Standard Dose Osimertinib Shows Mild Clinical Activity in EGFR Mutated NSCLC

Regular dose osimertinib (Tagrisso) demonstrated limited clinical activity in patients with non-small cell lung cancer (NSCLC) harboring an EGFR exon 20 insertion (ex20ins) who were treated in a phase 1/2 study, according to a presentation given during the American Association for Cancer Research (AACR) Annual Meeting 2021.

Ex20ins occur in approximately 4-12% of all patients with NSCLC. Patients with this insertion are known to be less sensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). In vitro models have shown that the third-generation EGFR TKI osimertinib is active against ex20ins in NCSLC, efficacy has yet to be fully evaluated.

The single-arm, multi-center, open-labeled, non-randomized study utilized a Simon’s two-stage design. In stage 1, 12 patients received 80 mg of osimertinib once daily until they met the termination criteria. In stage 2, patients received the same dose of osimertinib if more than 1 patient achieved partial remission (PR) or complete remission in stage 1.

The primary endpoint of the study was objective response rate (ORR) as assessed via response evolution criteria in solid tumors version 1.1. The secondary endpoint of the study was progression-free survival (PFS).

During the study, blood sampling was obtained at 4 weeks after starting the study drug in order to analyze pharmacokinetic parameters. A liquid biopsy was also performed for next-generation sequencing before and after the patient developed resistance to osimertinib in order to clarify resistance mechanism of osimertinib in EGFR ex20ins.

In order to participate, patients must have diagnosed advanced or metastatic NSCLC with EGFR ex20ins. Additionally, patients must have undergone 0-3 priory chemotherapy regimens. Patients with previous EGFR TKI treatment could participate if the treatment did not show clinical benefit. Patients with EGFR gene mutations such as exon 19 deletion, L858R, T79OM, G719X, and L861Q were excluded.

In total, 12 patients were enrolled. The median age was 63 (range, 22- 84). The cohort was split evenly between men and women. For 2 patients, it would be there first treatment, for 7 patients it was there second-line treatment, for 2 patients it was their third-line therapy, and for 1 patient it was there fourth-line therapy. Three patients had EGFR A767_V769dupASV mutation, 2 patients had EGFR H773_V774insH mutation, 1 patient had an EGFR H773_V774insAH, 1 patient had an EGFR D770 DelinsGY mutation, and 5 patients were not determined. 

No patients in the study achieved a complete or partial responses to therapy, resulting in an ORR of 0%. But, there were 7 cases of stable disease and fewer cses of progressive disease (n =5 ), resulting in a disease control rate of 58.3%. The PFS was 3.5 days and the overall survival was 473 days.

In total, 79 any-grade adverse events (AE) were reported. Serious AEs occurred in 41.7% of patients and 91.7% of patients experienced treatment-related AEs. Additionally, 16.7% of patients experienced severe treatment-related AEs. The most common related AE that was potentially related to the study drug was paronychia, followed by finger rash and gamma-glutamyl transferase increase. Pulmonary embolism, colon polyp, a decreased white blood cell count, and neutropenia were also reported, but were found to be probably unrelated to treatment. 

_REFERENCE:

_{Ichihara E, Yasuda H, Takashima Y, et al. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20. Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 4598.}