<i>In vivo</i> activity of ARRY-543, a potent, small molecule inhibitor of EGFR/ErbB-2 in combination with trastuzumab or docetaxel.

Lee, Pa; Anderson, Deborah; Avrutskaya, Anna V.; White, Allan J.; Pheneger, Tracy; Winkler, JD

doi:10.1158/0008-5472.sabcs-2150

Cited by 8 publications

(8 citation statements)

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“…Modification of linker Lapatinib/neratinib (41,42,59,60) Acquired: increase in HER3 transcription and phosphorylation combination with standard-of-care therapies, demonstrated significant growth inhibition in HER2-positive xenografts, including breast cancer models (47,48). Tucatinib also significantly enhanced survival in intracranial tumor xenograft models (49).…”

Section: Small-molecule Inhibitorsmentioning

confidence: 99%

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Meric‐Bernstam

Johnson

Dumbrava

et al. 2019

Clinical Cancer Research

265

177

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The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including smallmolecule inhibitors, antibody-drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2targeted therapies.

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Section: Small-molecule Inhibitorsmentioning

confidence: 99%

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Meric‐Bernstam

Johnson

Dumbrava

et al. 2019

Clinical Cancer Research

265

177

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“…Current efforts on improved direct targeting of Erb kinase activity, which have completed phase I trials, include the recent development of TKIs like neratinib (HKI-272) and BIBW-2992, 93 which bind irreversibly to Erb receptors or ARRY-334543 and TAK-285 which concomitantly inhibit multiple members of the Erb family. 94,95 …”

Section: Somatic Mutations Of the Erb Receptor Family In Other Cancersmentioning

confidence: 99%

A growing family: Adding mutated Erbb4 as a novel cancer target

Rudloff¹,

Samuels²

2010

Cell Cycle

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As the upward spiral of novel cancer gene discoveries and novel molecular compounds continues to accelerate, a repetitive theme in molecular drug development remains the lack of activity of initially promising agents when given to patients in clinical trials. It is however invigorating that a few targeted agents directed against a select group of a few ‘cancer gene superfamilies’ have escaped this all to common fate, and have evolved into novel, clinically meaningful molecular therapy strategies. Targeting dysregulated signaling of the epidermal growth factor family of transmembrane receptors (Erbb family) has encompassed over the last decade an ever increasing role in personalized treatment approaches in an increasing number of human malignancies. Erbbs are receptor tyrosine kinases that are important regulators of several signaling pathways. Two of its family members (Erbb1/EGFR and Erbb2/HER2) have previously been shown to be somatically mutated of human cancers. To determine if this family is somatically mutated in melanoma, its sequences were recently analyzed and one of its members, Erbb4, was found to be somatically mutated in 19% of melanoma cases. Functional analysis of seven of its mutations was shown to increase its catalytic and transformation abilities as well as providing essential survival signals. Similar to other Erbb family members, mutant Erbb4 seems to confer “oncogene addiction” on melanoma cells, making it an attractive therapeutic target. Gaining further understanding into the oncogenic mechanism of Erbb4 may not only help in the development of targeted therapy in melanoma patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents.

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“…ONT-380 also significantly inhibited phosphorylation of truncated HER2 (p110/p95), which is thought to be associated with trastuzumab resistance in HER2 þ breast cancer. Nonclinical in vivo pharmacology studies of ONT-380 as a single agent, as well as in combination with standard-of-care therapies, demonstrated significant tumor growth inhibition in HER2-dependent tumor xenograft models, including models of breast cancer (17,18).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC)

Moulder

Borges

Baetz

et al. 2017

Clinical Cancer Research

118

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ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase I study determined the MTD, pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2-positive advanced solid tumors, with an expansion cohort of patients with HER2 MBC. ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2 MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2 MBC ( = 22) treated at doses ≥ MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease ≥ 24 weeks) was 27%. ONT-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR inhibitors and showed notable antitumor activity in heavily pretreated HER2 MBC patients, supporting its continued development. .

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In vivo activity of ARRY-543, a potent, small molecule inhibitor of EGFR/ErbB-2 in combination with trastuzumab or docetaxel.

Cited by 8 publications

References 0 publications

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

A growing family: Adding mutated Erbb4 as a novel cancer target

Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC)

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