Elevated Dose of Osimertinib Induced Clinical Activity in EGFR Exon 20-Mutant NSCLC

A daily dose of the EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) at 160 mg was well-tolerated with clinical activity observed in patients with EGFR exon 20-mutant non–small cell lung cancer (NSCLC), according to results from the phase 2 ECOG-ACRIN 5162 trial (NCT03191149) during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

The confirmed overall response rate (ORR) was 24%, and the agent also induced a disease control rate of 82%. The median progression-free survival (PFS) was 9.6 months (95% CI, 4.1-10.7).

Of the 21 patients enrolled to the study, 17 were eligible and 15 were evaluable for response; 2 patients had no evaluable response assessment. Among these patients, the best responses included 1 complete response, 2 partial responses (PRs), and 1 unconfirmed PR. Additionally, 9 had stable disease and 1 patient had progressive disease (PD). At the data cut-off, 4 patients remained on therapy with osimertinib, while 17 had discontinued the drug due to RECIST PD in 8 patients, clinical PD in 4 patients, an adverse event (AE) in 1 patient, death in 1 patient, and other in 3 patients.

Overall, the safety findings for osimertinib at a 160 mg daily dose were consistent with prior reports of the study drug. Investigators noted they did not observe grade 3 rash or diarrhea in this study.

The most common all-grade treatment-related AEs (TRAEs) were diarrhea (76%), fatigue (67%), platelet decreases (67%), anemia (43%), white blood cell count decreases (43%), and anorexia (43%). Grade 3 TRAEs included fatigue (10%), anemia (10%), prolonged QTc (10%), anorexia (5%), mucositis oral (5%), and dyspnea (5%). Only 1 patient had grade 4 respiratory failure. One patient discontinued treatment due to grade 3 anemia.

Patients with NSCLC and an EGFR exon 20 insertions generally become refractory to first- or second-generation EGFR TKI therapy, but the activity of third-generation EGFR TKI osimertinib in this patient population was unknown. Preclinical data suggested that these patients may have a favorable therapeutic window for these types of therapy, which led to the development of this single-arm study of osimertinib.

Patients on the study received 160 mg of osimertinib daily until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point of the study was ORR, and secondary end points included safety, PFS, and overall survival.

Of the 21 patients enrolled in the study, only 4 were ineligible, which was due to non-EGFR exon 20 insertion mutation in 3 patients and screening labs were out of window for 1 patient. The median age among patients was 65 years (range, 46-81), and the majority were female (71%). The median number of prior lines of therapy was 2 (range, 1-3). In terms of EGFR exon 20 subtypes, 24% of patients had A767_V769dupASV while 10% of patients had V769_D770insASV, 10% of patients had D770_N771insG, and 10% of patients had H773_V774insPH.

To be eligible for the study, patients had to have advanced NSCLC with an EGFR exon 20 insertion. They also had to have at least 1 prior line of therapy, stable disease, and asymptomatic brain metastases. Patients had to have an ECOG performance status of 0 or 1, hemoglobin levels of 9.0 g/L or greater, leukocytes of 3,000/mcL or greater, absolute neutrophil counts of 1500/mcL or greater, and platelets of 100,000/mcL or greater, among other inclusion criteria.

Based on the findings from this study, the investigators plan to evaluate osimertinib further in this patient population of NSCLC with EGFR exon 20 insertions.

_Reference

_{Piotrowska Z, Wang Y, Sequist L, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (suppl; abstr 9513). DOI: 10.1200/JCO.2020.38.15_suppl.9513}

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