Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: An in vitro study

Kinoshita, Toshihiko; Kobayashi, Yohnosuke; Tomizawa, Kenji; Suda, Kenichi; Kosaka, Takayuki; Sesumi, Yuichi; Fujino, Toshio; Nishino, Masaya; Ohara, Shuta; Chiba, Masato; Shimoji, Masaki; Takemoto, Toshiki; Suzuki, Makoto; Jänne, Pasi A.; Mitsudomi, Tetsuya

doi:10.1016/j.lungcan.2018.10.019

Cited by 60 publications

(46 citation statements)

References 42 publications

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“…Conversely, other preclinical studies and preliminary clinical results have shown that ERBB2 exon 20 insertions/duplications may be sensitive to the selective EGFR/ERBB2 exon 20 inhibitor poziotinib, while they can cause resistance to EGFR-TKIs of all three generations. These studies also confirmed the heterogeneous inhibitory activity of neratinib on some of the insertions [111,163,164]. The recent “basket” trial SUMMIT for patients with advanced solid tumors harboring ERBB2 - or ERBB3 -mutations exhibited a very low RR to neratinib in the included NSCLC cases ( n = 26, all with ERBB2 -mutations), with PR confined to one NSCLC with a missense mutation in ERBB2 TK domain, whereas no OR was seen in NSCLCs with ERBB2 exon 20 insertions [157].…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinsupporting

confidence: 59%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

125

126

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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Section: Clinical and Preclinical Studies Shedding Light On Intrinsupporting

confidence: 59%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

125

126

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“…Others have suggested that cancers harboring exon 20 mutations that mediate resistance to lapatinib/trastuzumab may be sensitive to neratinib treatment [79]. Koga et al reported lower sensitivity index values for neratinib than lapatinib in lung adenocarcinomas harboring the HER2 exon 20 insertion mutations A775_G776insYVMA, G776delinsVC, and P780_Y781insGSP [80]. In the SUMMIT trial, 50% of patients in the breast cancer cohort in whom exon 20 insertions were observed responded to treatment with neratinib, unlike the non-small cell lung cancer cohort, in which response to neratinib was limited in patients with such mutations [81].…”

Section: Differentiating Features Of Lapatinib and Neratinibmentioning

confidence: 99%

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

Collins

Conlon

Kannan

et al. 2019

Cancers

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An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.

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“…The major mechanism of acquired resistance during poziotinib therapy was the secondary C805S mutation (31%) homologous to C797S in EGFR gene, and heat shock protein 90 inhibitors have been reported to have potent activity against poziotinib-resistant cells. 138 DS-8201a is a new HER2-targeting antibody-drug conjugate incorporating a novel topoisomerase I inhibitor. In HER2-mutant patients, it gave a clinically significant RR of 73% and a median PFS of 14.2 months 125 ; and a phase II trial (NCT03505710) is ongoing (see Table 6).…”

Section: Advances In Other Genomic Alterationsmentioning

confidence: 99%

Advanced-Stage Non–Small Cell Lung Cancer: Advances in Thoracic Oncology 2018

Remón

Ahn

Girard

et al. 2019

Journal of Thoracic Oncology

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In 2018 research in the field of advanced NSCLCs led to an expanded reach and impact of immune checkpoint inhibitors (ICIs) as part of a frontline treatment strategy, regardless of histologic subtype, with ICI use extended to include stage III disease, shifting the prognosis of all these patients. This new standard first-line approach opens a gap in standard second-line treatment, and older combinations may again become standard of care after progression during treatment with an ICI. The characterization of predictive *Corresponding author. Disclosure: Dr. Remon reports honoraria from Merck Sharp and Dohme and Boehringer Ingelheim for serving as an adviser, speaker fees from Pfizer, personal fees and nonfinancial support from Ose Immunotherapeutics, personal fees from Bristol-Myers Squibb and AstraZeneca for travel and serving as an adviser, and reimbursement fees for travel expenses from Roche outside the submitted work. Dr. Ahn reports personal fees from AstraZeneca, Takeda,

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Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: An in vitro study

Cited by 60 publications

References 42 publications

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

Advanced-Stage Non–Small Cell Lung Cancer: Advances in Thoracic Oncology 2018

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