Abivertinib Demonstrates Response and Survival Benefits in Pretreated EGFR T790M–Mutant NSCLC

Henry Ji, PhD

The novel third-generation EGFR inhibitor abivertinib (AC0010) generated a positive overall response rate (ORR) and overall survival (OS) in heavily pretreated Chinese patients with EGFR T790M–mutated non–small cell lung cancer (NSCLC) who failed treatment on a first-line EGFR TKI, according to long-term follow-up data from a phase 1/2 trial (NCT02330367).¹

At a median follow-up of 38.8 months, evaluable patients who received 300 mg of oral abivertinib twice per day during phase 2 (n = 209) achieved an ORR of 56.5%, including a complete response (CR) rate of 5.3%, per independent review committee (IRC) assessment. Additionally, patients experienced a median OS of 28.2 months per IRC assessment.

Based on these results, Sorrento Therapeutics is closing the trial to prepare materials for a pre–new drug application meeting with the FDA. The company could also submit for approvals to regulatory agencies in other countries.

“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 U.S. and global markets,” Henry Ji, PhD, the chairman and chief executive officer of Sorrento, stated in a press release.

Abivertinib is a pyrrolopyrimidine-based, third-generation EGFR inhibitor that is structurally distinct from osimertinib (Tagrisso). Abivertinib selectively inhibits EGFR-activating and resistant mutations with nearly 300-fold greater potency vs with EGFR wild-type.

Previously reported data from the phase 1/2 trial showed that at a median follow-up of 19.2 months (range, 0.11-32.6), abivertinib elicited a confirmed ORR of 52.2% (95% CI, 45.2%-59.1%) and a disease control rate (DCR) of 88% (95% CI, 82.9%-92.1%).² The median duration of response (DOR) was 8.5 months (95% CI, 6.1-9.2).

The median progression-free survival (PFS) was 7.5 months (95% CI, 6.0-8.8), and the median OS was 24.9 months (95% CI, 22.4–not reached).

The two-part, open-label, phase 1/2 study evaluated abivertinib in patients with previously treated NSCLC who had documented evidence of an activating EGFR mutation and failed treatment with an EGFR inhibitor such as erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif).³ Phase 1 consisted of a dose-escalation period with 28-day cycles and an optional treatment extension period starting on day 29, and phase 2 examined the activity and safety of abivertinib in patients with EGFR T790M mutations at the recommended phase 2 dose of 300 mg twice per day.

In both phases of the trial, patients were required to have a cytologically or histologically confirmed diagnosis of advanced or unresectable NSCLC with at least 1 measurable lesion per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. In phase 2, patients needed to have NSCLC harboring an EGFR T790M mutation with resistance to an EGFR TKI following progression or have a primary EGFR T790M mutation–positive tumor.

Patients were administered 300 mg of oral abivertinib twice per day for 21-day cycles, and they underwent safety assessment every 3 weeks, plus efficacy assessment every 6 weeks. Treatment continued until patients experienced disease progression, unacceptable toxicity, or withdrawal of consent.

ORR served as the primary end point of the trial. Secondary end points included DOR, PFS, DCR, OS, and safety.

Previously reported safety data from phase 2 of the trial showed that all 227 evaluable patients experienced at least 1 any-grade adverse effect (AE), including 96.9% of patients reporting at least 1 any-grade treatment-related AE (TRAE).2 The most common AEs of any grade were increased alanine aminotransferase (64.8%), diarrhea (61.2%), increased aspartate aminotransferase (57.3%), and rash (37.0%).

Additionally, 32.6% of patients reported at least 1 grade 3/4 AE, and 10 patients experienced a grade 5 AE. Seventeen patients discontinued treatment due to TRAEs, and 14 patients had dose reductions due to AEs.

Notably, interstitial lung disease (ILD) occurred in 5.3% of patients. Ten of 12 cases of ILD were considered serious AEs, and 9 cases were grade 3 or 4. No instances of ILD were fatal.

References

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). News release. Sorrento Therapeutics. August 23, 2022. Accessed August 23, 2022. https://bit.ly/3CzpPAK
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. Safety, pharmacokinetic and preliminary efficacy study of AC0010 in patients with EGFR T790M positive NSCLC. ClinicalTrials.gov. Updated September 10, 2021. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/NCT02330367