This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

P=N/A, N=300, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | Trial completion date: May 2024 --> Oct 2024

Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.

This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.

P=N/A, N=100, Not yet recruiting, Pfizer

P2, N=70, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Feb 2024 --> Nov 2024

This study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.

P2, N=104, Recruiting, National Cancer Centre, Singapore | Trial completion date: Jul 2026 --> Jun 2028

P2, N=118, Active, not recruiting, National Cancer Centre, Singapore | Trial completion date: Nov 2025 --> Mar 2026 | Trial primary completion date: Nov 2023 --> Mar 2026

P1, N=22, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

The PBPK modeling showed negligible change in dacomitinib maximum concentration (C) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.

Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.

We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2 breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2 breast cancer.

Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.

The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket...A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797...A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Dacomitinib may also be an option for these mutations given similar efficacy to afatinib. Superior CNS penetrance and well managed toxicity profile may also be reasons to consider osimertinib. Given that the choice of TKI may depend on the specific mutation, it is crucial that every patient diagnosed with NSCLC undergo comprehensive sequencing to identify these mutations.

BA has a protective effect through its anti-inflammatory, antifibrosis, and antibarrier disruption effects. Hence, BA is considered as a promising new drug for the treatment of chemotherapy-associated GIT problems, especially dacomitinib.

Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.

A phagocytosis checkpoint stanniocalcin-1 (STC1) was significantly inhibited in dacomitinib-treated xenografts. So here our study gives the first insight of the heterogeneity of the two classic models, and the translational potential of dacomitinib being used into a broader patient population rather than EGFR common activating mutation.

P=N/A, N=100, Not yet recruiting, Pfizer | Initiation date: Sep 2023 --> Jan 2024

P2, N=70, Not yet recruiting, National Cancer Institute (NCI)

Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.

P=N/A, N=20605, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P=N/A, N=100, Not yet recruiting, Pfizer

Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration. This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.

It brought significant PFS and OS improvement compared with Gefitinib in phase 3 randomize study ARCHER 1050. Temporary discontinuations and dose modification occurred in 2 (14.3%) and 1 (7.1%) patient, respectively. Conclusions Dacomitinib showed promising intracranial antitumor activity with a manageable safety profile as first-line therapy in EGFR-mutant NSCLC patients with multiple brain metastases.

Background Dacomitinib demonstrated superior survival benefit compared to gefitinib as a first-line treatment in EGFR-mutant non-small cell lung cancer (NSCLC) patients through the phase 3 trial, ARCHER 1050 study. Conclusions This study highlights the efficacy of dacomitinib as a promising first-line treatment for patients with EGFR-mutant NSCLC in a real-world setting. The detection rate of T790M mutation after dacomitinib treatment failure was similar to that of other 2nd generation EGFR-TKI.

Major treatment-related adverse events included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥grade 3 TRAEs. Conclusions Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations and could be a potential treatment option for these patients.

The most common grade 3-4 adverse events were rash (10.4%), diarrhea (9.1%), stomatitis (7.1%) and paronychia (4.5%). Conclusions First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among Chinese NSCLC patients with EGFR 21L858R mutation.

The tyrosine kinase inhibitor (TKI) dacomitinib demonstrated the strong binding potential to hinder TPX2, shielding the AURKA destabilization. This in silico study lays the foundation for repurposing targeted therapeutic options to impede the Protein-Protein Interactions (PPIs) in LUAD progression and aid in future translational investigations.

Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Materials & NSCLC patients under treatment with EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) who visited the department of dermatology or Chemotherapy skin care center of Seoul National University Hospital between 2015 and 2021 were included. This study revealed the characteristics of dAEs due to EGFR-TKIs in real world. The 2nd generation EGFR-TKI has the highest risk of dAEs. Among dAEs, especially papulopustular rash and paronychia are the main cause of dose interruption due to dAEs.

Dacomitinib is active in pts with brain metastasis, uncommon EGFR mutation, in patients with poor PS, and at 30 mg starting dose. Dacomitinib showed very good PFS with manageable safety profile.

Background Dacomitinib, a second-generation, irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), provided statistically significant progression-free survival improvement over gefitinib in treatment-naive patients with advanced EGFR mutation–positive non-small cell lung cancer (NSCLC) in a global phase 3 study (ARCHER 1050; NCT01774721). Interim analysis shows efficacy of 1L dacomitinib; safety data in the RW setting were generally consistent with dacomitinib's known safety profile. These results support 1L dacomitinib use in patients with advanced EGFR mutation–positive NSCLC.

P1, N=17, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Jul 2023 | Trial primary completion date: Nov 2024 --> Jul 2023

No abstract available

Therefore, understanding of clinical sign and collaboration between dermatologists and oncologists is essential. Effective management of dermatologic adverse event is mandatory for patient compliance

P=N/A, N=888, Recruiting, Pfizer | Active, not recruiting --> Recruiting | Trial completion date: May 2026 --> Jan 2027 | Trial primary completion date: May 2026 --> Jan 2027

In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients with Ex19del and exon 21 L858R EGFR mutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversible EGFR TKI, in patients with Ex19del and exon 21 L858R EGFR mutation-positive advanced NSCLC in Indian settings.

P1, N=93, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2025

The outcomes from molecular docking and molecular dynamics (MD) simulation further demonstrated the insertion of DAC into site III of BSA and hydrogen energy and van der Waals energy were the dominant energy of DAC-BSA stability. In addition, the influence of metal ions (Fe, Cu, Co, etc.) on the affinity of the system was explored.Communicated by Ramaswamy H. Sarma.

Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/BiS HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.