Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study

Abstract

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Advancing neoadjuvant therapies in resectable non-small cell lung cancer: implications for novel treatment strategies and biomarker discovery

“…Indeed, several other early studies also demonstrated potential use of targeted therapies in preoperative studies. NCT03433469 using 2 cycles of neoadjuvant osimertinib in stage IA-IIIA NSCLC with EGFR mutations demonstrated 15% mPR and 44% achieved lymph node downstaging [ 24 ] as well as NCT04201756 which utilized 2 to 4 cycles of neoadjuvant afatinib, achieved 9.1% mPR and 57.6% had pathological downstaging for stage III NSCLC [ 25 ]. Combinatory studies using targeted therapies with or without chemotherapy are also being explored: NCT04351555 (NeoADAURA; phase III osimertinib vs. osimertinib plus PDC vs. placebo plus PDC neoadjuvantly followed by physician’s choice adjuvant treatment of targeted therapy with or without chemotherapy) [ 26 ], NCT04302025 (NAUTIKA1; single arm phase II neoadjuvant use of alectinib for 8 weeks) [ 27 ], and NCT05015010 (ALNEO; single arm phase II neoadjuvant use of alectinib for 2 cycles followed by adjuvant use up to 24 cycles) [ 28 ].…”

Analysis of surgical complexity and short-term prognostic indicators in NSCLC patients: neoadjuvant targeted therapy versus neoadjuvant chemoimmunotherapy

“…Such adverse effects complicate the identification of tumor margins and relevant anatomical structures during operative procedures, thus increasing the risk of intraoperative bleeding and the complexity of postoperative recovery. 10 …”