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INTRODUCTION: It is becoming clear that eosinophilic esophagitis (EoE) activity cannot be measured by eosinophils alone, and that a more complete assessment is needed. The EoE Histology Scoring System (EoE HSS) measures the severity (grade) and extent (stage) of 8 histopathologic features in EoE: eosinophilic inflammation (EI); basal zone hyperplasia (BZH); eosinophilic abscess (EA); eosinophilic surface layering (SL); dilated intercellular spaces (DIS); surface epithelial alteration (SEA); dyskeratotic epithelial cells (DEC); and lamina propria fibrosis (LPF). We aimed to assess EoE histology at baseline using the EoE HSS, and to compare correlations between this and endoscopic and symptom outcomes. METHODS: This study analyzed baseline data from a 12-week, phase 2, randomized, placebo-controlled trial of budesonide oral suspension in patients with EoE (MPI 101-06; NCT01642212). Patients were eligible for inclusion if they were aged 11–40 years and had EoE with dysphagia. Esophageal biopsies from patients were examined, and mean EoE HSS total score ratios and mean individual feature scores were calculated at baseline for all patients (irrespective of treatment allocation). A correlation analysis was then performed to compare these scores with Dysphagia Symptom Questionnaire (DSQ) scores and those from the EoE Endoscopic Reference Score (EREFS) system at baseline. RESULTS: In total, 87 patients were included for analysis. At baseline, mean (standard deviation) EoE HSS grade and stage total score ratios for all patients were 0.5 (0.2) and 0.4 (0.1), respectively. For individual EoE HSS features, a summary of mean grade and stage scores at baseline is shown in Table 1; the most severe features for grade and stage were EI, BZH, DIS and LPF. At baseline, mean EoE HSS grade and stage total score ratios did not correlate with mean DSQ score, but did correlate significantly with mean EREFS score (grade: R = 0.3166; P = 0.0028; stage: R = 0.3344; P = 0.0015; Table 2). Similarly, mean scores for individual EoE HSS features did not correlate with mean DSQ score at baseline, but did correlate with mean EREFS score for 4 and 3 of the 8 features for grade and stage scores, respectively (Table 2). CONCLUSION: The most severe EoE HSS features at baseline for grade and stage were EI, BZH, DIS and LPF. At baseline, there were significant correlations between the EoE HSS and endoscopic severity, but not dysphagia. This suggests that the EoE HSS could become an essential and independent tool to measure EoE activity.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. METHODS: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed. RESULTS: A total of 322 patients were randomized (BOS, n = 215; placebo, n = 107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n = 213; placebo, n = 105) (Table 1). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, P < 0.001; 52.6% vs 39.1%, P = 0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n = 197) than the placebo group (n = 89) (−13.0 vs −9.1; P = 0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n = 202) than placebo (n = 93) (−4.0 vs −2.2; P < 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo. No life-threatening TEAEs were reported. CONCLUSION: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

Budesonide oral suspension (BOS) is a novel topical corticosteroid, which has been shown to improve symptoms and endoscopic appearance, and reduce peak eosinophil counts in patients with eosinophilic esophagitis (EoE). This trial evaluated the effect of BOS or placebo on the severity (grade) and extent (stage) of 8 histopathologic features observed in EoE, using the validated eosinophilic esophagitis histologic scoring system (EoE HSS). Patients with EoE aged 11 to 40 years with dysphagia were randomized to receive either BOS (2.0 mg twice daily) or placebo for 12 weeks. Mean (SD) EoE HSS grade and stage total scores at baseline for placebo and BOS groups were: grade, 0.42 (0.16) and 0.49 (0.14), respectively; stage: 0.38 (0.14) and 0.46 (0.11), respectively. These scores significantly decreased (improved) from baseline for patients receiving BOS versus placebo (grade: least squares mean change [SE]: placebo vs. BOS, −0.04 [0.03] vs. −0.24 [0.02]; P<0.0001; stage: −0.01 [0.02] vs. −0.19 [0.02]; P<0.0001). EoE HSS total scores improved for 6 of the 8 and 5 of the 8 histopathologic features for grade and stage, respectively, versus placebo. Change in EoE HSS total scores correlated moderately but significantly with change in endoscopic severity (endoscopic reference score; grade: R=0.5349; stage: R=0.5416; both P<0.0001). Change in EoE HSS stage total score correlated weakly with change in Dysphagia Symptom Questionnaire scores (grade: R=0.1925; P=0.0740; stage: R=0.2135; P=0.0471). These data demonstrate that the EoE HSS is a valuable endpoint of treatment response in randomized clinical trials and should be considered for future trials for EoE.

