429 342 49 37 59 339 DFS HR(95% CI) 0.71(0.59−0.86) 0.75 (0.61−0.93) 0.61(0.35−1.08) 0.48(0.25−0.92) 0.56(0.33−0.96) 0.75(0.60−0.92) OS events 167 131 22 13 23 130 OS HR(95% CI) 0.66(0.48−0.90) 0.65(0.46−0.92) 0.86(0.37−1.98) 0.36(0.11−1.18) 0.67(0.29−1.56) 0.64(0.45−0.91)

Adjuvant trastuzumab in combination with chemotherapy has significantly improved survival in patients with HER2-positive early breast cancer but, since introduction in 2005, the 12 months duration has been questioned and trials have tested shorter durations. A systematic review and meta-analysis using individual patient data (IPD) (when available) from non-inferiority trials of reduced duration trastuzumab was carried out according to PRISMA-IPD guidelines. Primary outcome was invasive disease-free survival (IDFS); secondary outcomes were distant relapse-free survival (DRFS) and overall survival (OS). Estimated survival was calculated using random-effects and fixed-effects modelling, reported by 5 year rates and analysed using non-inferiority methods. Illustrative comparative risks were also tabled as in Cochrane Systematic Reviews. Five trials were identified: PERSEPHONE, PHARE and HORG compared 12 months (m) with 6 m; SOLD and Short-HER compared 12 m with 9 weeks. In the 5-trial analysis (11 389 patients), and in the SOLD and Short-HER (3428 patients) analysis, non-inferiority of the shorter duration was not confirmed. In contrast, for the comparison of 12 m versus 6 m (7961 patients), non-inferiority was confirmed with a 2.5% critical margin, for IDFS, DRFS and OS. The Kaplan-Meier curves demonstrated overlap of credibility intervals throughout follow-up. For every 1000 patients given 6 m trastuzumab, by 5 years, there might be 11 extra IDFS events (in addition to 141 expected for 12 m), 12 more DRFS events (in addition to 106) and nine more deaths (in addition to 73). We have demonstrated that 6 m trastuzumab in early HER2-positive breast cancer is not inferior to 12 m and is an option for patients. CRD42020172267.

2002 Background: The 1st and 2 nd interim analyses of the CATNON trial on anaplastic glioma (NCT00626990) showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) in patients with IDH mutant (mt) tumors, but no benefit of concurrent (conc) TMZ regardless of Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status. We now present the final analysis and the exploratory molecular marker analysis of the study. Methods: The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ. Methylation status including MGMT promoter methylation status were assessed with the Infinium MethylationEPIC Beadchip. IDH mutation (mt) status and glioma specific alterations were assessed with a glioma targeted panel using Agilent SureSelect baits. Results: After a median follow-up of 10.9 years and with 499 events observed, in the intent-to-treat population the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.906 (95%CI 0.760, 1.082; p=0.28) and after adjTMZ 0.647 (95%CI 0.541, 0.773; p <0.0001). In 660 patients IDH status could be determined: IDH was mt in 444 tumors and wild type (wt) in 216 tumors. Median OS was 1.7 yrs in patients with IDHwt tumors and 8.5 years in patients with IDHmt tumors. Benefit to TMZ was limited to patients with anaplastic glioma IDHmt of which 199 were still alive (45%). For patients with IDHmt tumors the HR for concTMZ was 0.81 (95% CI 0.63-1.04; p=0.09) and for adjTMZ 0.54 (95% CI 0.42-0.69,p < 0.0001). No benefit was observed of concTMZ in IDHmt glioma patients that also received adjTMZ (HR 0.92 95% CI 0.63-1.36; p=0.69). In patients with IDHmt tumors that had received any TMZ median OS was 10.3 years, the median OS in patients treated with adjTMZ was 12.5 years (95% CI 9.4-15.0; p<0.0001). In exploratory analysis, high-copy number Amplification of PDGFR and CDK4 ; Homozygous deletion of the CDKN2A/B locus, total copy number alterations, methylation subtype (A_IDH vs A_IDH_HG, G-CIMP high versus low, MGMT -promoter methylation as determined by methylation arrays) were all associated with outcome but none was predictive for benefit to TMZ. Conclusions: Despite more follow-up, concTMZ did not improve OS regardless of IDH status. AdjTMZ increased OS in patients with IDHmt tumors but not in patients with IDHwt tumors. Molecular factors of known prognostic significance for IDHmt 1p/19q intact anaplastic glioma did not predict benefit to TMZ. Median OS in patients with IDHmt glioma having received adjTMZ after RT was 12.5 years. Standard of post-operative care in patients with high grade IDHmt astrocytoma should be RT followed by 12 cycles adjTMZ. Funding Source: MSD. Clinical trial information: NCT00626990 .