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Purpose: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.Experimental Design: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2–negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).Results: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway–amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway–amplified breast cancer.Conclusion: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification. Clin Cancer Res; 19(13); 3693–702. ©2013 AACR.

PDF file - 20K, Dovitinib effectively targets FGFR1 in vivo. FGF23 levels were measured from plasma taken at baseline and during dovitinib treatment in 18, 33, and 20 patients from the FGFR1+/HR+, FGFR1-/HR+, and FGFR1-/HR- patient groups, respectively. Error bars represent the 95% confidence intervals.

Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

PDF file - 49K, Supplemental Table 1. Criteria for defining dose-limiting criteria

PDF file - 57KB, Supplemental Figure 1 contains the longitudinal plot of model-adjusted fold change from baseline for plasma VEGF.

Supplementary Figure from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

PDF file - 61K, Growth Inhibition in FGFR1- and FGFR2-Amplified Cell Lines.

Purpose: Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC).Experimental Design: Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor.Results: Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%).Conclusion: Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012–22. ©2014 AACR.

PDF file - 20KB

PDF file - 22KB, Supplemental Table 1 contains the pharmacokinetic results from the study.

Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.Experimental Design: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients. Clin Cancer Res; 19(5); 1257–68. ©2012 AACR.

PDF file - 25KB, Supplemental Table 2 contains a summary of the newly occurring qualitative ECG abnormalities.

Purpose:Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non–small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges.Patients and Methods:Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.Results:Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6–52.0), 30.0% (16.6–46.5), 50.0% (21.1–78.9), and 59.1% (43.2–73.7); whole-body DCR (95% CI): 66.7% (50.5–80.4), 82.5% (67.2–92.7), 66.7% (34.9–90.1), and 70.5% (54.8–83.2); intracranial ORRs (95% CI): 39.3% (21.5–59.4), 27.6% (12.7–47.2), 28.6% (3.7–71.0), and 51.5% (33.5–69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6–41.4) and DCR was 66.7% (95% CI, 41.0–86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier.Conclusions:Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease.See related commentary by Murciano-Goroff et al., p. 2477

Background: Surufatinib (S, a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) showed encouraging antitumor activity in solid tumors (Cao YS, 2022). Programmed death ligand 1 (PD-L1) expression is the established biomarker for 1L immune checkpoint inhibitors therapy in advanced NSCLC. We conducted an open-label, multi-cohort, single-arm phase 2 study to evaluate the safety and efficacy of S+T in patients (pts) with advanced solid tumors. Here, we reported the results of advanced NSCLC with PD-L1 positive expression cohort. Methods: Eligible pts had histologically confirmed advanced NSCLC with no prior systemic chemotherapy, PD-L1 positive (defined as PD-L1 TPS expression ≥1% [sp263]), and without EGFR, ALK or ROS1 genetic alteration if non-sq-NSCLC. Enrolled pts received 21-day cycles of S (250 mg orally QD) plus T (240 mg IV, Q3W) until disease progression or intolerable toxicity or the maximum duration of treatment with toripalimab is 24 months. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From July 2020 to September 2021, 55 pts were screened, of whom 23 pts were enrolled and received the treatment of S+T. Median age was 66 years (range: 49-73), 16 (69.6%) were male and 12 (52.2%) had squamous histology. Pts with PD-L1 TPS ≥50% and Conclusion: Surufatinib and toripalimab combination showed a promising antitumor activity in 1L therapy for advanced PD-L1 positive NSCLC with manageable toxicity. This study might represent a potential treatment option for these pts. Clinical trial information: NCT04169672. Citation Format: Ying Cheng, Lin Shen, Zhendong Chen, Feng Ye, Xianjun Yu, Xing Zhang, Dongmei Ji, Baorui Liu, Lijie Song, Chunjiao Wu, Ming Lu, Wei Chen, Jingxun Wu, Heli Gao, Desheng Weng, Weina Shen, Rutian Li, Minjie Yang, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Songhua Fan, Michael Shi, Weiguo Su. Surufatinib plus toripalimab for first-line treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 positive expression: A multicenter, single-arm phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT225.

