Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Bergonzini, Cecilia; Leonetti, Alessandro; Tiseo, Marcello; Giovannetti, Elisa; Peters, Godefridus J.

doi:10.1080/14656566.2020.1746269

Cited by 14 publications

(12 citation statements)

References 56 publications

(75 reference statements)

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“…51 nM in the central nervous system 28 . Even though the effect of dacomitinib on brain metastases has not been studied in human patients, dacomitinib has displayed brain penetration in preclinical models and thus can be active as well in clinical settings 38,39 . Finally, we intend to increase the practicality of our model by incorporating other resistance mechanisms commonly observed in treated EGFR-m NSCLC and feature other targeted therapies in combination with EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

et al. 2021

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Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

et al. 2021

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“…Therefore, we changed the therapy to dacomitinib. Among the candidate TKIs, dacomitinib was chosen over afatinib because it has been speculated that dacomitinib might be active in the brain due to its increased brain penetration compared to afatinib ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report

Shen

Chen

et al. 2021

Front. Oncol.

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BackgroundAdvanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has been successfully treated with tyrosine kinase inhibitors (TKIs). However, resistance to osimertinib, a third-generation TKI, can be difficult to overcome in this small subset of patients and is attributed to secondary resistant mutations. Here, we report a case of acquired EGFR L858R/L718Q mutation with advanced NSCLC that resistant to osimertinib, which was successfully overcome using dacomitinib.Case PresentationA 64-year-old non-smoker woman was diagnosed with stage IV non-small cell lung adenocarcinoma with EGFR L858R mutation and brain metastasis in November 2018. Treatment with gefitinib and gamma knife radiosurgery was started as the first-line treatment. After 7 months, she experienced disease progression with increased primary lung lesions and switched to osimertinib based on an acquired EGFR T790M mutation. After another 4 months, the disease progressed, and she was switched to chemotherapy. During chemotherapy, brain MRI showed an increasing number of parietal lobe metastases. Hence, gamma knife radiosurgery was performed again. After 12 months, the disease progression resumed, and an EGFR L718Q mutation was found on biopsy. The patient was then challenged with dacomitinib, and the disease was partially responsive and under control for 6 months.ConclusionCurrently, there are no established guidelines for overcoming osimertinib resistance caused by the L718Q mutation. The acquired EGFR L718Q mutation in subsequent resistance to osimertinib could be overcome using dacomitinib, indicating a promising treatment option in the clinic.

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“…Nevertheless, a preliminary analysis of the first 24 patients has shown that overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were similar to historical data obtained with the EXTREME regimen [14]. In trials enrolling patients with both metastatic and locoregional disease, dacomitinib, a second-generation irreversible EGFR TKI, led to inconclusive results [15].…”

Section: Egfr Tkismentioning

confidence: 96%

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC) is characterized by a high mortality rate owing to very few available oncological treatments. For many years, a combination of platinum-based chemotherapy and anti-EGFR antibody cetuximab has represented the only available option for first-line therapy. Recently, immunotherapy has been presented an alternative for positive PD-L1 HNSCC. However, the oncologists’ community foresees that a new therapeutic era is approaching. In fact, no-chemo options and some molecular targets are on the horizon. This narrative review addresses past, present, and future therapeutic options for HNSCC from a translational point of view.

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Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Cited by 14 publications

References 56 publications

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

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