Abstract Context Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. Objective To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. Design Open-label extension study; 5-year interim analysis. Setting 12 US centers. Patients Adults (N = 49) with chronic hypoparathyroidism. Intervention(s) rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. Main Outcome Measure(s) Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. Results Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. Conclusion Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

NAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) at 6 and 12 months. Analyses were derived from all patients in NAPOLI-1 randomized to receive nal-IRI+5-FU/LV, nal-IRI monotherapy, or 5-FU/LV combination therapy. OS was associated with baseline factors using univariate and multivariable Cox analyses. A predictive nomogram was derived and validated using a concordance index and calibration plots. The univariate analyses identified 21 independent factors that contributed to OS, with eight factors significantly associated with OS. The Karnofsky Performance Score contributed the largest number of points (100), followed by presence of liver metastasis (98) and randomization to nal-IRI+5-FU/LV (96). The other baseline factors showing effects were albumin (g/dL), neutrophil/lymphocyte ratio, carbohydrate antigen 19-9 (U/mL), disease stage at diagnosis, and body mass index (kg/m2). The nomogram was used to predict the 6- and 12-month survival probability. The mean absolute errors between the observed and predicted probabilities for OS at 3, 6, and 9 months were 0.07, 0.08, and 0.07, respectively. This nomogram, based on NAPOLI-1, provides additional insight to aid decision-making for patients with mPDAC after previous gemcitabine-based therapy.

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

Background:Maintenance therapy (MT) in NDMM has been increasingly used to prolong duration of response achieved by ASCT. TOURMALINE‐MM3 is a phase 3, double‐blind, placebo‐controlled study, where ixazomib improved PFS, and is the first study to evaluate the impact of MT on HRQoL post ASCT in NDMM (Dimopoulos et al., Lancet 2019;393:253). HRQoL is an important consideration during MT in NDMM patients with minimal disease burden post ASCT (Anderson et al., Leukemia 2008;22:231).Aims:To assess HRQoL in patients randomized to ixazomib vs. placebo MT in TOURMALINE‐MM3.Methods:In TOURMALINE‐MM3, NDMM patients post ASCT were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo. HRQoL was assessed by EORTC QLQ‐C30 (overall/subscale score range, 1–100) at screening, the start of every cycle (1–26), end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. MM‐specific symptoms were assessed by EORTC QLQ‐MY20 (subscale score range, 1–100) at screening, the start of every 3 cycles between cycles 1–25, end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. For both instruments, higher scores for global and functional domains indicate better HRQoL, while higher scores on symptom scales represent higher levels of symptomatology. Change from study entry in subscale scores, defined in terms of 30 four‐week intervals, was analyzed using a linear mixed‐effects model among patients who reported HRQoL outcomes at study entry and completed at least one post‐study entry assessment.Results:Characteristics at study entry were well balanced between ixazomib (n = 386) and placebo (n = 251) arms; median age: 58 years; ECOG performance status 0–1: 97%; 79% had at least a very good partial response post ASCT at study entry. At study entry, least squares (LS) mean scores for ixazomib vs. placebo on the EORTC QLQ‐C30 were: Global Health Status/QoL, 69.8 vs. 69.1; Physical Functioning, 82.1 vs. 82.0; Pain, 25.3 vs. 25.7; Nausea/Vomiting, 2.3 vs. 2.0; Diarrhea, 5.9 vs. 6.0; and on the EORTC QLQ‐MY20 were: Disease Symptoms, 20.3 vs. 19.2; Peripheral Neuropathy, 25.0 vs. 25.6. Compliance with study assessments, averaged across cycles, was high in the treatment phase (≥94%) and similar between treatment groups.Changes in subscale scores across the 4‐week intervals were generally similar between the ixazomib and placebo groups, with treatment differences not reaching the established minimal important difference (MID) of 10 in MM (Kvam et al., Eur J Haematol 2011;87:330). LS mean (95% CI) score changes at interval 24 (week 96) for ixazomib vs. placebo on the EORTC QLQ‐C30 included: Global Health Status/QoL, –0.4 (–3.4, 2.7) vs. 1.8 (–1.7, 5.2); Physical Functioning, 0.7 (–1.8, 3.1) vs. 3.0 (0.3, 5.8); Pain, 4.1 (0.5, 7.7) vs. –1.4 (–5.5, 2.7); and on the EORTC QLQ‐MY20 were: Disease Symptoms, 5.1 (2.4, 7.9) vs. 0.8 (–2.3, 3.8); Peripheral Neuropathy, –0.7 (–5.1, 3.7) vs. –6.2 (–11.1, –1.3). EORTC QLQ‐C30 Nausea/Vomiting and Diarrhea subscales, while consistently worse for ixazomib than placebo (LS mean [95% CI] change at interval 24, 5.0 [3.0, 7.0] vs. 1.0 [–1.3, 3.3] and 4.0 [1.1, 6.8] vs. 0.5 [–2.8, 3.8], respectively), were in line with the ixazomib toxicity profile; treatment differences did not exceed the MID.Summary/Conclusion:In addition to improvements in PFS with ixazomib, HRQoL was maintained during the protocol‐defined treatment period in both arms, and active treatment with ixazomib did not have an adverse impact on HRQoL.

