EGF816 Exerts Anticancer Effects in Non–Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor

Abstract

Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to firstgeneration EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M.

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

“…Rociletinib resistant cells were treated with rociletinib and crizotinib, MET inhibitor, with consequent restoration of rociletinib sensitivity. Similar results were obtained also with a new third-generation EGFR-TKI, as EGF816 combined INC280, a cMET inhibitor (46). Moreover, to address resistance via MET amplification recently a bispecific EGFR-cMET antibody was developed with very encouraging results in vitro and in vivo (47).…”

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

“…Pre-treatment time points show a significantly different profile as compared to post-treatment samples with an immediate quantitative rise in the number of EGFR copies after therapy reflecting cell apoptosis within days of exposure to drug (Figure 1). Pre-clinical studies of third generation anti- EGFR tyrosine kinase inhibitors in tumor xenograft mouse models demonstrated a strong inhibition of both phospho- EGFR and downstream signaling pathways with significant tumor shrinkage at days 5 to 7 from dose initiation (25-27). Third generation anti- EGFR inhibitors are known to cause apoptosis in pre-clinical models, and the combination of Bcl-2 and Bcl-XL inhibitors with third generation inhibitors induced more apoptosis demonstrating the importance of apoptotic pathways in cytoreduction on third generation TKI therapy (28).…”

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

“…Preclinical data show activities against cell lines and xenograft models harboring EGFR L858R/T790M , EGFR del19/T790M , EGFR del19 , and EGFR L858R , while having little effect on cell lines harboring EGFR wt [63]. In an early-phase clinical study (ClinicalTrials.gov, NCT02108964), 152 patients were enrolled to receive orally administered EGF816 at 75–350 mg/day.…”

“…In a preclinical study, EGF816 also showed activity against EGFR exon 20 insertion. Therefore, the early-phase study also enrolled patients with tumors harboring this genetic alteration [63]. A study of the combination therapy of EGF816 and nivolumab (an anti-PD-1 monoclonal antibody) is ongoing (ClinicalTrials.gov, NCT02323126).…”

“…Dual inhibition of EGFR and cMET with EGF816 and INC280 (a MET inhibitor) can overcome this resistance mechanism [63]. A phase Ib/II study of EGF816 and INC280 combination therapy for advanced EGFR mutation-positive NSCLC is in progress (ClinicalTrials.gov, NCT02335944).…”