Olita (olmutinib)

A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.

Compounds 6e, 7a, 7b, 7d, 10c and 10e displayed the highest antitumor activity against all tested cell lines compared to Doxorubicin. Docking results of compounds 6e and 10e into the pocket of EGFR active site showed their similar main binding features with Olmutinib, while compounds 7d and 10e showed only moderate fitting into DHFR compared to methotrexate. In silico studies revealed that most of the tested compounds obeyed Lipinski's RO5 and showed positive drug likeness scores.

Molecular docking indicated strong binding of poziotinib and olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of -9.4 kcal/mol and -8.5 kcal/mol, respectively, on interacting with STK-11. Combining poziotinib and olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in lung cancer patients, as suggested by this study's mechanisms.

When co-administration of lurasidone with olmutinib in rats, the AUC and AUC of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CL was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.

Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

P2, N=162, Terminated, Hanmi Pharmaceutical Company Limited | Trial completion date: Aug 2020 --> Dec 2020 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2020 --> Dec 2020; Study termination by the Sponsor

Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

In this review, we profiled many of the third-generation EGFR TKIs in late stage clinical development (e.g. almonertinib, lazertinib, alflutinib, rezivertinib, ASK120069, SH-1028, D-0316 and abivertinib) of their interim results of phase 1-3 trials and their chemical structures when publicly available. Additionally, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, maverlertinib) including phase 3 results of rociletinib and naquotinib. We further profiled the next-generation combination clinical trial design of third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704) and ACROSS2 (NCT04500717).

Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

In vivo, olmutinib enhanced the inhibitory effects of Dox on ETS1-overexpressing K562/ADR cell xenograft growth. CONCLUSIONS Our results suggest that the novel EGFR TKI olmutinib enhances the sensitivity of ETS1-overexpressing leukemia cells to Dox.

P1b, N=2, Terminated, Hanmi Pharmaceutical Company Limited

P2, N=162, Active, not recruiting, Hanmi Pharmaceutical Company Limited | Trial completion date: Dec 2018 --> Aug 2020 | Trial primary completion date: Oct 2018 --> Aug 2020

EGFR mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR inhibitors.

In the current study, a new series of EGFR-TKIs with thieno[3,2-d]pyrimidine derivatives(6a-6r) bearing quinolin-2(1H)-ones were designed and synthesized, through conformational constrained strategy from the third generation of EGFR-TKI olmutinib...Specifically, 6o could significantly inhibit the colony formation, wound healing and the expression of p-EGFR and its downstream p-ERK in EGFR H1975 lung cancer cells. Our findings suggest that the thieno[3,2-d]pyrimidine compounds, especially 6l and 6o, can selectively target the mutant EGFR in vitro and at cellular level and may serve as the lead compounds for generating new series of the third-generation EGFR-TKIs.

Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.