Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program

Prelaj, Arsela; Bottiglieri, Achille; Proto, Claudia; Russo, Giuseppe Lo; Signorelli, Diego; Ferrara, Roberto; Galli, Giulia; Toma, Alessandro De; Viscardi, Giuseppe; Brambilla, Marta; Lobefaro, Riccardo; Nichetti, Federico; Manglaviti, Sara; Occhipinti, Mario; Labianca, Alice; Ganzinelli, Monica; Gallucci, Rosaria; Zilembo, Nicoletta; Greco, Gabriella; Torri, Valter; Braud, Filippo de; Garassino, Marina Chiara

doi:10.1016/j.ejca.2021.02.038

Cited by 50 publications

(44 citation statements)

References 22 publications

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“…Recently, novel targeted therapies against EGFR exon 20 insertion mutations, such as poziotinib, mobocertinib, and amivantmab have been developed 17 – 20 . Poziotinib, a potent TKI against EGFR and HER2 exon 20 insertion mutations, showed an ORR of 15–44% and PFS of 4.2–5.6 months in the phase II trial and results from the expanded access program 38 – 40 . Mobocertinib is an EGFR-TKI with potent and selective preclinical inhibitory activity against EGFR exon 20 insertions, with an ORR of 43% and PFS of 7.3 months in a phase II trial 41 .…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics of advanced non-small cell lung cancer patients with EGFR exon 20 insertions

Morita¹,

Yoshida²,

Shirasawa³

et al. 2021

Sci Rep

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Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4–12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27–88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.

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Section: Discussionmentioning

confidence: 99%

Clinical characteristics of advanced non-small cell lung cancer patients with EGFR exon 20 insertions

Morita¹,

Yoshida²,

Shirasawa³

et al. 2021

Sci Rep

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“…Specific inhibitors of the EGFR ins20 (poziotinib and mobocertinib) were developed, as these mutations are not sufficiently sensitive to first–second–third-generation EGFR-TKIs. Poziotinib showed clinical activity in patients with EGFR/HER2-exon-20-ins-mutation but with high rates of adverse events leading to treatment discontinuation or posology reductions that underline the necessity of further trials [ 47 ]. Mobocertinib showed a more favorable toxicity profile in preclinical studies and phase I/II trials [ 42 ].…”

Section: Mechanisms Of Resistance To Egfr-tkismentioning

confidence: 99%

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

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“…Early trials have shown a high incidence of rash (33%-97%), making these Nibs more toxic than the EGFR-MET bispecific antibody amivantamab also used to target exon 20 insertions. [132][133][134] EGFR tyrosine kinase signaling leads to downstream activation of the heterodimeric lipid kinase PI3K, and mutations in the PIK3CA gene have been associated with resistance to endocrine therapy in hormone receptor-positive breast cancers. 135 Initial failures of the first-generation PI3K inhibitors led to the development of the orally bioavailable alpelisib, which inhibits the PI3K alpha isoform and prevents its downstream signaling.…”

Section: Egfr-pi3k-akt Inhibitorsmentioning

confidence: 99%

Diverse landscape of dermatologic toxicities from small‐molecule inhibitor cancer therapy

et al. 2021

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Background: Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. Methods: We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis.Results: Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions.Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs.Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs.Conclusions: Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."

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Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program

Cited by 50 publications

References 22 publications

Clinical characteristics of advanced non-small cell lung cancer patients with EGFR exon 20 insertions

Clinical characteristics of advanced non-small cell lung cancer patients with EGFR exon 20 insertions

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Diverse landscape of dermatologic toxicities from small‐molecule inhibitor cancer therapy

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