Ono Pharmaceutical (Japan)

Magrolimab (ONO-7913) is an anti-cluster of differentiation 47 (CD47) monoclonal antibody. This was a phase 1, open-label, uncontrolled, dose-escalation study that assessed the tolerability and safety of intravenous magrolimab (priming dose: 1 mg/kg; maintenance dose: 20 mg/kg [Cohort 1] or 30 mg/kg [Cohort 2]; 28-day treatment cycle) in Japanese adult patients with histologically or cytologically confirmed advanced or metastatic solid tumors, ≥ 1 measurable lesion, an Eastern Cooperative Oncology Group performance score of 0–1, and an expected survival ≥ 3 months. Seven patients were enrolled and received magrolimab (Cohort 1, n = 4; Cohort 2, n = 3) with the median follow-up of 170.0 (34–491) days. All 7 patients discontinued the magrolimab monotherapy, and 4 (57.1%) patients completed the study as per the protocol. No dose-limiting toxicities were observed in both cohorts, and the maximum tolerated dose was not reached. All patients experienced treatment-emergent adverse events (TEAEs) but not any serious adverse events, TEAEs leading to treatment discontinuation or interruption, or TEAE-related deaths. No complete or partial responses occurred, while the disease control rate was 42.9% (best overall response: stable disease, n = 3; disease progression, n = 3; not evaluable, n = 1). Magrolimab was well tolerated in Japanese patients with advanced or metastatic solid tumors. Trial registration: NCT04403308, submitted on May 21, 2020.

BackgroundA Japanese phase 2 trial of encorafenib plus binimetinib met the primary endpoint of the centrally assessed objective response rate in patients with unresectable BRAF V600E-mutated thyroid cancer. Consequently, encorafenib plus binimetinib has been approved in Japan. We present the health-related quality of life (HR-QoL) outcomes from the trial.MethodsThe multicenter, open-label, uncontrolled phase 2 trial enrolled patients with unresectable locally advanced or metastatic BRAF V600E-mutated thyroid cancer. HR-QoL score, one of the secondary endpoints, was assessed using the EORTC QLQ-C30 and QLQ-THY34 at baseline and during follow-up. The minimal important change (MIC) threshold was set at 10 points.ResultsWe enrolled 22 patients with BRAF V600E-mutated thyroid cancer. The median follow-up was 11.5 months. Completion rates for the questionnaires were 100% (22 of 22 patients) at baseline and 68% (15 of 22) at week 20. Until week 20, changes from baseline were below MIC at most time points in 29 of all 32 domains in QLQ-C30 and QLQ-THY34. In the other 3 domains, patients showed tendencies toward improvement (social support and appetite loss) or deterioration (joint pain) for consecutive time points. Patients with anaplastic thyroid cancer showed tendencies toward improvement for swallowing, restlessness, body image, and discomfort in the head and neck, from the first assessment after the initial treatment.ConclusionThe combination therapy of encorafenib plus binimetinib for unresectable BRAF V600E-mutated thyroid cancer was associated with generally maintained HR-QoL. Considering the efficacy and safety data from the trial, the regimen may provide clinical benefits while maintaining HR-QoL.

ABSTRACTBackgroundThis post-marketing surveillance evaluated the safety and effectiveness of tirabrutinib in patients with relapsed/refractory primary central nervous system lymphoma (r/r PCNSL) in a real-world setting in Japan.MethodsAll patients with r/r PCNSL who started treatment with tirabrutinib between May 20 and 31 October 2020, were registered. Adverse drug reactions (ADRs) and effectiveness were assessed over 52-weeks from the start of tirabrutinib treatment.ResultsOf the 189 patients assessed for safety, 52.4% were male, the median age was 70.0 years (range 30–88), and 49.2% of patients had a Karnofsky performance status score of ≤60. ADRs of any grade and grade ≥3 were observed in 55.6% and 24.3% of patients, respectively. The most common ADRs were rash (11.6%), neutrophil (10.1%) and platelet (5.3%) count decreased. Most of the ADRs corresponding to infections, clinically significant skin disorders, myelosuppression, hypersensitivity, interstitial lung diseases, hepatic function disorders, and hemorrhages resolved or were in the process of resolving. Among the 121 patients assessed for effectiveness, the overall response rate evaluated by the treating physicians was 61.2%, and the 365-day survival rate was 69.8%.ConclusionThis surveillance confirmed the tolerability and effectiveness of tirabrutinib in patients with r/r PCNSL in the real-world setting.Clinical trial registrationJapan Registry of Clinical Trials: jRCT2011210002.

