36MO Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 Exon 20 mutant non-small cell lung cancer

Sacher, Adrian G.; Le, Xiuning; Cornelissen, Robin; Shum, Elaine; Suga, Jennifer M.; Socinski, Mark A.; Molina, Julian R.; Haura, Eric B.; Clarke, Jeffrey; Bhat, Gajanan; Lebel, François; Garassino, M.C.

doi:10.1016/j.annonc.2021.01.051

Cited by 30 publications

(34 citation statements)

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“…Contrary to results demonstrated in a previous study ( 34 ), efficacy was observed with afatinib across all treatment lines, including in patients with previous chemotherapy or EGFR TKI failure. Afatinib was also active in some patients with tumors harboring exon 20 insertions or ‘other’ EGFR mutations; however, novel therapies including mobocertinib ( 35 ), poziotinib ( 36 ) and the recently approved amivantamab ( 37 ) have shown promising activity in early phase clinical trials in tumors harboring exon 20 insertions, and may prove to be more effective for this subgroup of patients. Nevertheless, while new effective treatment options are becoming available, it is unclear whether all exon 20 insertion mutations respond to amivantamab and other agents.…”

Section: Discussionmentioning

confidence: 99%

Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies

Passaro

Marinis

et al. 2021

Front. Oncol.

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BackgroundAfatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients.MethodsEGFR-TKI-naïve patients with EGFRm+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommon EGFR mutations (plus other factors).Results1108 patients were treated. Median age was 61 years (range, 25–89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0–13.8]; median TTSP was 14.8 months (95% CI: 13.9–16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations.ConclusionsAfatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommon EGFR mutations.

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Section: Discussionmentioning

confidence: 99%

Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies

Passaro

Marinis

et al. 2021

Front. Oncol.

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“…Thus, poziotinib has a unique clinical effect on LM patients with ERBB2 exon 20 insertion. What's more, poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants (22,23). In a phase II trial of poziotinib, the objective response rate (ORR) of 11 NSCLC patients with EGFR exon 20 mutations was 64% and the median progression-free survival (PFS) duration had not been reached at 6.6 months.…”

Section: Discussionmentioning

confidence: 99%

HER2 exon 20 insertion mutations in lung adenocarcinoma with leptomeningeal metastasis: a case report and response to poziotinib

et al. 2022

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Leptomeningeal metastasis (LM) is associated with poor prognosis and represents a terminal event of non-small cell lung cancers (NSCLC). In previous studies, most of LM-patients have detected epidermal growth factor receptor (EGFR) mutation and responded to the third generation of EGFR-tyrosine kinase inhibitor (TKI). This study aimed to report a case of ERBB2 (HER2) exon 20 insertion mutations in the cerebrospinal fluid (CSF) of LM-patient which response to poziotinib. At the beginning, postoperative pathology showed a primary invasive adenocarcinoma with no mutations in EGFR and ROS-1. Pemetrexed plus carboplatin combined with bevacizumab was administered as the first-line followed by bevacizumab alone for continuation maintenance therapy. Targeted therapy and immunotherapy were given after the disease progressed in two months. Subsequently, the patient developed mental symptoms and adenocarcinoma cells were found in the CSF. Next-generation sequencing (NGS) results showed HER2 exon 20 insertion mutations in the primary tissue, CSF and plasma samples. Then, poziotinib was administered and the symptoms improved significantly after 3 days and the progress free survival was nearly 2 months. Therefore, we speculate that the CSF concentration and penetration rate of poziotinib may significantly higher than of other TKIs so that it achieves a higher CSF concentration than standard dosing, and successfully controlled LM. It may provide a new therapeutic option for LM-patient and may be especially who are lung adenocarcinoma with HER2 exon 20 insertion.

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“…However, NSCLC patients with EGFR exon 20 insertion designate still a crucial unmet need. Recent preliminary data presented on March 2021 at ESMO Targeted Anticancer Therapies (TAT) Virtual Congress by Sacher et al demonstrated that poziotinib, initially conceived as a HER2-inhibitor, has significant clinical activity on this particular subset of patients [119]. Although further evaluations are warranted, one could speculate that EGFR-positive patients harboring a complex mutation, alike an exon 20 insertion and a sensitive genetic alteration (19Del/p.L858R/p.L861Q) might benefit from a treatment with a potent irreversible TKI, such as poziotinib.…”

Section: Discussionmentioning

confidence: 99%

“…Although further evaluations are warranted, one could speculate that EGFR-positive patients harboring a complex mutation, alike an exon 20 insertion and a sensitive genetic alteration (19Del/p.L858R/p.L861Q) might benefit from a treatment with a potent irreversible TKI, such as poziotinib. Collectively, it is challenging to estimate the efficacy of EGFR-TKIs in NSCLC patients harboring uncommon complex EGFR genetic alterations due to the great heterogeneity of the mutations detected [119,120]. Previous clinical trials have evaluated that first-generation EGFR-TKIs showed poor efficacy for uncommon mutations (alone or plus a compound mutation) [121].…”

Section: Discussionmentioning

confidence: 99%

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

Gristina

Mantia

Galvano

et al. 2021

JMP

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The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell lung cancer (NSCLC). Latest investigations by using next-generation sequencing (NGS) have shown that other oncogenic driver mutations, believed mutually exclusive for decades, could coexist in EGFR-mutated NSCLC patients. However, the exact clinical and pathological role of concomitant genomic aberrations needs to be investigated. In this systematic review, we aimed to summarize the recent data on the oncogenic role of concurrent genomic alterations, by specifically evaluating the characteristics, the pathological significance, and their potential impact on the treatment approach.

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36MO Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 Exon 20 mutant non-small cell lung cancer

Cited by 30 publications

References 0 publications

Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies

Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies

HER2 exon 20 insertion mutations in lung adenocarcinoma with leptomeningeal metastasis: a case report and response to poziotinib

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

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