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Ref Type Abstract
Authors Jianming Xu, Jianping Xiong, Shanzhi Gu, Zuoxing Niu, Fei Yin, Beicheng Sun, Lan Zhang, Fuxiang Zhou, Chunyi Hao, Yueyin Pan, Wensheng Qiu, Yi Gao, Yongxin Ren, Songhua Fan, Michael Shi, Weiguo Su
Title A phase 2 study of HMPL-453, a selective FGFR tyrosine kinase inhibitor (TKI), in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
Abstract Text Background: Patients (pts) with advanced cholangiocarcinoma (CCA) who progressed on or after 1L chemotherapy have few treatment options. FGFR2 fusions or rearrangements occur in 10–16% of pts in global and 6.14% in Chinese pts with intrahepatic cholangiocarcinoma (iCCA), and may predict tumor susceptibility to FGFR inhibitors. HMPL-453 is a novel, selective tyrosine kinase inhibitor against FGFR1, 2, and 3. Here, we report results from an open-label, multi-cohort, single-arm phase 2 study (NCT04353375). Methods: Pts with histologically or cytologically confirmed locally advanced or metastatic iCCA with FGFR2 fusions who were treated at least one previous line of systemic therapy were eligible and included in this analysis. They received 21-day cycles of HMPL-453 orally with 150 mg (QD, cohort 1) or 300 mg (QD, 2w on/1w off, cohort 2) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: At data cutoff (Sep 21, 2022), a total of 25 iCCA pts (12 in cohort 1, 13 in cohort 2) were enrolled and treated with HMPL-453. Median age was 51 yrs (range 28-76) and 12 (48%) were male. All pts had received ≥1 prior treatment line and 21 (84%) had received previous gemcitabine-based chemotherapy. The median follow-up duration was 12 months (mos) and 4.1 mos for cohort 1 and cohort 2, respectively. Of 22 evaluable pts (12 in cohort 1 and 10 in cohort 2) who had at least one post-baseline tumor assessment, the best overall response by investigator assessment was confirmed partial response in seven (31.8%) pts and stable disease in an additional 12 pts (54.5%), resulting in a disease control rate (DCR) of 86.4%. Specifically, in cohort 2 the confirmed ORR was 50% (95% CI, 18.7%–81.3%) and DCR was 90% (95% CI, 55.5%–99.7%). Duration of response was not reached in either cohort. Median progression-free survival was 5.7 (95% CI, 2.6, NR) mos in cohort 1 and not yet mature in cohort 2. Of all pts, 23 (92%) experienced ≥1 treatment-related adverse events (TRAEs). The most common TRAEs (any grade) were diarrhea (56%), dry mouth (44%), and blood phosphorus increased (44%). The common Gr ≥3 TRAEs (≥5% pts) were decreased neutrophil count (8%), nail toxicity (8%) and palmar-plantar erythrodysesthesia syndrome (8%). Compared to cohort 1, pts in cohort 2 experienced a lower incidence of Gr ≥3 TRAEs (23.1% vs 58.3%), less dose interruption/reduction (32.0% vs 41.7%) and less treatment discontinuation (0.0% vs 16.7%) due to TRAE. Based on the better safety profile and preliminary efficacy, 300mg, QD, 2w on/1w off was chosen as the recommended phase 2 dose (RP2D). Conclusions: HMPL-453 showed promising efficacy, particularly in RP2D regimen (300 mg, QD, 2w on/1w off) and acceptable toxicity in pts with previously-treated advanced iCCA and FGFR fusions. These results warrant further study in pts with advanced iCCA. Clinical trial information: NCT04353375.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 fusion intrahepatic cholangiocarcinoma predicted - sensitive HMPL-453 Phase II Actionable In a Phase II trial, HMPL-453 treatment demonstrated acceptable toxicity in patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions, and resulted in an overall response rate of 31.8% (7/22, all partial responses) and disease control rate (DCR) of 86.4% (19/22), with stable disease in 12 patients, with an objective response rate of 50% and DCR of 90% at a dose of 300mg (n=10) (J Clin Oncol 41, 2023 (suppl 16; abstr e16118); NCT04353375). detail...