PURPOSE MET amplification ( METamp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with METamp ( MET gene copy number [GCN] ≥5), including high-level METamp ( MET GCN ≥10). METHODS Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to METamp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with METamp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression. RESULTS Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level METamp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had METamp. Disease control was achieved by 11/15 patients with METamp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level METamp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level METamp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years. CONCLUSION High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.
4094 Background: In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC ( P<0.0001); OS was noninferior. In this post-hoc analysis, we determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes. Methods: In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review. Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test. Results: 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population. In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of <200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%). In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table). Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/ CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%). Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS. OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented. Conclusions: TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms. Clinical trial information: NCT01761266 . [Table: see text]
AIM: DONATE (NCT03156985) is a large-scale real-world study investigating the safety of dapagliflozin in Chinese type 2 diabetes mellitus (T2DM) patients. This post-hoc analysis aims to further evaluate the real-world safety of dapagliflozin plus metformin. METHODS: Safety outcomes were assessed in patients receiving concomitant dapagliflozin and metformin, with or without other antidiabetics. The safety of dapagliflozin-based dual-therapies and dapagliflozin and metformin-based triple-therapies were also analysed. RESULTS: Among the 2,990 patients in DONATE, 2,165 (72.4%) received concomitant metformin. Among these 2,165 patients, 780 (36.0%) experienced ≥1 adverse event (AE), 129 (6.0%) experienced serious AE (SAE), and 96 (4.4%) experienced AE leading to dapagliflozin discontinuation. The most common AEs were upper respiratory tract infection (4.0%), urinary tract infection (UTI, 2.1%) and constipation (1.5%). The most common AEs of special interest of dapagliflozin were UTI (2.3%), genital tract infection (1.5%) and hypoglycaemia (1.1%). In the dapagliflozin and metformin dual-therapy subgroup, the incidences of AE, SAE and AE leading to dapagliflozin discontinuation were 26.7%, 2.5%, and 1.9%, respectively, numerically lower than that of the total population and most other dual-therapy subgroups. These patients also had numerically improved metabolic outcomes than baseline. CONCLUSION: Dapagliflozin and metformin combination therapy is well-tolerated in real-world Chinese T2DM patients.
Background and Aim HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, epsilon PA-44, for CHB. Approach and Results A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 mu g or 900 mu g epsilon PA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 mu g epsilon PA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 mu g epsilon PA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 mu g (18.1%) and 600 mu g (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 mu g epsilon PA-44-treated patients experienced serologic relapse. The safety profile of epsilon PA-44 was comparable to that of placebo. Conclusions Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 mu g epsilon PA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).
