Osimertinib Lacks Activity in Neoadjuvant Setting for Early-Stage Non-Small Cell Lung Cancer With EGFR Mutation

According to results from a phase 2 study, neoadjuvant osimertinib did not improve the major pathological response (MPR) rate among patients with early-stage non-small cell lung cancer (NSCLC) harboring an EGFR mutation. 

“Osimertinib is the current standard first-line therapy for patients with metastatic non-small cell lung cancer harboring an EGFR exon 21 p.L858R mutation or exon 19 deletion on the basis of the FLAURA trial,” stated Collin M. Blakely, MD, PhD, University of California, San Francisco, and coauthors. “Whether treatment with osimertinib before surgery in patients with early-stage, surgically resectable EGFR-mutated NSCLC is safe or effective is unknown.”

In this single-arm, open-label study, 27 patients with stage IA-IIIA NSCLC harboring an EGFR mutation received 80 mg of osimertinib once daily in 28-day cycles (for up to 2 cycles) prior to surgical resection. Patients were permitted to undergo dose reductions (down to 40 mg) at the investigator’s discretion. The primary end point was MPR rate. Secondary efficacy end points included pathological response rate (pCR), objective response rate (ORR), median disease-free survival (DFS), and safety. 

At analysis, the median treatment duration was 56 days, and 24 patients underwent surgical resection. The MPR rate was 14.8% among all enrolled patients and 16.7% among patients who underwent surgery. The rate of conversion to inoperable status was 11.1% and there were no pathological responses observed. The rate of <50% viable tumor was 54.2%, the rate of positive surgical margins was 4.2%, and the rate of pathological upstaging was 16.7%. The ORR was 52% and the median DFS was 40.9 months. 

Grade 3/4 treatment-related adverse events were experienced by 3 patients and included stomatitis (n = 1), pulmonary embolism (n = 1), and atrial fibrillation (n = 1). Due to adverse events, 8 patients were placed on a dose hold, 3 patients underwent dose reductions, and 2 patients discontinued treatment. No patients experienced a delay in surgery or became ineligible for surgery because of an adverse event. During the postoperative monitoring period, the most common adverse events included atrial fibrillation (25%), dyspnea (20.8%), and chest pain (16.7%). One patient experienced a serious grade 3 pulmonary embolism with grade 3 dyspnea. 

As Dr Blakely et al concluded, “Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate…. However, neoadjuvant osimertinib did not lead to unanticipated [adverse events], surgical delays, nor result in a significant unresectability rate.” 

According to Journal of Clinical Oncology Associate Editor Thomas E. Stinchcombe, MD, Duke Cancer Center, Durham, North Carolina, “The pathological response data indicate single agent osimertinib has insufficient activity as preoperative therapy… trials of combination therapy are ongoing.” 

Source:

Blakely CM, Urisman A, Gubens MA, et al. Neoadjuvant osimertinib for the treatment of stage I-IIIA epidermal growth factor receptor–mutated non-small cell lung cancer: A phase II multicenter study. J Clin Oncol. Published online: July 19, 2024. doi: 10.1200/JCO.24.00071