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  • 1
    In: Journal of the National Cancer Center, Elsevier BV, ( 2023-8)
    Type of Medium: Online Resource
    ISSN: 2667-0054
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT030-CT030
    Abstract: Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRASG12C. Data from prior data cutoffs (primary: Feb, 2022; initial update: July, 2022) showed that IBI351 (GFH925) was well-tolerated and demonstrated promising efficacy in patients (pts) with advanced solid tumors harboring KRAS p.G12C mutation. Here, we update results of this phase I study evaluating IBI351 (GFH925) in pts with advanced solid tumors again. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRASG12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg once daily (QD) and a Bayesian optimal interval (BOIN) design with 450-900mg QD and 450-750mg twice daily (BID). The primary endpoints were safety and tolerability. The secondary endpoints were pharmacokinetics (PK), anti-tumor activity of IBI351 (GFH925) monotherapy per RECIST v1.1, and overall survival. Results: As of November 30th, 2022, 74 pts (1 at 250mg QD, 3 at 450mg QD, 9 at 700mg QD, 5 at 900mg QD, 21 at 450mg BID, 31 at 600mg BID and 4 at 750mg BID; 62 men, 12 women; median age: 64 yrs, range: 42-76 yrs) were enrolled, among whom 67 pts had non-small cell lung cancer (NSCLC). Among 67 NSCLC pts, 44.8% pts received ≥2 prior lines of treatment (tx), 38.8% pts had brain metastases; adenocarcinoma was the most common histology (n=66, 98.5%). All 74 pts were included for safety analysis. No dose-limiting toxicity (DLT) were observed in any dose cohorts. The overall safety profile was consistent with the latest previous report, with no new safety signals identified. As of December 15th, 2022, among 67 response-evaluable NSCLC pts across all dose levels, the ORR (by investigator assessment) was 58.2% (95% CI, 45.5-70.2), and the confirmed ORR was 44.8% (95% CI, 32.6-57.4); the disease control rate (DCR) was 92.5% (95% CI, 83.4-97.5). At the 600mg BID dose level (RP2D), the ORR was 63.3% (95% CI, 43.9-80.1), and the confirmed ORR was 50.0% (95% CI, 31.3-68.7), the DCR was 96.7% (95% CI, 82.8-99.9). With a median progression-free survival (PFS) follow-up of 5.5 months (95% CI, 5.3-6.8) for NSCLC pts at the 600mg BID dose level, 21 (70%) pts were continuing treatments, and the median duration of response (DoR) and PFS were not reached. Thirteen out of 15 confirmed responders were still in response. Conclusion: IBI351 (GFH925) was well-tolerated across all doses explored in patients with advanced solid tumors harboring KRAS p.G12C mutation. The data also demonstrated promising efficacy and durable response of IBI351 (GFH925) in previously treated advanced NSCLC. Clinical trial information: NCT05005234. Citation Format: Qing Zhou, Nong Yang, Jun Zhao, Mingfang Zhao, Yan Yu, Ying Yuan, Huijuan Wang, Xingya Li, Xiaorong Dong, Longhua Sun, Tongmei Zhang, Dingzhi Huang, Qian Chu, Jingjing Huang, Sujie Zhang, Mengna Huang, Yuping Shen, Yi-Long Wu. Phase I study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors: Updated results of the phase I 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 CT030.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
    In: Thoracic Cancer, Wiley, Vol. 14, No. 34 ( 2023-12), p. 3421-3429
    Abstract: Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.
