7501 Background: R/R ENKTL is a rare and aggressive type of non-Hodgkin’s lymphoma. Responses to chemotherapy after failure of prior asparaginase-based regimen were not durable with a median OS of < 7 months (mos) and 1-year OS rate of < 20% (Lim et al, Ann Oncol 2017; Bellei et al, Haematologica 2018). The only targeted therapy approved in China for R/R peripheral T cell lymphoma (ENKTL included) showed an ORR of 18.8% and a CR rate of 6.3% (Shi et al, Ann Oncol 2015). Here, we present the primary analysis from GEMSTONE-201, the largest registrational study reported to date to evaluate an anti-PD-L1 mAb in R/R ENKTL. Suge received breakthrough therapy designation from US FDA in 2021 for adult R/R ENKTL pts based on preliminary data of this study. Methods: Pts with ECOG PS of 0/1 and histologically confirmed ENKTL who failed prior asparaginase-based regimen were enrolled. Pts accepted suge at 1200 mg Q3W, iv, for up to 24 mos, until progression, death, or withdrawal from study. The primary endpoint was ORR (CR+PR) assessed by independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included investigator-assessed ORR, CR and PR rate, DoR assessed by IRRC and investigators, and safety. Results: As of the data cutoff date, Nov 10, 2021, 80 pts were enrolled and treated (median follow-up of 13.4 mos). Median age was 48 years (range 29-74); 64% were males; 74% had ECOG PS of 1 at baseline; 68% had stage IV disease; about half (49%) received ≥ 2 lines of prior systemic therapy. The median duration of treatment was 5.2 mos (range 0.7-37.4); 23 pts remained on treatment. Among the 78 evaluable pts as per IRRC, ORR was 46.2% (95% CI: 34.8%, 57.8%); 29 (37.2%) pts achieved CR; median DoR was not reached (NR); 12-mo DoR rate was 86%. Investigator’s assessments in 79 evaluable pts were consistent with IRRC results, i.e. ORR of 45.6% (95% CI: 34.3%, 57.2%), 24 (30.4%) pts with CR, and median DoR of NR. The 1- and 2-year OS rates were 68.6% and 54.6%, respectively; median OS was NR (range 0.9-37.2+ mos). Of all pts, 96% (n = 77) had at least one AE. The most common AEs were pyrexia and WBC decreased (n = 24 each, 30%). Grade ≥ 3 AEs occurred in 31 (39%) pts. Suge-related AEs occurred in 61 (76%) pts and were mostly (60%) Grade 1/2. The most common irAE assessed by sponsor was hypothyroidism (n = 13, 16%). SAEs occurred in 18 (23%) pts; 5 (6%) pts had suge-related SAEs which had all been resolved (1 with sequelae). Fatal AEs occurred in 5 (6%) pts and none were suge-related as assessed by investigators. Conclusions: Suge has demonstrated deep and durable anti-tumor activity in R/R ENKTL pts, with a high CR rate and a promising OS benefit trend comparing to historical data. Suge had a well-tolerated safety profile and no new safety signals were detected. Primary analysis indicates that suge could provide a new treatment option to R/R ENKTL pts. Clinical trial information: NCT03595657.

e16191 Background: CS1003 is a novel humanized, recombinant IgG4 anti-PD-1 monoclonal antibody. LEN, a multi-kinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT, is approved as 1L treatment in pts with uHCC in multiple countries. A multi-regional, double-blinded, randomized phase 3 trial (CS1003-305, NCT04194775) of CS1003/placebo in combination with LEN as 1L treatment in uHCC is underway. The preliminary efficacy and safety data from the open-label phase 1b study of CS1003 + LEN as 1L treatment in uHCC after a median 6.2 months of follow-up were previously reported at ESMO Congress 2020. Here we present the updated results with a median 18.0 months of follow-up. Methods: Pts with uHCC, BCLC stage B or C, Child-Pugh class A, and ECOG PS ≤ 1 received 200 mg CS1003 intravenously once every 3 weeks and LEN orally (body weight ≥ 60 kg: 12 mg; < 60 kg: 8 mg) daily as 1L treatment. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Data cutoff for this final analysis was August 13, 2021. Results: At data cutoff, a total of 20 pts had received treatment. Compared with the last preliminary analysis, confirmed ORR was changed from 30.0% to 45.0% (95% CI: 23.06%, 68.47%) with 9 pts achieving partial response. DCR was 90.0% with 9 pts having stable disease as best overall response. DOR ranged from 4.2 to 18.7+ months, and median DOR in all responders had not been reached. Median PFS was extended compared with the previous study readout from 8.4 months to 10.4 months (95% CI: 6.2, not estimable) with 6-month and 12-month PFS rates of 85.0% and 48.2%, respectively. Median OS had not been reached. All adverse events (AEs) were grade 1-3. Grade 3 AEs attributed to CS1003 and/or LEN occurred in 9 (45.0%) pts with the most common being gamma-glutamyltransferase increased (2 pts, 10.0%). Six (6) pts experienced grade 3 CS1003-related AEs, among whom, 4 pts also experienced grade 3 AEs related to LEN. Only 2 pts discontinued treatment due to AEs. There were no deaths due to AEs, and no new safety signals were identified. Conclusions: The antitumor activity of CS1003 + LEN combination as 1L treatment in Chinese pts with uHCC remains encouraging and durable through a longer follow-up period, and the safety profile is well tolerated and manageable. The PFS is longer and the ORR is higher compared to the data previously reported, which support further development as a combination treatment for improving outcomes in uHCC pts. The ongoing multi-regional, double-blinded, randomized, placebo-controlled, phase 3 trial (CS1003-305, NCT04194775) is currently recruiting and will further evaluate adding CS1003 to LEN as a 1L treatment in uHCC. Clinical trial information: NCT03809767.

