Abivertinib Yields Significant Responses in 3-Year Follow-Up in EGFR T70M–Mutated Advanced NSCLC

Abivertinib yielded promising response in patients with advanced EGFR T70M–mutated non–small cell lung cancer (NSCLC), according to a press release on the mature long-term follow-up findings from a phase 1/2 study (NCT02330367) by the agent’s developer, Sorrento.¹

Treatment with abivertinib, a pyrrolopyrimidine-based third-generation EGFR inhibitor distinct from osimertinib (Tagrisso), resulted in an overall response rate (ORR) of 56.5% by independent review committee (IRC) and a complete response of 5.3%. Moreover, the median overall survival was 28.2 months. This trial was a 3-year long-term follow-up analysis and based on the response materials are being prepared for a pre-new drug application meeting with the FDA.

“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 US and global markets,” Henry Ji, PhD, chairman and chief executive officer of Sorrento, said in the press release.

Results of the study’s investigator assessed interim analysis were previously published in Clinical Cancer Research and included a total of 878 patients who were Chinese.² In phase 1 of the trial, 140 patients received treatment, along with 227 in phase 2. Exclusion from the trial occurred when patients tested negative for an EGFR T790M mutation. At data cutoff, abivertinib was received at a median range of 21.7 weeks, with 5.0% of patients still receiving treatment in phase 1. In phase 2, the median treatment time was 24.6 weeks and 5.3% were still receiving treatment. The median follow-up was 19.2 months and 35.2% of patients were still in the follow-up period a year after the cutoff date.

Phase 1 Responses and Safety With Abivertinib

In the phase 1 portion of the study among patients who were EGFR T790M–positive, responses were observed across the 100 mg to 300 mg twice-a-day dose levels. The hgihest ORR was observed in the 200 mg twice daily group at 40.0% and at 300 mg twice daily at 39.5%. The disease control rates (DCRs) in both respective arms were 70.0% and 89.5%.

The maximum tolerated dose was not identified in the phase 1 portion of the study, although 3 dose limiting toxicities occurred including grade 3 diarrhea, grade 4 liver damage, and grade 3 white blood cell count decrease in patients who received 100 mg, 300 mg, and 350 mg doses of abivertinib twice a day, respectively.

Adverse effects (AEs) of any grade were reported in 97.9% of patients, and 91.4% had treatment-related AEs (TRAEs). The most common TRAEs were alanine aminotransferase increase (ALT; 51.4%), aspartate aminotransferase increase (AST; 50.7%), diarrhea (46.4%), and rash (30.7%). Dose interruptions occurred in 22.9% of patients because of AEs, 13.6% of which were drug-related AEs. Patients experienced more frequent dose interruptions when they were treated with abivertinib at 350 mg twice a day dose level (66.7%). Serious AEs were observed in 22.9% of patients, and 4.3% were considered treatment related. Death occurred in 7.1% of patients, with only 1 case being potentially treatment related.

Phase 2 Survival and Responses Following Abivertinib Treatment

Among those treated in the phase 2 portion of the study, the ORR was 52.2% (95% CI, 45.2%-59.1%) at the 300 mg twice daily dose level. Moreover, 35.9% of patients had stable disease and 12.0% had progressive disease by RECIST 1.1 criteria. Patients had a median duration of response of 8.5 months (95% CI, 6.1-9.2), and the DCR rate was 88.0% (95% CI, 82.9%-92.1%).Progression-free survival (PFS) was evaluated at cutoff in 82.8% of patients, of whom 76.1% had disease progression and 24.5% had central nervous system progression as a primary site; of these patients, 6.7% died.

In a population of censored patients (n = 36/209) receipt of treatment was ongoing in 5.7% who they remained disease free. The median PFS was 7.5 months (95% CI, 6.0-8.8), and the median overall survival was 24.9 months (95% CI, 22.4-not reached). At cutoff, 39.7% of patients had died.

AEs were reported in 96.9% of patients. Common any-grade TRAEs included ALT increase (64.8%), diarrhea (61.2%), AST increase (57.3%), and rash (37.0%). Grade 3/4 AEs occurred in 32.6% of patients and 4.4% had grade 5 AEs. Serious AEs occurred in 13.7% of patients and included intestinal lung disease, liver malfunction, liver damage, and vomiting.

Treatment was discontinued in 7.5% of patients because of TRAEs and 6.2% experienced AEs that led to a dose reduction. Interstitial lung disease occurred in 5.3% of patients, with 4.4% being serious AEs; almost all events were grade 3 or 4 but no cases 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. August 23, 2022. Accessed August 25, 2022. https://yhoo.it/3pL4Zaa
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