erlotinib

P2, N=720, Recruiting, Canadian Cancer Trials Group | Trial primary completion date: Jan 2026 --> Dec 2026

P2/3, N=1, Completed, Eli Lilly & Co. | Active, not recruiting --> Completed

The CCA cell line carrying an IDH mutation utilized mitophagy as a novel metabolic compensatory mechanism activated through EGFR-specific signaling. Mitophagy acted as a metabolic synthetic lethality partner to the EGFR inhibitor erlotinib. These findings strongly suggest the potential of erlotinib as a therapeutic strategy for patients with IDH1-mutant CCA.

Despite the development of first-generation reversible inhibitors like Gefitinib and Erlotinib, acquired resistance necessitated the discovery of highly potent irreversible inhibitors effective against drug-resistant mutants. Herein, we report the design, synthesis and biological evaluation of novel 4-anilino quinazoline derivatives, bearing various alkynyl substituents at position 6, expected to bind to the hinge Met793 residue of EGFR. The effects of the derivatives on various cancer cell lines in terms of cytotoxic/cytostatic activity, interference with cell cycle phase distribution, and suppression of EGFR phosphorylation set the basis for the design of more potent derivatives.

Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.

In addition, molecules 7c, 8b, 7e, 7b and 8c, with IC50 values of 0.25, 0.32, 0.35, 0.45 and 0.50 µM, respectively, displayed very good EGFRT790M inhibition. Furthermore, molecules 7c, 7e and 8b exhibited excellent ADMET profile compared to sorafenib and erlotinib.

P1/2, N=9, Not yet recruiting, The First Affiliated Hospital with Nanjing Medical University

P1, N=498, Active, not recruiting, Genentech, Inc. | Trial completion date: Sep 2026 --> Dec 2027 | Trial primary completion date: Sep 2026 --> Dec 2027

This integrative computational and mathematical approach elucidates the putative mechanistic interplay between drugs and phytochemicals, highlighting the potential of Artemisinin-Erlotinib (ART-ERL) combination therapy in overcoming drug resistance in NSCLC. The findings offer a promising framework for rational design of future combination strategies to improve clinical outcomes in lung cancer therapy.

This review provides a comprehensive overview of the evolution of four generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs): first-generation reversible inhibitors such as gefitinib and erlotinib; second- and third-generation irreversible inhibitors, including afatinib, dacomitinib, and osimertinib; and emerging fourth-generation agents, such as amivantamab. Future studies should explore combination therapies, antibody-drug conjugates, and next-generation allosteric inhibitors as promising strategies to overcome resistance. The evolution of EGFR-targeted therapy exemplifies the progress of precision oncology and serves as a basis for designing new paradigms in the management of lung cancer.

These targets were found to bind DSF with very high affinity (7.45 -6.15 -6.65 kcal/mol, respectively) in comparison to reference inhibitors (Erlotinib, Celecoxib, Sorafenib). The article presents mechanistic support to the multi-target effect of DSF in ALDH + NSCLC through inhibition of EGFR, COX-2, and MAPK1, potent agents of stemness and resistance to drugs. It is believed that the reuse of DSF would be effective in treating NSCLC therapeutic resistance and promote its use in practice.

Cytotoxic effects on A549 cell lines, compared to sorafenib (4.04 μM) and erlotinib (5.49 μM), showed that compounds 4, 5, 6, 7, 8, 10 and 11 with the IC50 values of 5.50-8.00 μM exhibited very high activities. Molecular docking was carried out for all derivatives to show their binding affinities and orientations inside the active sites of VEGFR-2 and EGFRT790M receptors to support the in vitro results. The data obtained from docking is highly matched with that obtained from biological testing.