    Type of Medium: Online Resource
    ISSN: 1759-7706 , 1759-7714
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3007-3007
    Abstract: 3007 Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included ( 〉 25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in 〉 2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. Hypertension, QT interval prolongation, platelets decrease and lymphocytes decrease (leading to 1 st gen SRI dose delays and modifications frequently) were rare ( 〈 5%) and low-grade. The exposure increased dose-dependently and the mean half-life was found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest 〉 11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1 st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1 st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
    In: Cell Biology International, Wiley, Vol. 46, No. 6 ( 2022-06), p. 933-946
    Abstract: Polydopamine nanoparticles are artificial melanin nanoparticles (MNPs) that show strong antioxidant activity. The effects of MNPs on the neuroprotection of mesenchymal stem cells (MSCs) against hypoxic‐ischemic injury and the underlying mechanism have not yet been revealed. In this study, an oxygen–glucose deprivation (OGD)‐injured neuron model was used to mimic neuronal hypoxic‐ischemic injury in vitro. MSCs pretreated with MNPs and then cocultured with OGD‐injured neurons were used to investigate the potential effects of MNPs on the neuroprotection of MSCs and to elucidate the underlying mechanism. After coculturing with MNPs‐pretreated MSCs, MSCs, and MNPs in a transwell coculture system, the OGD‐injured neurons were rescued by 91.24%, 79.32%, and 59.97%, respectively. Further data demonstrated that MNPs enhanced the neuroprotection against hypoxic‐ischemic injury of MSCs by scavenging reactive oxygen species and superoxide and attenuating neuronal apoptosis by deactivating caspase‐3, downregulating the expression of proapoptotic Bax proteins, and upregulating the expression of antiapoptotic Bcl‐2 proteins. These findings suggest that MNPs enhance the neuroprotective effect of MSCs against hypoxic‐ischemic injury by inhibiting apoptosis and upregulating antioxidant defense, which could provide some evidence for the potential application of combined MNPs and MSCs in the therapy for ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 1065-6995 , 1095-8355
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 6
    In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2023-08-05)
    Abstract: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. Methods This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Results Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6–17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5–34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5–18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). Conclusions Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. Trial registration ClinicalTrials.gov identifier: NCT03736837.
    Type of Medium: Online Resource
    ISSN: 1476-4598
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 7
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9069-9069
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9069-9069
    Abstract: 9069 Background: Anti-PD-1/L1 therapies have improved overall survival (OS) by 2-4 months vs docetaxel in patients with advanced non−small cell lung cancer (NSCLC) who progressed after receiving a platinum regimen. Tislelizumab, an anti-PD-1 antibody, has been tested as monotherapy in the RATONALE (NCT 03358875) trial, which found that tislelizumab prolonged OS (median OS difference 5.3 months in ITT population) as compared to docetaxel, improved progression-free survival (median 4.1 vs 2.6 months), as well as overall response rate (ORR difference = 14.9%).Here we report health-related quality of life (HRQoL) of patients receiving tislelizumab vs docetaxel in this clinical trial. Methods: NSCLC patients in this open-label, multicenter Phase 3 study were randomized to either the tislelizumab or docetaxel. HRQoL was measured using the QLQ-C30 global health status/quality of life score (GHS/QoL) from EORTC QLQ-C30 as well as the lung cancer specific subscales of the EORTC QLQ-LC13. Descriptive analysis for the GHS/QoL score was performed for baseline through cycle 10; changes from baseline to cycle 12 were examined for the symptom subscales. Results: 805 patients were randomized to tislelizumab (n = 535) or docetaxel (n = 270). Patients were 77% male with an average age of 60 years (range 28-88 years). The compliance rates were mostly 〉 98% and were similar across arms. The GHS/QoL score in the tislelizumab arm improved relative to baseline from cycles 5 through 10 while declining in cycles 6 through 10 in the docetaxel arm. The tislelizumab arm showed a reduction from baseline at cycle 12 in the symptom scores of coughing, chest pain, and dyspnea while patients in the docetaxel arm experienced an increase in symptoms. Conclusions: The study results show that tislelizumab monotherapy improved HRQoL in patients who previously failed treatment with a platinum containing chemotherapy; this is especially important as the NSCLC patients treated with tislelizumab not only experienced improvements in OS, but also reductions in their symptomology. Clinical trial information: NCT 03358875.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3586-3586