Background:Deepened response has been associated with prolonged progression‐free (PFS) and overall survival in multiple myeloma, including in the maintenance therapy setting. In the Myeloma XI trial, post‐ASCT maintenance with lenalidomide vs observation resulted in improved responses in 15.8% vs 11.0% of patients (pts) and a median PFS of 56.9 vs 30.1 months (Jackson et al, ASH 2017). In the phase 3, double‐blind, placebo‐controlled TOURMALINE‐MM3 study (NCT02181413), post‐ASCT maintenance therapy with the oral proteasome inhibitor (PI) ixazomib vs placebo resulted in a 39% improvement in PFS (median 26.5 vs 21.3 months; HR 0.72; 95% CI: 0.58–0.89; p = 0.002), with a favorable safety profile (Dimopoulos et al, Lancet 2019). We report improvements in depth of response and the impact on outcomes in TOURMALINE‐MM3.Aims:To evaluate the rates and timing of response improvement during ixazomib vs placebo maintenance and the impact on PFS in TOURMALINE‐MM3.Methods:Pts who had achieved ≥partial response (PR) to induction therapy with a PI and/or immunomodulatory drug followed by single ASCT were randomized 3:2 to receive ixazomib (N = 395) or placebo (N = 261) on day 1, 8, and 15 of 28‐d cycles for up to 2 years or until progressive disease or unacceptable toxicity. Randomization was stratified by induction regimen, pre‐induction ISS stage, and post‐ASCT response (complete response [CR] or very good PR [VGPR] vs PR). Ixazomib dose was 3 mg in cycles 1–4 and 4 mg from cycle 5 if tolerated in cycles 1–4. Minimal residual disease (MRD) was assessed at screening by flow cytometry (10–5 sensitivity). The primary endpoint was PFS per independent review committee (IRC). Other endpoints included rate of response improvement in pts enrolled in VGPR or PR.Results:At study entry, 60 (15%), 213 (54%), and 89 (23%) pts in the ixazomib arm and 54 (21%), 152 (58%), and 35 (13%) in the placebo arm had CR, VGPR, and PR, respectively, by IRC. Deepening responses were seen in 139/302 (46%) ixazomib vs 60/187 (32%) placebo pts with VGPR/PR at enrollment (relative risk [RR] 1.41, 95% CI 1.1–1.8, p = 0.004), including 92/213 (43%) vs 48/152 (32%) VGPR to CR (RR 1.37, p = 0.025) and 47/89 (53%) vs 12/35 (34%) PR to VGPR/CR (RR 1.54, p = 0.063). On Kaplan‐Meier analysis of time to best deepened response in VGPR/PR pts (Figure), 24‐month rates of deepening response were 54.2% vs 41.4%, and there was a 38.4% improvement in the chance of deepening response over time with ixazomib vs placebo (HR 1.384, p = 0.034). A pooled analysis across arms among pts enrolled in VGPR/PR showed that deepening response vs no improvement was associated with prolonged PFS (median not reached vs 15.9 months; HR 0.245, 95% CI 0.184–0.325, p < 0.0001). Analysis by treatment arm showed that, in VGPR/PR pts with deepening response, 24‐month PFS rates were 77.4% vs 68.3% with ixazomib vs placebo (medians not reached; HR 0.875; 12.5% risk reduction; 95% CI 0.52–1.47; p = 0.615); in VGPR/PR pts without deepening response 24‐month PFS rates were 33.4% vs 23.6% (median 17.9 vs 14.1 months; HR 0.780; 22% risk reduction; 95% CI 0.59–1.03; p = 0.080). Baseline MRD status was a strong predictor of deepening response; deepening responses were seen in 63% (78/124) vs 32% (94/293) of MRD‐ vs MRD+ pts enrolled in VGPR/PR.Summary/Conclusion:Post‐ASCT maintenance with ixazomib resulted in a significantly higher rate of deepening response vs placebo; deepening response was associated with prolonged PFS. Ixazomib resulted in non‐significant PFS benefit vs placebo in VGPR/PR pts with and without deepening response; prolonged follow‐up would be needed to confirm these results.image