Phase Iia Study to Evaluate the Biological Activity of Aslan001 in Her-1/2 Co-Expressing or Her-2 Amplified Advanced Gastric Cancer

Kim, Jihyeung; Im, Seock‐Ah; Lee, K.; Kim, J.W.; Han, Sae‐Won; Kim, T.; Choi, Inhee; Oh, Do‐Youn; Lee, N.; Song, Chang-Liang; Foster, M. E.; McHale, Mark; Barge, Alan; Kim, W.H.; Bang, Yung‐Jue

doi:10.1093/annonc/mdu334.49

Cited by 2 publications

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“…From our experimental results, varlitinib suppressed cell viability in most of TNBC cells, however, MDA-MB-231 cells were resistant to apoptotic effect of varlitinib (Figure 1). Varlitinib is a reversible pan-HER inhibitor with nanomolar potency against HER1, HER2 and HER4 in cell-based assays of gastric cancer [17]. HER3 has defective tyrosine kinase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Varlitinib (formally known as ASLAN001) is a highly potent, reversible, oral nanomolar small molecule pan-HER inhibitor of the receptor tyrosine. Both in vitro and in vivo experiments have been conducted to demonstrate varlitinib’s efficacy [17]. In addition, two varlitinib clinical trials in patients with HER2 positive metastatic breast cancer have been conducted and showed signs of clinical activity [18] (ClinicalTrials.gov Identifier: NCT02338245 and NCT02396108).…”

Section: Introductionmentioning

confidence: 99%

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Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells

Liu

Chu

Huang

et al. 2019

Cancers

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Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells

Liu

Chu

Huang

et al. 2019

Cancers

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“…Varlitinib is a highly potent, orally administered, smallmolecule inhibitor targeting HER1, HER2, and HER4 [16]. Varlitinib inhibits the phosphorylation and activation of these receptors, and has demonstrated activity in gastric, biliary tract, and breast cancers [17][18][19][20][21]. It has been granted orphan drug designation in the USA since 2015 for the treatment of cholangiocarcinoma and gastric cancer [22].…”

Section: Introductionmentioning

confidence: 99%

“…The half maximal inhibitory concentration of varlitinib for inhibiting the phosphorylation of HER1, HER2, and HER4 are 7nM, 2nM, and 4nM, respectively, which is lower, and thus more potent, than other small-molecule EGFR inhibitors such as lapatinib (HER1: 10.8 nM, HER2: 9.3 nM) and neratinib (HER1: 12 nM, HER2: 39 nM, HER4: 19 nM) [ 17 , 23 – 26 ]. In prior studies of varlitinib as monotherapy (ARRAY 543-103) and as combination therapy with docetaxel (ARRAY 543-104), the continuous dose of 500 mg twice a day was found to be the maximum tolerated dose (MTD) [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin ± Trastuzumab in Advanced Solid Tumors

Lee

Wong

et al. 2022

Targ Oncol

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Background Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers. Objective We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab. Methods Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed. Results Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m 2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on singleagent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel. Conclusions The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108).

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Phase Iia Study to Evaluate the Biological Activity of Aslan001 in Her-1/2 Co-Expressing or Her-2 Amplified Advanced Gastric Cancer

Cited by 2 publications

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Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells

Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells

Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin ± Trastuzumab in Advanced Solid Tumors

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