    Abstract: 3586 Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRAS G12C and has demonstrated promising anti-tumor activity with acceptable safety in advanced solid tumors. Here, we report a pooled analysis of two phase I studies (NCT05005234, NCT05497336) evaluating the efficacy and safety of IBI351 (GFH925) monotherapy for metastatic colorectal cancer (CRC) harboring KRAS G12C mutation. Methods: Eligible metastatic CRC patients (pts) with KRAS G12C mutation were included. Pts received IBI351 (GFH925) orally at dose levels of 700mg once daily (QD), or 450/600/750mg twice daily (BID). The primary endpoint was objective response rate (ORR) assessed by investigator per RECIST v1.1. Data cutoff for the analyses was November 30, 2022 unless otherwise specified. Results: A total of 45 pts were enrolled (median age: 58.0 years; male: 57.8%; ECOG PS 1: 71.1%; pts with ≥2 prior lines of treatment: 66.7%), including 3, 4, 37, and 1 pts in 700mg QD, 450mg BID, 600mg BID, and 750mg BID cohorts, respectively. The median exposure to therapy was 84 days (range, 7-286), and 36 pts (80.0%) were still on treatment including one patient at 450mg BID with treatment exposure for 286 days. As of December 15, 2022, ORR was 47.5% (19/40, 95% CI: 31.5%-63.9%) and disease control rate (DCR) was 85.0% (95% CI: 70.2%-94.3%) for the efficacy-evaluable pts across all dose levels. The median duration of response (DOR) was not reached. For 32 efficacy-evaluable patients at 600mg BID, ORR and DCR were 43.8% (14/32) and 87.5%, respectively. Treatment-related adverse events (TRAEs) occurred in 40 (88.9%) pts, with the most common being anaemia, white blood cell count decreased, alanine aminotransferase increased, and pruritus. Grade ≥ 3 TRAEs occurred in 9 (20.0%) pts. No drug-related adverse events leading to treatment discontinuation or death occurred. Conclusions: IBI351 (GFH925) monotherapy demonstrated promising anti-tumor activity with manageable safety profile in metastatic CRC patients harboring KRAS G12C mutation. These two studies are still ongoing and longer follow-up will provide more solid evidence. Updated data will be presented at the meeting. Clinical trial information: NCT05005234 , NCT05497336 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 9
    In: BMC Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-11-23)
    Abstract: Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC). Methods In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators. Results Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%] ), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%] ). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2–78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26–23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06–25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6–57.0), median PFS was 6.73 months (95% CI, 4.73–8.54), and median DoR was 6.60 months (95% CI, 3.77–13.3). Conclusions In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously. Trial registration ClinicalTrials.gov, NCT02695550.
    Type of Medium: Online Resource
    ISSN: 1741-7015
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 10
    Online Resource
    Online Resource
    Becaris Publishing Limited ; 2023
    In:  Journal of Comparative Effectiveness Research Vol. 12, No. 5 ( 2023-05)
    In: Journal of Comparative Effectiveness Research, Becaris Publishing Limited, Vol. 12, No. 5 ( 2023-05)
    Abstract: Whether PD-1 immune checkpoint inhibitor plus chemotherapy is superior to bevacizumab plus chemotherapy as first-line treatment for advanced non-squamous non-small cell lung cancer (nsNSCLC) remains unclear. The study aimed to compare the effectiveness of the two regimens in advanced nsNSCLC. What were the results? We found that PD-1-targeted immune checkpoint inhibitor plus chemotherapy was superior to bevacizumab plus chemotherapy as first-line treatment for advanced nsNSCLC without driver gene mutations, however this conclusion is debatable for patients with PD-L1 〈 1%. What do the results of the study mean? Current clinical studies that directly comparing PD-1 inhibitor plus chemotherapy and bevacizumab plus chemotherapy are lacking. It is still unclear which of these two regimens was superior as first-line treatment for advanced nsNSCLC, especially for patients with PD-L1 〈 1%. This study confirmed that PD-1 inhibitor plus chemotherapy was superior to bevacizumab plus chemotherapy for advanced non-squamous non-small cell lung cancer (nsNSCLC), but not for those patients with PD-L1 〈 1%. Prospective studies are needed to determine which regimen is better for patients with PD-L1 〈 1%.
    Type of Medium: Online Resource
    ISSN: 2042-6305 , 2042-6313
    Language: English
    Publisher: Becaris Publishing Limited
    Publication Date: 2023
    detail.hit.zdb_id: 2669725-7
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