Auswahl der wissenschaftlichen Literatur zum Thema „Innocare“

Orelabrutinib (ICP-022) is a novel and highly selective irreversible BTK inhibitor. We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and demonstrated excellent safety and efficacy profiles at median follow-up of 8.7 months in a Phase I/II trial of refractory/relapsed (r/r) CLL/SLL (Chronic Lymphocytic Leukemia/Small Cell Leukemia). Here we present an updated analysis of efficacy and safety results from the clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL following extended treatment. This is an open-label, multicenter, phase II study with objectives to evaluate its safety and efficacy following an oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for partial remission (PR) with lymphocytosis (PR-L) (Hallek 2012) or the Lugano Classification (Cheson, 2014) for CLL and SLL, respectively. Results: A total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. Eligible patients had relapsed after or were refractory to ≥1 prior treatment with median age of 60.0 (range, 36.0-78.0 years). There are 70% of patients for Rai stage 3-4 disease, 22.5% for 17p13.1 deletion [del(17p)] and/or TP53 mutation, 41.3% for unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% for 11q22.3 deletion [del(11q)]. The median follow-up time was 14.3 months (range, 0.2-21.6 months), and the last patient completed a minimum of 12 cycles of orelabrutinib treatment. Efficacy: The efficacy results presented here were evaluated by IRC (Independent review committee). Following a minimum of 12 cycles treatment, the ORR (PR-L or above) was 91.3% (95% confidence interval [CI]: 82.80 ~ 96.41%) with 10.0% of patients having complete response (CR), 63.8% PR and 17.5% PR-L. Median time for achieving first response was 1.87 months (range, 1.84 - 1.94 months). The median DOR and PFS were not reached. The estimated 12-month DOR was 77.1% (95% CI: 62.50-86.60%), PFS 81.1% (95% CI: 70.53 - 88.13%) and OS 86.3% (95% CI: 76.55 - 92.14%). Patients with Del(17p) and/or TP53 mutation achieved 100% ORR. The ORR is 94.7% for Del(11q)) and 93.9% for unmutated IGHV. Comparing to the first analysis results of which the median follow-up was 8.7 months, the CR rate had increased from 3.8% to 10.0%, and 8 patients with PR-L had converted to a deeper response. So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment. Safety: Most adverse events (AEs) were mild to moderate, similar to the first reported safety profiles at median follow-up of 8.7 months. Extended follow-up analysis did not reveal new safety nor toxicity concerns. The most frequent adverse events (AEs) of any cause/any grade were well characterized as hematological toxicities: thrombocytopenia, neutropenia, and anemia; upper respiratory tract infection, pneumonia and hypokalemia. No case of atrial fibrillation nor secondary malignancy was reported, no patient was observed for ≥3 hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year-old male patient with more than 10 years hypertension) and the other with vitreous hemorrhage which were resulted from posterior vitreous detachment that was assessed as unlikely related to the treatment of orelabrutinib. Once again, it has been further confirmed that orelabrutinib has excellent safety profiles following extended treatment. Conclusion: This updated and extended study further confirms that orelabrutinib is efficacious in treating r/r CLL patients with a higher CR rate, durable response and improved safety profiles. As a highly selective BTK inhibitor with favorable pharmacokinetic and pharmacodynamic properties, orelabrutinib provides a favorable therapeutic choice for patients with r/r CLL/SLL and a potential best candidate for combination therapy. Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

Background: Bruton tyrosine kinase (BTK) is one of the key kinases implicated in the pathogenesis of multiple B cell malignancies. Orelabrutinib is a novel, highly selective and potent irreversible BTK inhibitor with minimal activities against other kinases (ITK, EGFR, ERBB2, etc.). As thus orelabrutinib may avoid off-target related adverse events and shall have improved safety profiles comparing to other BTK inhibitors. Here we present the safety profile of orelabrutinib analyzed based on data from 5 ongoing clinical studies in B cell malignancies (Table 1). Methods: Safety data of 266 patients (pts) from 5 ongoing orelabrutinib monotherapy studies were pooled and analyzed. All pts have been treated with at least one dose of oral orelabrutinib at ≥150 mg daily. The analysis includes the frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation or dose modifications. Results: Safety data were pooled from 266 pts with median age of 60 years (range 35.0-79.0, 69.2% males). The median duration of exposure was 11.0 months (range 0.2-22.0). The most common (occurring in ≥15% of pts) AEs were neutropenia (28.6%), thrombocytopenia (25.9%), Upper respiratory tract infection (24.4%), leukopenia (18.0%), anemia (16.2%) and rash (15.8%). Treatment related serious AEs (SAEs) were reported in 14.7% pts. The most common treatment related SAEs included thrombocytopenia (3.0%), lung infection (3.0%), pneumonitis (1.9%), anemia (1.1%) and lymphadentis (0.8%), The safety profiles were comparable in pts with various subtypes of B cell malignancies. It's noted that orelabrutinib has much less frequency of BTK off-target related adverse events, such as atrial fibrillation, diarrhea, major hemorrhage etc. Among all 266 pts, only one patient was reported with one episode of transient grade 1 atrial fibrillation, and no grade ≥3 atrial fibrillation was observed. Diarrhea of any grade was 7.1% and only one case (0.4%) was reported as grade 3. The major hemorrhage, defined as serious or ≥ G3 bleeding of any site, or central nervous system bleeding of any grade, was rarely observed; as only one case of cerebral hemorrhage, in 65-year-old male patient with more than 10 years hypertension was reported; the other three cases were subcutaneous hemorrhage, vitreous hemorrhage and vitreous hemorrhage/retinal hemorrhage. The later 2 cases of vitreous hemorrhage and/or retinal hemorrhage were resulted from posterior vitreous detachment and macular degeneration and both events were assessed as unlikely related to the treatment. Among 266 pts, the second primary malignancies were reported in only one pt with r/r MCL during orelabrutinib treatment. Grade ≥3 infection occurred in 41 pts (15.4%); most common infections were upper respiratory tract infection and lung infection. Most of the AEs were occurred during the early treatment, the frequency of the new event occurrence was significantly decreased during the later cycles. Dose reductions due to AEs occurred in 15 pts (5.6%), and treatment discontinuation due to AEs in 5.3% of pts with 2.3% related to orelabrutinib. Conclusions: Orelabrutinib shows excellent safety profiles and tolerability across various B-cell malignancies in long-term treatment. These data suggested orelabrutinib as a favorable treatment choice including the combinational therapy for B-cell malignancies. . Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( > 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.