No abstract

572 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]

Background: SCB-313 is a recombinant human TRAIL-Trimer™ fusion protein engineered using a stabilized trimeric form of the TRAIL-protein. Binding of SCB-313 to the death receptors 4 and 5 leads to the activation of the extrinsic apoptosis pathway. Method: We performed a pooled analysis of two phase 1 studies conducted in Australia and China (NCT03443674 and NCT04051112, respectively). SCB-313 was given by intraperitoneal infusion 4 times at day D1, D4, D8, D11 in Australia study and D1, D8, D9, D10 in China study. Five dose cohorts: 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg were evaluated using a sequential dose escalation design (accelerated titration dosing combined with 3+3 design) in pts with MA. The primary objective for both studies was safety and tolerability. Secondary objectives included PK/PD and efficacy. Results: 7 pts were enrolled in Australia (by data cutoff Mar 5th, 2021) and 12 pts in China (by data cutoff May 21st, 2021). 16 pts completed DLT observation period. Median age 57.6y, ECOG 1-2, 36.8% male. Colon cancer, n=5; ovarian cancer, n=4; breast cancer, n=3; gastric cancer, n=2; other cancers, n=5. Treatment-emergent adverse events (TEAE) were reported in 19 pts (100.0%). Most AEs were mild to moderate in severity (Grade 1 or 2). There were 9 (47.4%) pts who experienced Grade 3 AEs and no Grade 4 or 5 AEs were reported. No SCB-313 related SAEs or AEs leading to study discontinuations or death were reported. No DLT occurred. The most common TEAE included abdominal pain, pyrexia, abdominal distension. In Australia study, median (min, max) ascites flow rate of pts with MA (n=7) was 800 (400, 1091) ml/24h at baseline and 163.8 (-767, 412), 137.7 (-796.6, 392.6), -91.5 (-844.8, 517.5) and 120 (-47.92, 1105) ml/24h post first, second, third and the fourth SCB-313 administration respectively. In China study, the median flow rate at baseline (n=11) and post each subsequent SCB-313 dosing were respectively 723.1 (108.2, 1175), 12.1 (-335.1, 965.9), 84.2 (-442.5, 882), -13.9 (-404.4, 431.8) and -57.85 (-446.4, 2028) ml/24h. Estimated half-life of SCB-313 in peritoneal fluid after 1st injection is 3-4 hours (min, max: 1.85, 5.05). Cmax and AUC showed a nonlinear dose-dependent increase and near complete elimination from the peritoneal fluid by 24 hrs. In Australia study, apoptosis specific serum CK-18 concentrations increased following the first dose and remained above baseline for 5/7 pts. Conclusion: Although the MTD was not defined by these studies, SCB-313 therapy presents an acceptable safety profile at all tested dose levels. Measurable ascites flow rate decrease were observed at all dose- levels. These data support further development of SCB-313 for pts with MA. Citation Format: Ye Guo, Aflah Roohullah, Junli Xue, Wei Zhao, Morteza Aghmesheh, David Martin, Yu Zhou, Chao Gao, Yixuan Yang, Derek-Zhen Xu, Jin Li. First-in-human (FIH) phase I studies of SCB-313, a novel TNF-related apoptosis-inducing ligand TRAIL-Trimer™ fusion protein, for treatment of patients (pts) with malignant ascites (MA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6180.