erlotinib

P3, N=545, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2025 --> Dec 2026

The compound 2j significantly inhibited the MDA-MB-231 cells proliferation by downregulation of EGFR, p-EGFR, and p-AKT protein expression levels. Molecular docking studies revealed that compound 2j had a strong binding affinity and interacted closely with key catalytic residues of EGFR, outperforming erlotinib, a known EGFR inhibitor, suggesting its potential as an anti-breast cancer drug candidate.

P1/2, N=92, Completed, Exelixis | Phase classification: P1b/2 --> P1/2

P=N/A, N=3000, Not yet recruiting, Guangzhou University of Traditional Chinese Medicine

Compound 19 was the most potent inhibitor of WT EGFR (3.0 nM) observed, more potent than the EGFR WT inhibitor Erlotinib (5.9 nM). Compounds 48 and 49 demonstrated better activity for the double-mutant EGFR (3.0 & 2.0 nM, respectively) than Osimertinib (12.8 nM)...Kinetic evaluation of 48 (propenamide moiety) vs 49 (acrylamide electrophile) confirms kinact/Ki values consistent with a covalent mode of action for the latter, but not the former. 2009 Elsevier Ltd.

Compound 7 significantly inhibited EGFR (IC₅₀ = 0.12 ± 0.004 μg mL-1), comparable to erlotinib, confirming its mechanism-based action...Molecular dynamics confirmed stable complex formation with favorable flexibility, while ADMET profiling indicated acceptable drug-likeness but limited oral absorption and potential metabolic liabilities. Overall, compound 7 emerged as the most promising EGFR-targeted lead with strong selectivity toward MCF-7 cells, induction of apoptosis, inhibition of HIF-VEGF signaling, and favorable electronic behavior, highlighting its ability to modulate the EGFR-PI3K/AKT-HIF-VEGF axis as a potential multi-pathway strategy for breast cancer therapy.

P3, N=674, Completed, AstraZeneca | Active, not recruiting --> Completed

OCS is the most aggressive, drug-resistant gynaecological malignancy and eribulin-based combination therapies, particularly triple combination therapies, have the potential to improve patient outcomes.

These values are comparable to or lower than those of the reference drug Osimertinib (GI50 = 0.343 µM for CAKI-1 and 1.95 µM for RPMI-8226 cell lines). To rationalize this behavior, toxicity profiling revealed a coordinated activation of Nrf2-mediated oxidative stress, p53-dependent DNA damage response, and androgen receptor (AR-LBD) signaling pathways. Molecular docking studies further demonstrated favorable binding interactions of compounds 3f, 3n, and 3o within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), with predicted affinities surpassing that of Erlotinib.

The progressive development of EGFR tyrosine kinase inhibitors (TKIs), from first-generation ATP-competitive inhibitors (e.g., gefitinib, erlotinib) to third-generation covalent agents (e.g., osimertinib) and emerging fourth-generation allosteric and degradation approaches, are critically examined for their mechanisms, efficacy, and clinical limitations. The combination strategies with immunotherapy, and anti-angiogenic agents are considered in the context of improving patient outcomes. Together, ongoing advances in understanding EGFR signaling and resistance mechanisms are driving the development of next-generation inhibitors and personalized therapies, with the ultimate goal of overcoming drug resistance and improve patient outcomes in EGFR-mutant cancers.

Guideline-discordant erlotinib rechallenge accelerated lymphocyte depletion, culminating in high-grade CMV viremia with CD4+ lymphocytopenia (0.16×109/L) and irreversible pulmonary fibrosis despite ganciclovir-induced virologic clearance. Lymphocytopenia in this setting mandates urgent viral exclusion before attributing injury to drug toxicity and precludes TKI rechallenge during active infection or severe immunosuppression. BAL-NGS requires rigorous clinicoradiologic correlation.

FDA-approved drugs like Gefitinib, Erlotinib, Afatinib, Dacomitinib, and Vandetanib validate the therapeutic significance of the quinazoline framework in modulating different cancer pathways. Structure activity relationship (SAR) analyses reveal that adding halogen, methoxy, or heteroaryl groups at specific ring positions enhance kinase affinity and cytotoxic efficacy. Overall, this review highlights recent progress linking synthetic design, molecular docking, and biological response, establishing quinazoline derivatives as promising multitargeted scaffolds for the design of next-generation anticancer agents.