Safety and preliminary efficacy from the phase 1 portion of MasterKey-01: A First-in-human dose-escalation study to determine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary antitumor activity of BDTX-189, an inhibitor of allosteric <i>ErbB</i> mutations, in patients (pts) with advanced solid malignancies.

Schram, Alison M.; Ahnert, Jordi Rodón; Patel, Manish R.; Jauhari, Shekeab; Sachdev, Jasgit C.; Zhu, Viola W.; LoRusso, Patricia; Nguyen, Danny; Le, Xiuning; O’Connor, Matthew; Waters, Nigel J.; Cook, Carl; Witt, Karsten; Humphrey, Rachel; Hamilton, Erika

doi:10.1200/jco.2021.39.15_suppl.3086

Cited by 12 publications

(12 citation statements)

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“…Oncogenic mutations in HER2 have been identified in multiple solid tumours including BC, and most of these occur at allosteric sites outside the ATP-binding site of HER2. BDTX-189 is an oral, ATP-competitive, irreversible, small-molecule inhibitor of EGFR/HER2 alterations and HER2 wild type, designed to spare EGFR wild type to minimize toxicity 155 . BDTX-189 demonstrated potent, sustained inactivation of multiple allosteric ERBB mutants in vivo.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

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Targeting HER2-positive breast cancer: advances and future directions

Swain

Shastry

Hamilton

2022

Nat Rev Drug Discov

212

150

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The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug -the monoclonal antibody trastuzumab -almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2targeted therapy and new therapeutic approaches and agents, including Nature Reviews Drug Discovery Review articlethan half of patients with metastatic HER2 + disease are diagnosed de novo, further demonstrating that most patients presenting with early disease are cured 6 .However, despite this success, metastatic HER2 + tumours inevitably develop resistance, leading to disease progression. As such, the goal of therapy in HER2 + BC is to expand the number of patients cured in the early setting and prevent recurrence. In those HER2 + cancers that do present with de novo stage IV disease or ultimately recur, development of novel therapies is needed as these tumours continue to be dependent on HER2 signalling. Therefore, extensive research is ongoing in the preclinical, translational and clinical arenas to develop original and more potent therapies for this exceptionally sensitive target, HER2.Advances in targeting HER2 include further exploitation of antibody-drug conjugates (ADCs), altering the linkers, payload or antibody scaffold to optimize efficacy 7,8 . Another approach is the development of bispecific antibodies, which use binding of two different HER2 epitopes to maximize efficacy 9 . As immunotherapy has shown benefit in triple-negative breast cancer (TNBC), attempts to mobilize the immune system in HER2 + disease are also ongoing. Immunotherapy is being approached from various angles including administering

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Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…A phase I trial in advanced solid tumours harbouring specific allosteric HER2 or HER3 mutations or other EGFR/ HER2 alterations is ongoing. Early data show activity with BDTX-189 in HER2-amplified tumours and in patients with non-small-cell lung cancer (NSCLC) with EGFR and HER2 exon 20 insertions 155 .…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Targeting HER2-positive breast cancer: advances and future directions

Swain

Shastry

Hamilton

2022

Nat Rev Drug Discov

212

150

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“…BDTX-189 is an oral, irreversible TKI with high selectivity in preclinical studies for HER2 and EGFR mutations over wild-type EGFR [ 94 ].…”

Section: Future Compoundsmentioning

confidence: 99%

“…In the phase I/II MasterKey-01 study of patients with advanced EGFR , HER2 , or HER3 mutations (NCT04209465), preliminary data from 46 patients, including five HER2 exon20ins and five EGFR exon20ins, were presented at the ASCO 2021 meeting [ 94 ]. The ORR was 7%, though neither patient with response had exon20ins.…”

Section: Future Compoundsmentioning

confidence: 99%

Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations: Diagnosis and Treatment Options

Brazel

Kroening²,

Nagasaka³

2022

BioDrugs

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Molecular testing is performed upon diagnosis of non-small cell lung cancer (NSCLC) because of the large success of targeted therapies for oncogenic mutations. Epidermal growth factor receptor (EGFR) mutations are the most commonly identified mutation in NSCLC, and EGFR exon 20 insertion mutations (exon20ins) are the third most common mutation in EGFR following EGFR exon 19 deletions and exon 21 L858R mutations. EGFR exon20ins have regularly demonstrated resistance to classical EGFR inhibition. Two treatments-mobocertinib and amivantamab-have recently been the first drugs to be approved by the US Food and Drug Administration (FDA) for treatment of lung cancers with these mutations following platinum-based therapy. Research surrounding these two drugs demonstrates strong efficacy, but with an intense array of side effects. Another targetable driver mutation is the human epidermal growth factor receptor 2 (HER2) exon20ins, representing approximately 2-3% of NSCLC patients. This mutation has been heavily studied in vitro as well as clinically, and trastuzumab deruxtecan was just recently granted accelerated FDA approval based on the high efficacy demonstrated in the Destiny-Lung01 study. However, similar to their EGFR counterparts, HER2 inhibitors also have evidence of toxicity in clinical studies. In this paper, we discuss the limited response of EGFR and HER2 exon20ins to a wide range of standard treatment regimens, such as platinum-based chemotherapy and classic EGFR tyrosine kinase inhibitors, as well as immunotherapy. We also review recently approved and upcoming targeted therapeutic options, considering what research is presently being done regarding efficacy and the reduction of side effects, as well as the agents' risks and benefits for incorporation into an approved treatment regimen.

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“…Currently, a number of other agents targeting EGFR ex20ins are being developed (32,34,(53)(54)(55)(56) (Table 4). Poziotinib (formerly HM781-36B) is a covalent and irreversible inhibitor of EGFR and HER2 (57).…”

Section: Other Egfr Ex20ins Targeting Agents Under Investigationmentioning

confidence: 99%

Emerging therapies for non-small cell lung cancer harboring EGFR exon 20 insertion mutations: narrative review

Watanabe¹,

Horio²,

Fujiwara³

2022

Ann Transl Med

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Background and Objective: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) are uncommon in non-small cell lung cancer (NSCLC). These mutations are generally resistant to first-generation EGFR tyrosine kinase inhibitors, unlike common EGFR mutations, including exon 19 deletions or exon 21 L858R point mutation. The development of effective targeted therapies for NSCLC harboring EGFR ex20ins has been eagerly anticipated over the years. Recently, the therapeutic landscape of this subgroup of EGFR-mutant NSCLC patients has rapidly evolved due to the emergence of new drugs.In 2021, several novel agents, such as amivantamab and mobocertinib, have been approved by the US Food and Drug Administration for patients with advanced platinum-resistant NSCLC harboring EGFR ex20ins.In this review, we mainly focus on emerging therapies targeting NSCLC with EGFR ex20ins, as well as important ongoing clinical trials.

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Cited by 12 publications

References 0 publications

Targeting HER2-positive breast cancer: advances and future directions

Targeting HER2-positive breast cancer: advances and future directions

Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations: Diagnosis and Treatment Options

Emerging therapies for non-small cell lung cancer harboring EGFR exon 20 insertion mutations: narrative review

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