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive matrix deposition and vascular dysfunction. Vascular abnormalities, including aberrant angiogenesis and vascular leak have been shown to accompany IPF progression. Recent findings from our group and others have revealed a marked heterogeneity within the lung vasculature, yet the specific contribution of distinct endothelial cell (EC) subpopulations to IPF pathogenesis remains unclear. We reported the expansion of venous ECs (VECs) expressing atypical chemokine receptor 1 (ACKR1) in mouse lungs with progressive fibrosis and in human IPF lungs. Here, we sought to investigate the role of ACKR1+VEC remodeling following lung injury and explore ACKR1-associated signaling pathways in lung fibrosis pathogenesis. Methods: We analyzed scRNA-seq datasets from bleomycin-treated mouse lungs and human IPF lungs. Additionally, we carried out spatial transcriptomic analysis on human IPF lungs exhibiting different degree of fibrosis. Immunohistochemistry was performed to validate gene expression at the protein level. ACKR1+VECs were isolated using MACS and characterized by qPCR and Western blot. Finally, co-cultures of ACKR1+VECs with lung fibroblasts were carried out to assess the paracrine effect of ACKR1+VECs. Results: scRNA-seq analysis showed that ACKR1 was selectively expressed in an expanding population of VECs in bleomycin-treated and human IPF lungs. Transcriptional analysis revealed that ACKR1+VECs expressed high levels of genes associated with glycolysis, hypoxia, and immune cell recruitment. Spatial transcriptomics coupled with immunohistochemistry analysis of IPF lungs demonstrated that ACKR1+VECs were surrounded by CD45+ immune cells, suggesting a role of these VECs in immune cell recruitment. ACKR1+VECs were primarily located around airways as well as in distal alveolar regions exhibiting fibroblastic foci and aberrant basaloid cell accumulation, indicating cross communications between these pathogenic cells. In vitro analysis of freshly isolated IPF-derived ACKR1+VECs showed elevated expression of pro-fibrotic genes compared to ACKR1 negative (ACKR1-) ECs. Strikingly, co-culture of ACKR1+VECs with lung fibroblasts resulted in a strong upregulation of profibrotic genes and enhanced contractility relative to ACKR1-ECs. Conclusion: ACKR1+VECs are spatially restricted to lung areas exhibiting immune cell aggregation, fibroblastic foci, and aberrant basaloid cells in fibrotic lungs supporting their profibrotic function. IPF-derived ACKR1+VECs promote fibroblast activation in vitro, suggesting that ACKR1+VEC expansion contributes to fibrosis progression through paracrine signaling-mediated fibroblast activation. Taken together, our data offer a distinctive picture of the VEC dynamics associated with pulmonary fibrosis and suggest that aberrant expansion of ACKR1+VECs in IPF lungs may play a critical role in lung fibroblast activation and fibrosis progression.

This study was designed to assess the quantitative performance of endogenous drug–drug interaction (DDI) biomarkers (N1‐methylnicotinamide (1‐NMN), N1‐methyladenosine (m1A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CLr) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CLr ratio (CLrR) of 1‐NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CLrR of m1A was less than that of 1‐NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CLr of creatinine was significantly decreased only by cimetidine 800 mg. Individual CLrR of 1‐NMN and m1A showed a positive correlation with the corresponding CLrR of metformin with r2 of 0.58 and 0.55, respectively. When evaluated individually, m1A showed a better correlation during cimetidine periods (r2 0.64) than 1‐NMN (r2 0.36), but vice versa during dolutegravir periods (r2 1‐NMN, 0.80; m1A, 0.32). These results suggest that 1‐NMN and m1A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CLrR change.

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

BackgroundThis study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease.MethodsThis retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy).ResultsIn the adjuvant cohort (n = 17,062), the most common regimen during October 2008–May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019–March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence.ConclusionsThis study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations.

ObjectiveAs first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited.MethodsLIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information.ResultsWe analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0–9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3–4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3–4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2–7.6) and 5.8 (4.3–7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively.ConclusionsLIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

BackgroundNivolumab with modified FOLFIRINOX (mFOLFIRINOX) may have additive antitumour effects while minimising chemotherapy cytotoxicity. We assessed the efficacy and safety of nivolumab+mFOLFIRINOX in metastatic pancreatic cancer.MethodsThirty-one treatment-naïve patients aged ≥20 years with metastatic unresectable/recurrent pancreatic cancer (≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1) and Eastern Cooperative Oncology Group 0/1 score and life expectancy ≥90 days received nivolumab (480 mg, every 4 weeks) plus mFOLFIRINOX. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety.ResultsAt the median follow-up of 13.4 months, the ORR was 32.3% (complete response 0%; partial response 32.3%) and the median duration of response was 7.4 (range: 3.5–21.9) months; the primary endpoint was not met. Median OS and PFS were 13.4 (95% confidence interval [CI]: 10.6–16.6) months and 7.4 (95% CI: 3.9–9.2) months, respectively. The 1-year survival rate was 54.8% (95% CI: 36.0%–70.3%). Drug-related serious adverse events were reported in 29.0% of the patients; 3.2% drug-related adverse events led to discontinuation, and none led to death within 30-day safety window.ConclusionNivolumab+mFOLFIRINOX was tolerable in patients with metastatic pancreatic cancer. ORR and survival were comparable to previously reported data. (JapicCTI-184230)