Association between pathologic response and survival after neoadjuvant therapy in lung cancer.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (pCR, 0% residual viable tumor [RVT] in primary tumor [PT]+lymph nodes [LNs]), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pCR and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-PD-1) plus chemotherapy in patients with resectable lung cancer. RVT, regression, and necrosis were quantified (0%-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (HR = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (AUC = 0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with 0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% RVT associated with a 0.017 HR increase for EFS. Combining pathologic response from PT+LNs helped differentiate outcomes. When compared to radiographic response and ctDNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted.