Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials.

INTRODUCTION: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. METHODS: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. RESULTS: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97(95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. CONCLUSION: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study.

PURPOSE: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. PATIENTS AND METHODS: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. RESULTS: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3-24.2). One DLT of T-VEC-related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0-5.8] and 5.8 months (95% Cl, 2.9-11.4), respectively. CONCLUSIONS: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia.

Minimal (or 'measurable') residual disease in acute lymphoblastic leukemia appears to be a prognostic indicator, with potential value in informing individualized treatment decisions. Complete understanding of the strength of the association between minimal residual disease and long-term outcomes is, however, lacking. A systematic literature review and meta-analysis were performed to elucidate the clinical significance of minimal residual disease with respect to relapse-free survival and overall survival in precursor B-cell acute lymphoblastic leukemia. A total of 23 articles and abstracts, most published between 2012 and 2016, were identified for inclusion in the primary meta-analysis. Typically, patients were in their first complete remission at the time of minimal residual disease assessment; in two studies, all patients were in their second, or later, complete remission. The primary analysis revealed improved relapse-free survival across all studies for patients who achieved minimal residual disease negativity (random effects hazard ratio, 2.34; 95% confidence interval, 1.91-2.86). Improved overall survival for patients who achieved minimal residual disease negativity was also observed (hazard ratio, 2.19; 95% confidence interval, 1.63-2.94). There was no observed difference in the impact of minimal residual disease status in subgroups based on disease stage, minimal residual disease sensitivity threshold level, Philadelphia chromosome status, histological phenotype, risk group, minimal residual disease testing location, minimal residual disease timing after induction, or minimal residual disease detection method. Despite heterogeneity in study design and patient populations between the contributing studies, these data provide a compelling argument for minimal residual disease as a clinical tool for assessing prognosis and guiding treatment decisions in precursor B-cell acute lymphoblastic leukemia.

Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab.

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis.

Improvements in hip trabecular, subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab.

In the FREEDOM study, denosumab treatment (60 mg every 6 months) decreased bone resorption, increased bone mineral density (BMD), and reduced new vertebral, nonvertebral, and hip fractures over 36 months in postmenopausal women with osteoporosis. In a subset of these women, hip quantitative computed tomography (QCT) was performed at baseline and months 12, 24, and 36. These scans were analyzed using Medical Image Analysis Framework (MIAF) software, which allowed assessment of total hip integral, trabecular, subcortical, and cortical compartments; the cortical compartment was further divided into 2 areas of interest (outer and inner cortex). This substudy reports changes in BMD and bone mineral content (BMC) from baseline and compared placebo with denosumab over 36 months of treatment (placebo N=26; denosumab N=36). Denosumab treatment resulted in significant improvements in total hip integral volumetric BMD (vBMD) and BMC from baseline at each time point. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively (both p<0.0001). These gains were accounted for by significant increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo group, total hip integral vBMD and BMC decreased at month 36 from baseline by -1.5% and -2.6%, respectively (both p<0.05). The differences between denosumab and placebo were also significant at months 12, 24, and 36 for integral, trabecular, subcortical, and cortical vBMD and BMC (all p<0.05 to <0.0001). While the largest percentage differences occurred in trabecular vBMD and BMC, the largest absolute differences occurred in cortical vBMD and BMC. In summary, denosumab significantly improved both vBMD and BMC from baseline and placebo, assessed by QCT MIAF, in the integral, trabecular, subcortical, and cortical hip compartments, all of which are relevant to bone strength.