We developed paclitaxel-, doxorubicin-, and cisplatin-resistant MDA-MB-231 cells to study MYC's role in upregulating DNA repair genes during drug resistance development...The combined use of asiRNA-VP (Vinylphosphonate) with dacomitinib or talazoparib was synthetic lethal in TNBC cell lines...We confirmed that MYC knockdown upregulated cFLIP, BCL2, STAT1, pSTAT1, STAT2, and cleaved saspase-3 in both TNBC and non-small cell lung cancer (NSCLC) cell lines. Finally, we recommend a combination treatment approach that synergizes with MYC inhibition rather than monotherapy or indirect targeting via upstream regulators such as the BRD4 and RRM2 genes or selective modulation at the protein level to suppress anti-apoptotic genes (cFLIP and BCL2) at the same time.

P=N/A, N=100, Recruiting, Pfizer | Not yet recruiting --> Recruiting | Initiation date: Apr 2024 --> Jul 2024

P=N/A, N=187, Enrolling by invitation, Pfizer | N=1200 --> 187

Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings emphasize the indispensable roles of ErbB signaling in WM integrity and function and provide insights into the multifaceted contributions of WM abnormalities to cognitive impairment.

Aim: We investigated association between skin adverse events (AEs) and efficacy with dacomitinib in patients with EGFR-positive non-small-cell lung cancer (NSCLC). Post hoc analyses from ARCHER 1050 evaluated efficacy in patients who did and did not experience grade ≥2 skin AEs with dacomitinib. Landmark analyses were performed at 3 and 6 months. In patients who had skin AEs (72.2%) vs. those who did not (27.7%), median progression-free survival was 16.0 vs. 9.2 months, median overall survival (OS) was 37.7 vs. 21.6 months, and objective response rate was 80.2 vs. 61.5%; OS was improved at 3 and 6 months landmark analyses. Presence of grade ≥2 skin AEs was associated with numerically improved efficacy and represents a valuable biomarker of treatment outcome with dacomitinib in patients with advanced NSCLC.Clinical Trial Registration: NCT01774721 (ClinicalTrials.gov).

P=N/A, N=40, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=888 --> 40 | Trial completion date: Jan 2027 --> Aug 2026 | Trial primary completion date: Jan 2027 --> Aug 2026

In the phase III ARCHER1050 trial, both progression-free survival (PFS) and overall survival (OS) were improved with first line dacomitinib compared to gefitinib. Conclusions ATORG-003 prospectively showed dacomitinib with dose titration is a viable strategy in advanced EGFR mutated NSCLC, to maintain efficacy but improve tolerability. Dacomitinib has substantial intracranial activity and high rates of T790M resistance for sequential treatment approaches.

The incidence of grade 3-4 rash was significantly higher in the 45 mg group than that in the 30 mg group (21.9% vs. 7.5%, P=0.042). First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

P=N/A, N=1, Completed, Pfizer | Recruiting --> Completed | N=20605 --> 1 | Trial completion date: Feb 2025 --> Jan 2024 | Trial primary completion date: Feb 2025 --> Jan 2024

P=N/A, N=307, Completed, Pfizer | Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> May 2024

Dacomitinib is a potential treatment option for NSCLC patients with EGFR L718Q mutation after resistance to Osimertinib. Further research is needed to validate the efficacy of Dacomitinib in this context.

P3, N=200, Recruiting, Region Skane

Subsequently, he was treated with a combination of cisplatin, pemetrexed, and bevacizumab resulting in a partial response. Our findings highlight the importance of NGS for identifying RET fusions and suggest the potential combination of dacomitinib and selpercatinib to overcome this resistance. For NSCLC patients with RET rearrangements and no access to RET inhibitors, pemetrexed-based chemotherapy provides a feasible alternative.

Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

Lastly, treatment of Huh7 cells overexpressing DBF4 with the ERBB2 inhibitor dacomitinib demonstrated the ability of ERBB2 inhibition to reverse the promoting effect of DBF4 overexpression on the proliferative, migratory, and invasive abilities of HCC cells. DBF4 plays a pivotal oncogenic role in HCC by promoting the ERBB signaling pathway and activating its downstream PI3K/AKT, JNK/STAT3, and MAPK signaling pathways. DBF4 may serve as a prognostic biomarker for patients with HCC.

P2, N=70, Recruiting, National Cancer Institute (NCI) | Initiation date: Nov 2024 --> May 2024

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

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.