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Background: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. Methods: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1–4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0–1 (or equivalent for adolescents aged 12–17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Findings: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) pa

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatm

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to Fc 3R on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Methods Patients (aged >=18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab

Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcgammaR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (>12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for >12 mo. In these 63 pts, median age was 64 yr and 70% had received >=1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (>=1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for >12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in >=15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade >=3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for >12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status

Background: Tislelizumab, a humanized IgG4 monoclonal Ab with high affinity and specificity forPD-1, was engineered to minimize binding to FcgammaRonmacrophages, thus abrogating antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports fromthis first-in-human study (NCT02407990), and other early phase studies, suggested tislelizumab was generally well tolerated and had antitumor activity in pts with advanced solid tumors.Here we report the effects of tislelizumab in a subset of pts enrolled in phase 1A/1B. Method(s): Eligible patients with advanced esophageal [EC], gastric [GC], hepatocellular [HCC], and non-small cell lung [NSCLC] cancers were treated with tislelizumab 2 or 5 mg/kg every 2 wks or 3 wks (Q3W); 97% received 5mg/kg Q3W. Adverse events (AEs) were assessed per NCI-CTCAE 4.03 criteria and tumor assessments performed every 9 wks using RECIST v1.1. Result(s): Of the 207 pts (EC=54; GC=54; HCC=50; NSCLC=49), 114 were male 111 were Asian, 78 were Caucasian and all but one received>=1 prior anticancer therapy. Treatment-related AEs (TRAEs) occurring in >=5% of pts were fatigue (8.7%) decreased appetite (6.8%), rash (6.8%), hypothyroidism(6.3%), and nausea (6.3%). Grade >=3 TRAEs occurring in >=2 pts were pneumonitis (n=3), elevated AST (n=3) and elevated ALT (n=2). Grade 5 TRAEs occurred in two pts: pneumonitis in a pt with NSCLC with compromised pulmonary function and acute hepatitis in a pt with HCC with rapidly progressing disease. As of 27 Apr 2018, a total of 23 pts remained on study treatment; median duration of study follow-up ranged from 4.9-9.9 mo. Responses in each tumor type are presented in the table. (Table Presented) Conclusion(s): Tislelizumab was generally well tolerated and antitumor activity was observed in each tumor type. Tislelizumab, as monotherapy and in combination, is being evaluated in multiple phase 2 and phase 3 studies.

BACKGROUND: Hepatitis B virus (HBV) quasispecies are crucial in the pathogenesis of chronic liver disease. Next-generation sequencing (NGS) is powerful for identifying viral quasispecies. To improve mapping quality and single nucleotide variant (SNV) calling accuracy in the NGS analysis of HBV, we compared different mapping references, including the sample-specific reference sequence, same genotype sequences and different genotype sequences, according to the sample. METHODS: Real Illumina HBV datasets from 86 patients, and simulated datasets from 158 HBV strains in the GenBank database, were used to assess mapping quality. SNV calling accuracy was evaluated using different mapping references to align Real Illumina datasets from a single HBV clone. RESULTS: Using the sample-specific reference sequence as a mapping reference produced the largest number of mappable reads and coverages. With a different genotype mapping reference, the consensus sequence derived from the Real Illumina datasets of the single HBV clone showed 21 false SNV callings in polymerase and surface genes, the regions most divergent between the mapping reference and this HBV clone. A ~6 % coverage of most of these false SNVs was yielded even with a same genotype mapping reference, but none with the sample-specific reference sequence. CONCLUSIONS: Using sample-specific reference sequences as a mapping reference in NGS analysis optimized mapping quality and the SNV calling accuracy for HBV quasispecies.