9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]
Background: GLS-010 is a novel fully human anti-PD-1 mAb developed by the OMT transgenic rat platform. In Phase 1a study, GLS-010 exhibited good tolerance and 240mg (Q2W) was selected. Phase 1b study was conducted to evaluate the safety,anti-tumor activity and explore biomarkers of GLS-010 in pts with advanced solid tumors or lymphomas. Methods: All pts enrolled received GLS-010 240 mg every 2 weeks. Tumor response was assessed by RECIST 1.1 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Several biomarkers were explored, including PD-L1 by SP263 assay, tissue tumor mutation burden (tTMB) by whole exome sequencing (WES) from FFPE tissue, blood TMB (bTMB) by multi-gene panel based next-generation sequencing (NGS) from blood ctDNA. Results: As of 19 JUL 2019, 213 pts, median age of 55 (range: 21-75) years, were enrolled and 109 of 213 pts were still in treatment. The median dosing number was 7.5 (range: 1~41). Treatment-related AEs (TRAEs) occurred in 185 patients (70%), of which mostly were CTCAE grade 1-2. The most frequent TRAEs were related to hepatotoxicity, included “ALT increased” (32/213), “AST increased” (32/213), “blood bilirubin increased” (25/213). 53 of 163 pts, who received ≥1 response evaluation, achieved response (PR+CR, unconfirmed response included), including GC (4/21), EC (5/25), BTC (3/10), NSCLC (8/32), nasopharynx cancer (10/26),UC (2/8), HCC (0/12), cHL (18/21) and peripheral T/NK cell lymphoma (3/8). In all solid tumor types, pts with PD-L1-positive tumors experienced clinical benefit with significantly higher ORR (39.6% vs 14.5%, p=0.0025) and longer PFS (p=0.0241). ORR was higher for PD-L1 positive (TC≥25%) pts with lung cancer (66.7% vs 20.0%, p=0.051). For pan-caner analysis, ORR benefits of GLS-010 were also enhanced (51.9% versus 26.4%, p=0.0298) in pts with tTMB-high (>75th percentile, of each tumor type) versus tTMB-low. Pairing tTMB and survival data were analyzed in 129 pts, and tTMB-high pts benefit more with a significantly improved PFS (p=0.011). Also, improved PFS was observed in tTMB-high pts with EC (p=0.0059). For bTMB-high group, pts with EC achieved higher ORR (42.9% vs 6.3%, p=0.0672), which translated into PFS benefits (p=0.03). Conclusion: In conclusion, it is suggested that GLS-010 was well tolerated and had durable antitumor activity in Chinese tumor pts. PD-L1 has showed to be predictive of GLS-010 activity in solid tumors, especially in lung cancer. For pan-cancer analysis, it is preliminarily demonstrated that tTMB may be valuable biomarkers to predict the treatment response and benefit of GLS-010. For Chinese EC pts, tTMB and bTMB may be of value in predicting the response to PD-1 inhibitor. Citation Format: Lin Shen, Jifang Gong, Yuqin Song, Dingwei Ye, Zhihao Lu, Siyang Wang, Peijian Peng, Jianhua Chen, Ou Jiang, Guojun Zhang, Yuxian Bai, Jianji Pan, Chunguang Ma, Li Chen, Yi Ba, Qi Li, Ping Lu, Lingli Zhang, Xianli Yin, Shanzhi Gu, Huilai Zhang, Hang Su, Yongsheng Jiang, Bangwei Cao, Weiqing Han, Yan Sun, Feng Zhang, Weiwei Ouyang, Haiying Dong, Jianming Guo, Yabing Guo, Chongyuan Xu, Junyuan Qi, Li Wang, Jun Lv, Xiang Wang, Chris Chen, Jing Li, Yong Zheng, Ge Jin, Yining Yang, Guodong Zhao, Fan Yang, Kehui Xu, Xiangying Liang, Zhaoyang Pan, Haijin Meng. GLS-010, a novel fully human anti-PD-1 mAb in patients with advanced tumor: Preliminary results of a Phase Ib clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3275.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.