The novel targeted therapy abivertinib showed efficacy in a clinical trial of patients with EGFR T790M mutations who previously received an EGFR inhibitor.
Abivertinib, a third-generation EGFR inhibitor, demonstrated strong efficacy in patients with EGFR-mutated non–small cell lung cancer (NSCLC) with resistance to prior EGFR therapy, according to long-term follow-up data announced by Sorrento Therapeutics.1
At a median follow-up of 38.8 months, the phase 1/2 study (NCT02330367) of 209 evaluable patients in China showed an overall response rate (ORR) of 56.5% as assessed by an independent review committee (IRC). This included 11 patients (5.3%) with a complete response. Additionally, the median overall survival (OS) was 28.2 months.
“We are very encouraged by the significant positive results of abivertinib assessed by the IRC with long-term follow-up data and look forward to meeting with the FDA and other regulatory authorities for the possibility of bringing abivertinib to the United States and global markets,” Henry Ji, PhD, chairman and CEO of Sorrento, said in a statement.
Abivertinib is a highly-selective, small molecule, irreversible third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that is structurally distinct from osimertinib (Tagrisso), an approved first-line therapy for patients with EGFR exon 19 deletions or exon 21 mutations in NSCLC.
The phase 1/2 trial was designed to investigate the efficacy and tolerability of abivertinib in previously-treated patients with EGFR T790M mutations who have progressed following treatment with an EGFR inhibitor such as erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif). The T790M point mutation is associated with progression following first-line therapy with an EGFR inhibitor.
The primary end point was ORR, and secondary end points included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), OS, and adverse events (AEs).
During the phase 1 dose escalation part of the study, doses of 50 mg to 350 mg of abivertinib twice a day were evaluated in patients. The recommended phase 2 dose (RP2D) was determined to be 300 mg twice daily. In the phase 2 part, 227 patients received the RP2D in 21-day cycles. At a previous data cut-off of March 15, 2019, patients in phase 2 had received a median range of 24.6 weeks (0.43–129) of abivertinib treatment and 5.3% (12/227) of patients were still receiving therapy.2
The 56.5.6% ORR for patients with abivertinib is comparable with the efficacy of osimertinib in the AURA study (NCT01802632) phase 2 extension study for patients with a T790M mutation who progressed on EGFR-TKI treatment. The ORR for osimertinib in this similar patient population was 62.0% but did not include any complete responses.3
In previous data presented with 19.2 months follow-up for these 209 patients, ORR was 52.2% (95% CI, 45.2%-59.1%), while 35.9% of patients had stable disease and 12.0% had progressive disease.2 The ORR for the 143 patients with an exon 19 deletion was 60.8% and for the 67 patients with an exon 21 L858R mutation was 32.8%.
At this previous follow-up, the median DOR was 8.5 months (95% CI, 6.1-9.2). The median PFS was 7.5 months (95% CI, 6.0-8.8) and median OS was 24.9 months (95% CI, 22.4–not reached). The DCR was 88.0%.
In terms of safety, 220 out of 227 patients (96.9%) reported a treatment-related AE. The most common any-grade AEs were alanine aminotransferase increase (64.8%), diarrhea (61.2%), aspartate aminotransferase increase (57.3%), and rash (37.0%). Grade 3 or higher treatment-related AEs were reported by 32.6% of patients, and no reported grade 5 AEs were considered treatment-related. Dose reduction due to AEs were required in 14 patients (6.2%), while treatment discontinuation occurred in 17 patients (7.5%). Interstitial lung disease was experienced by 12 patients (5.3%), and 10 of these (4.4%) were considered serious adverse events, though none led to death.
Based on the significant efficacy in patients who are resistant to prior EGFR-targeted therapy, Sorrento is preparing to request a meeting with the FDA before submitting abivertinib for a New Drug Application (NDA) and will potentially submit for approvals to regulatory agencies in other countries.1
1. Sorrento announces significant positive pivotal trial results as assessed by an independent review committee (IRC) with matured long-term (over three years) follow-up data of abivertinib for the treatment of advanced non-small cell lung cancer (NSCLC). Sorrento Therapeutics. August 23, 2022. Accessed August 24, 2022. https://bit.ly/3wr6y0w
2. Zhou Q, Wu L, Hu P, et al. A novel third-generation EGFR tyrosine kinase inhibitor abivertinib for EGFR T790M-mutant non–small cell lung cancer: a multicenter phase I/II study. Clin Cancer Res. 2022;28(6):1127-1135. doi:10.1158/1078-0432.CCR-21-2595
3. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 2017;35(12):1288-1296. doi:10.1200/JCO.2016.70.3223