Introduction: Bruton’s tyrosine kinase (BTK), a member of the Tec family, plays a crucial role in signaling through B-cell receptor (BCR). BTK inhibition blocks BCR signals and prevents B-cell activation and growth. First-generation BTK inhibitors such as ibrutinib covalently binds to a cysteine residue (C481) of BTK. Their most frequent acquired resistance is the development of a serine mutation in the binding site (C481S). Next generation BTK inhibitors such as LOXO-305 and ARQ 531 are being developed to overcome this resistance to first-generation inhibitors. Methods: HMPL-760 was tested in biochemical assays using recombinant human wild type (WT) and C481S mutant BTKs. Its selectivity was carried out using Eurofins Cerep KinaseProfilerTM panel. Cellular activity of HMPL-760 was evaluated in HEK293 cells stably transfected with BTKWT or BTKC481S, and other tumor cell lines, which are either human diffuse large B cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) cell lines. The in vivo antitumor activity and PKPD correlation of HMPL-760 was studied in HBL-1 xenograft mouse models bearing BTKWT or BTKC481S respectively. Results: In biochemical assays, HMPL-760 strongly inhibits BTK kinase activities towards wild-type BTK (BTKWT) and C481S mutant (BTKC481S), and binds to BTK in a reversible way. HMPL-760 demonstrates high selectivity in a panel containing 413 kinases. In cellular assays, HMPL-760 displays strong anti-proliferative activities in B-cell lymphoma cells (TMD-8, OCI-LY10, REC-1, HBL-1 and HBL-1-BTKC481S) harboring either BTKWT or BTKC481S (GI50: 0.0015-0.046 μM). In human whole blood assay, HMPL-760 inhibits activation of B-cells at nanomolar concentrations measured by inhibition of immunoglobulin-induced CD69 expression in CD19+cells. HMPL-760 shows ≥ 10-fold inhibitory potency than ARQ 531 in both BTKWT and BTKC481S cells, and ~3-fold higher inhibitory potency than that of LOXO-305 in BTKC481S cells. In cellular assay by detecting p-BTK after compound washout, HMPL-760 maintains a longer duration of target inhibition than LOXO-305 in both BTK wild type (HBL-1) and BTK mutant (HBL-1-BTKC481S) cell lines. HMPL-760 displays dose-dependent antitumor efficacy in multiple human B cell lymphoma xenograft models in mice when orally administered at 3~50 mg/kg once daily. Complete tumor regression occurs in most of the tested models at the high dose levels. HMPL-760 shows much stronger antitumor efficacy than LOXO-305 and ARQ 531 at similar dose level, which may be associated with HMPL-760’s higher drug exposures and more sustainable inhibition on BTK phosphorylation in the tumor tissues. Conclusion: HMPL-760 is a reversible, selective, highly potent, BTK inhibitor targeting both BTKWT and BTKC481S. The first-in-human Phase 1 clinical trials of HMPL-760 are under way in patients with r/r B-NHL (NCT05190068, NCT05176691). Citation Format: Linfang Wang, Junqing Liang, Zhihu Gao, Jia Hu, Weigang He, Xianwen Yang, Fangfang Mao, Wei Zhang, Ying Yu, Qihang Zhang, Na Yang, Chun Zhang, Jian Wang, Yu Cai, Xiong Li, Weiguo Qing, Guangxiu Dai, Yongxin Ren, Michael Shi, Weiguo Su. HMPL-760 is a highly potent and selective reversible BTK inhibitor, targeting BTK and BTKC481S in B-cell malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4020.

A descriptive retrospective study was conducted using the Flatiron Health-Foundation Medicine Inc. (FMI) clinico-genomic database. Patients withOf 91The median time from biopsy to test results appears 1 week shorter for PD-L1 than for FMI NGS. Chemotherapy and IO monotherapy were the most common regimens utilized but with limited PFS.

Summary X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model., Highlights • hiPSC-derived retinal organoid model recapitulates key features of XLRS • CRISPR/Cas9 correction normalizes RS1 secretion and retinal development • Transcriptome analysis links XLRS to other hereditary retinopathies, Chiou, Schlaeger, and colleagues use hiPSC-derived retinal organoids to model X-linked juvenile retinoschisis. They show that patient hiPSC-derived retinal organoids replicate key pathologies observed in patients, including retinal splitting and photoreceptor deficit. The observed abnormalities were normalized in organoids derived from isogenic CRISPR/Cas9 gene-corrected hiPSCs. This validated XLRS in vitro model could be used to test and optimize therapeutic approaches.