P26.02 A Phase II Trial of Neoadjuvant Osimertinib for Surgically Resectable EGFR-Mutant Non-Small Cell Lung Cancer: Updated Results

Abstract

The third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Adjuvant osimertinib therapy also significantly decreases the risk of disease recurrence for patients with surgically resected (stage IB-IIIA) EGFR-mutant NSCLC. The benefit of neoadjuvant osimertinib for the treatment of surgically resectable EGFR-mutant NSCLC is unknown. The use of neoadjuvant targeted therapies in oncogene-driven NSCLC may offer the advantages of increased pathologic response rates as well as more favorable toxicity profiles compared to cytotoxic chemotherapy. These trials also offer the opportunity to identify mechanisms underlying cancer cell persistence despite optimal oncogene-targeted therapy. This abstract is an update of https://doi.org/10.1016/j.jtho.2019.08.1209. This is an ongoing multi-institution phase II trial of neoadjuvant osimertinib (NCT03433469), which aims to enroll 27 patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutant (exon 19 del or L858R) NSCLC. Eligible patients are treated with one to two 28-day cycles of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint of the study is major pathological response (mPR) rate. Secondary endpoints include safety, unanticipated delays to surgery, surgical complication rate, pathological response rate (0-49% residual viable tumor), pathological complete response rate (pCR), unconfirmed objective response rate, rate of lymph node downstaging, disease-free survival (DFS), and overall survival (OS). As of April 2021, 13 patients with early-stage (6 stage IA/B, 2 Stage IIA/B, and 5 Stage IIIA) EGFR-mutant (7 exon 19 del, 6 L858R) NSCLC have been enrolled and treated with osimertinib for an average of 59 days prior to surgical resection. The mPR rate was 15% (2 of 13). The pathological response rate was 69% (9 of 13). No pCR’s were observed. Partial radiographic responses (PR) were observed in 46% (6 of 13) of patients and stable disease (SD) in 7 patients (100% DCR). Lymph node downstaging was achieved in 4 of 5 patients (80%) with positive lymph nodes detected prior to treatment. DFS and OS data are immature. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. One patient developed grade 2 treatment-related pneumonitis that resolved without steroid treatment. Pre-treatment tumor biopsies were available for targeted exome sequencing analysis of ∼ 500 cancer-related genes from 7 patients. Loss of function mutations in RBM10 were identified in 3 of 4 (75%) tumors that showed no evidence of pathological response to osimertinib treatment. Interim analysis of this phase II study indicates that neoadjuvant osimertinib treatment in surgically resectable, EGFR-mutant NSCLC is well-tolerated without unforeseen delays in surgery and can induce pathological responses and lymph node-downstaging of disease. However, major pathological responses are rare and complete pathological responses to neoadjuvant osimertinib are not observed. RBM10 mutations were observed in the majority of tumors that did not exhibit a pathological response to osimertinib. Combination therapy approaches, as are being studied in the NeoADAURA trial (NCT04351555), are likely needed to achieve clinically meaningful major pathological response rates in EGFR-mutant lung cancers.