Oritinib Shows Promise in EGFR T790M+ NSCLC

The third generation EGFR tyrosine kinase inhibitor (TKI) oritinib (SH-1028) demonstrated almost complete disease control in previously treated patients with EGFR T790M–mutant, locally advanced or metastatic non–small cell lung cancer (NSCLC).

Among 227 treated patients, the disease control rate was 92.5% (95% CI, 88.3%-95.6%) and the objective response rate was 60.4% (95% CI, 53.7%-66.8%). The findings of the phase 2 trial (NCT03823807) were presented at the European Lung Cancer Congress 2022.

Oritinib demonstrated potential clinical benefit in [patients with] advanced NSCLC with EGFR T790M mutation following prior therapy with first- and/or second-generation EGFR TKIs,” said lead study author Caicun Zhou, MD, PhD, director of the Department of Oncology, Shanghai Pulmonary Hospital; director of Cancer Institute of Tongji University Medical School; and chairman of the Oncology Department of Tongji University in China.

Between December 2019 and March 2021, 228 patients were enrolled in the single-arm study across 47 sites in China, and 227 patients were treated with at least 1 dose of oritinib. Patients were eligible if they had locally advanced or metastatic NSCLC and had progressed on at least 1 prior EGFR TKI, and had an EGFR T790M mutation.

Patients received oritinib at 200 mg orally once daily. The investigators performed tumor assessments by RECIST 1.1 criteria every 6 weeks until disease progression. In the follow-up stage, assessments were done every 6 weeks for progression-free survival (PFS) and every 12 weeks for overall survival (OS). The primary end point was objective response rate and secondary end points were disease control rate, PFS, and, OS.

The median age of all treated patients was 62.0 years (range, 35-87) with 41.4% of patients being age 65 or older. The majority of patients were female (57.3%), had an ECOG performance status of 1 (87.2%), and were never smokers (87.2%). Patients had EGFR T790M mutations of exon 19 deletion (63.4%), L858R (30.4%), or other mutation. Brain mutations were reported in 35.2% of patients and 24.7% had received prior chemotherapy in addition to EGFR TKIs.

All responses by independent radiology review committee were partial (60.4%). Stable disease was reported in 30.0% of patients and 2.2% had neither a complete response nor progressive disease. Only 3.5% had progressive disease and response was not evaluable in 4.0%.

The median PFS was 12.6 months (95% CI, 9.7-15.3) with events occurring in 40.1% of patients. The median duration of response was 12.5 months (95% CI, 11.2-not available). Median OS data were immature at the time of data cutoff on September 17, 2021.

In terms of safety, investigator-assessed adverse events (AEs) were reported in 94.3% of patients and were considered drug related in 83.7% (TABLE). The investigators observed grade 3 or higher AEs in 28.6% of patients and serious events in 17.6%. Dose interruptions due to AEs were reported in 13.2% of patients, dose reductions in 1.3%, and drug discontinuations in 4.4%. AEs led to death in 4.8% of patients.

The most common treatment-related events of any grade were diarrhea (41.9%), increased blood creatine phosphokinase levels (23.8%), decreased white blood cell count (13.2%), increased blood creatine phosphokinase isoenzyme (12.3%), increased aspartate aminotransferase levels (10.6%), and increased serum creatine (10.6%). The most common AEs of grade 3 or higher were increased blood creatine phosphokinase levels in 4.0% of patients, diarrhea in 2.2%, and decreased lymphocyte count in 1.8%.

Investigators are continuing to study oritinib in a randomized, controlled, double-blind phase 3 trial (NCT04239833) that will compare oritinib and gefitinib (Iressa) in the first-line treatment of patients with advanced NSCLC harboring EGFR-sensitizing mutations. Enrollment in this trial has already been completed.

_REFERENCE

_{Zhou C, Xiong A, Zhao J, et al. Oritinib (SH 1028), a third-gener- ation EGFR tyrosine kinase inhibitor in locally advanced or meta- static NSCLC patients with positive EGFR T790M mutation: results of a single-arm phase II trial. Ann Oncol. 2022;33(suppl 2):S31. doi:10.1016/j.annonc.2022.02.016}