Pathologic Complete Response Predicts Long‐Term Survival Following Neoadjuvant Induction Chemotherapy and Chemo‐Radiotherapy in Stage‐ III Non‐Small Cell Lung Cancer

Background To analyze the association of pathologic‐complete‐response (PCR) and survival after neoadjuvant concurrent chemo‐radiotherapy, we evaluated a large cohort of patients with potentially resectable stage IIIA–IIIC non‐small cell lung cancer (NSCLC) treated with a trimodality approach. Methods Consecutive patients underwent neoadjuvant induction chemotherapy, followed by concurrent chemo‐radiotherapy and surgery. Patients received established imaging, and diagnostics. Leave‐one‐out cross‐validation was employed to identify the most effective prognostic classifier. Results Altogether, 403 patients treated between 06/2000 and 01/2020 were included. Median follow‐up was 111 months (IQR: 71–127 months). PCR was achieved in 34% (137 patients) after neoadjuvant therapy and major‐pathologic response without PCR in 30% (MPR > 0%–≤ 10% defined as viable cells in > 0% and ≤ 10% of the sample). PCR was significantly dependent on histology ( p = 0.0005) and radiotherapy fractionation schedule ( p = 0.027). PCR rates were higher for squamous than for non‐squamous carcinoma with 46.2% (95% CI: 37.8%–54.7%) versus 27.3% (95% CI: 22.0%–33.2%). PCR was the most significant prognostic factor for long‐term survival with an associated hazard ratio of 0.272 (0.192–0.386), while MPR was associated with a hazard ratio of 0.671 (0.498–0.905) in comparison to lesser response. Overall survival at 5/10 years with PCR was 72.9% (95% CI: 64.4%–79.6%)/ 62.8% (53.0%–71.1%)/ event‐free survival at 5 years 69.5% (60.9%–76.7%). Identified through cross‐validation, key prognostic features included PCR, MPR, and treatment period following 18 F‐FDG‐PET/CT‐guided staging. Conclusions Induction chemotherapy followed by chemo‐radiotherapy results in high PCR rates. In this investigation, PCR is followed by high event‐free and overall survival rates. These data warrant further investigation of chemo‐radiotherapy as a significant component of neoadjuvant treatment regimens in trials combined with immunotherapy. This strategy may increase the PCR rates, particularly for patients with more advanced, potentially resectable stage III NSCLC.